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ARAR0332 Page 1 Activated: Version Date: August 30, 2006 Closed: CHILDREN’S ONCOLOGY GROUP ARAR0332 Treatment of Adrenocortical Tumors with Surgery plus Lymph Node Dissection and Multiagent Chemotherapy A Groupwide Phase III Study THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE CHILDRENS ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. STUDY CHAIR Carlos Rodriguez-Galindo, MD Department of Hematology-Oncology St. Jude Children’s Research Hospital 332 N Lauderdale St., MS 260 Memphis, TN 38105 Phone: (901) 495-2203 Fax: (901) 521-9005 E-mail: [email protected] For Statistics and Data Center Contact Person see: http://members.childrensoncologygroup.org

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Page 1: CHILDREN’S ONCOLOGY GROUP ARAR0332 Treatment of Adrenocortical … · 2016-01-20 · 2.3 Clinical Characteristics of Adrenocortical Tumors 11 2.4 Adrenocortical Tumors in Children

ARAR0332

Page 1

Activated: Version Date: August 30, 2006 Closed:

CHILDREN’S ONCOLOGY GROUP

ARAR0332

Treatment of Adrenocortical Tumors with Surgery plus Lymph Node Dissection and Multiagent

Chemotherapy

A Groupwide Phase III Study

THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION.

STUDY CHAIR Carlos Rodriguez-Galindo, MD Department of Hematology-Oncology St. Jude Children’s Research Hospital 332 N Lauderdale St., MS 260 Memphis, TN 38105 Phone: (901) 495-2203 Fax: (901) 521-9005 E-mail: [email protected]

For Statistics and Data Center Contact Person see: http://members.childrensoncologygroup.org

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TABLE OF CONTENTS SECTION PAGE

STUDY COMMITTEE 5 ABSTRACT 8 EXPERIMENTAL DESIGN SCHEMA 9 1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 10 2.0 BACKGROUND 10

2.1 Epidemiology of Adrenocortical Tumors 10 2.2 Biology of Adrenocortical Tumors 11 2.3 Clinical Characteristics of Adrenocortical Tumors 11 2.4 Adrenocortical Tumors in Children 12 2.5 Treatment of Adrenocortical Tumors 14 2.6 Rationale for Current Protocol 16

3.0 STUDY ENROLLMENT AND PATIENT ELIGIBILITY 17 3.1 Study Enrollment 17 3.2 Patient Criteria 18

4.0 TREATMENT PLAN 20 4.1 Overview of Treatment plan 20 4.2 Surgical Guidelines 20 4.3 Administration of Chemotherapy 20 4.4 Administration Schedule for Patients on Stratum 3 during Induction 21 4.5 Administration Schedule for Patients on Stratum 3 during Continuation Therapy 25

5.0 DOSE MODIFICATIONS FOR TOXICITIES 29 5.1 Myelosuppression 29 5.2 Ototoxicity 29 5.3 Nephrotoxicity 29 5.4 Cardiac Toxicity 30 5.5 Mitotane Toxicity 30

6.0 DRUG INFORMATION 31 6.1 CISPLATIN (Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ) NSC

#119875 31 6.2 DOXORUBICIN (Adriamycin®) NSC #123127 32 6.3 ETOPOSIDE (VePesid®, Etopophos®,VP-16) NSC #141540 34 6.4 FILGRASTIM (Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF,

Neupogen®) NSC #614629 36 6.5 MITOTANE (Lysodren®, o,p'DDD ) NSC# 38721 37

7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 38 7.1 Required and Optional Clinical, Laboratory and Disease Evaluations 38 7.2 Specimen Submission 41 7.3 Required Material for QARC Central Review 42 7.4 Evaluations during Follow-Up and After Completion of Therapy 42

8.0 SUPPORTIVE CARE GUIDELINES 42 8.1 Pneumocystis Prophylaxis 42 8.2 Hormonal Replacement 43 8.3 Venous Access 43

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8.4 Nutritional Management 43 8.5 Concomitant Medications 43

9.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 44 9.1 Criteria for Removal From Protocol Therapy 44 9.2 Off Study Criteria 44

10.0 STATISTICAL CONSIDERATIONS 44 10.1 Statistical Design 44 10.2 Patient Accrual and Expected Duration of Trial 44 10.3 Statistical Analysis Methods 45 10.4 Gender and Minority Accrual Estimates 49

11.0 EVALUATION CRITERIA 49 11.1 Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 49 11.2 Response Criteria for Patients with Solid Tumors 49

12.0 ADVERSE EVENT REPORTING REQUIREMENTS 51 12.1 Purpose 51 12.2 Determination of Reporting Requirements 52 12.3 Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway 52 12.4 Reporting of Adverse Events Related to the Surgical Procedures 53 12.5 Reporting Secondary AML/MDS 53

13.0 RECORDS AND REPORTING 54 13.1 Categories of Research Records 54 13.2 CDUS 54

14.0 SURGICAL GUIDELINES 54 14.1 Rationale for surgery 54 14.2 Pre-operative Management 54 14.3 Operative Management 55 14.4 Post-operative Management 56

15.0 PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 56 15.1 Pathology Guidelines for Diagnosis 56 15.2 Pathology Review Requirements 57

16.0 SPECIAL STUDIES SPECIMEN REQUIREMENTS 58 16.1 Specimen Submission 58 16.2 Specimens Requested for Biologic Studies 58 16.3 Specimen Shipping 59

17.0 IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 60 17.1 Timing of Imaging Studies: 60 17.2 Imaging of the Primary Tumor 60 17.3 Imaging of Metastatic Disease 60 17.4 Submitting Imaging for Central Review 60

REFERENCES 62 APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 65 APPENDIX II: STAGING SYSTEM OF ADRENOCORTICAL TUMORS 66 APPENDIX III: GUIDELINE DIAGRAMS FOR RETROPERITONEAL LYMPH NODE

DISSECTION 67

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SAMPLE INFORMED CONSENT FORM / PARENTAL PERMISSION FOR PARTICIPATION IN RESEARCH 68

SAMPLE INFORMED CONSENT FORM / PARENTAL PERMISSION FOR PARTICIPATION IN RESEARCH 90

SAMPLE INFORMED CONSENT FORM / PARENTAL PERMISSION FOR PARTICIPATION IN RESEARCH 91

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STUDY COMMITTEE STUDY CHAIR Michael LaQuaglia, M.D. Carlos Rodriguez-Galindo, M.D. Surgery Hematology/Oncology Memorial Sloan Kettering Cancer Center St. Jude Children's Research Hospital Dept of Pediatric Surgery 332 N. Lauderdale St., MS 260 1275 York Avenue Box 325 Memphis, TN 38105 New York, NY 10021 Phone: (901) 495-2203 Phone: (212) 639-7002 Fax: (901) 521-9005 Fax: (212) 717-3373 E-mail: [email protected] E-mail: [email protected] STUDY VICE CHAIR Alberto Pappo, M.D. Raul Correa Ribeiro, M.D. Hematology/Oncology Hematology/Oncology Texas Children's Cancer Center at Baylor College of Medicine St. Jude Children's Research Hospital Pediatrics Hematology/Oncology 332 N. Lauderdale St., MS 721 6621 Fannin Street Memphis, TN 38105 CC1510.00 Phone: (901) 495-3694 Houston, TX 77030-2399 Fax: (901) 495-3122 Phone: (832) 822-4248 E-mail: [email protected] Fax: (832) 825-1503 E-mail: [email protected] STUDY STATISTICIAN Mark Krailo, Ph.D. Justin Theodore Gerstle, M.D. Statistics General Surgery Children's Oncology Group - Operations Center Hospital for Sick Children 440 E. Huntington Drive 555 University Avenue P.O. Box 60012 Room 1526 Arcadia, CA 91066-6012 Toronto ON M5G 1X8 Phone: (626) 241-1529 Canada Fax: (626) 445-4334 Phone: (416) 813-6401 E-mail: [email protected] Fax: (416) 813-7477 E-mail: [email protected] STUDY COMMITTEE MEMBERS RoseAnne Speights, B.A., CCRP Bonald C. Figueiredo, M.D. Data Management Federal University of Parana Hospital de Clinicas St. Jude Children's Research Hospital Rua Agostinho Lead JR, 400 Hematology/Oncology Alto DA Gloria 332 N. Lauderdale St., MS 260 Curitiba, PR, Memphis TN 38105 Brazil Phone: (901) 495-3561 Phone: 55-41-30-29-32-04 Fax: (901) 495-5482 Fax: 55-41-30-29-32-04 E-mail: [email protected] E-mail: [email protected] David Malkin, M.D. John Hicks, M.D Hematology/Oncology Pathology Hospital for Sick Children Texas Children's Cancer Center at Division of Hematology/Oncology Baylor College of Medicine 555 University Avenue 6621 Fannin Street Toronto, ON M5G1X8 Houston, TX 77030 Canada Phone: (832) 824-1869 Phone: (416) 813-5977 Fax: (832) 825-1032 Fax: (416) 813-5327 E-mail: [email protected] E-mail: [email protected]

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Bhaskar Narayan Rao, M.D. Mara Albonei D. Pianovski, M.D. Surgery Department of Pediatric Hem/Onc St. Jude Children's Research Hospital Hospital de Clinicas - Universidade Federal do Parana 332 N. Lauderdale St., MS 721 Rua Agostinho Leao Junior, 400- Alto da Gloria Memphis TN 38105 Curitiba, PR 80240-000 Phone: (901) 495-5318 Brazil Fax: (901) 495-2270 Phone: 55 41 3029-3204 E-mail: [email protected] Fax: 55 41 3029-3204 E-mail: [email protected] Milton Finegold, M.D. Pathology Antonio Goncalves de Oliveira Filho, M.D. Texas Children's Cancer Center at Centro Infantil Boldrini, Dept. of Surgery Baylor College of Medicine Rua Gabriel Porto, 1270 6621 Fannin Street Cidade Universitaria Houston TX 77030 Campinas SP 13083-210 Phone: (832) 824-1856 Brazil Fax: (832) 825-1032 Phone: 55 11 3787-5000 E-mail: [email protected] Fax: 55 19 3289-3571 E-mail: [email protected] Mary Beth McCarville, M.D. Diagnostic Imaging Maria Jose Mastellaro, M.D. St. Jude Children's Research Hospital Centro Infantil Boldrini, Dept. of Hem/Onc 332 N. Lauderdale St., MS 210 Rua Gabriel Porto, 1270 Memphis, TN 38105-2794 Cidade Universitaria Phone: (901) 495-2399 Campinas SP 13083-210 Fax: (901) 495-3962 Brazil E-mail: [email protected] Phone: 55 11 3787-5000 Fax: 55 19 3289-3571 Gerard Paul Zambetti, Ph.D. E-mail: [email protected] Biochemistry St. Jude Children's Research Hospital Antonio Sergio Petrilli, M.D., Ph.D. 332 N. Lauderdale St., MS 340 Instituto De Oncologia Pediatrica Memphis TN 38105 Rua Botucatu 743 - Vila Clementino Phone: (901) 495-3429 Sao Paulo 04023-062 Fax: (901) 525-8025 Brazil E-mail: [email protected] Phone: 55 11 5080-8475 Fax: 55 11 5080-8480 Deborah A. Ward, PharmD E-mail: [email protected] Pharmacy St. Jude Children's Research Hospital Memphis Eliana Caran, M.D. 332 N. Lauderdale, Mail Stop #150 Instituto de Oncologia Pediatrica Memphis, TN 38105-2794 Rua Botucatu, 743 Phone: (901) 495-3660 Vila Mariana SP 04023-062 Fax: (901) 495-3111 Brazil E-mail: [email protected] Phone: 55 11 5080-8400 Fax: 55 11 5080-8487 Catherine F. Shannon, M.S Protocol/Scientific Writer Edson L. Michalkiewicz, M.D. Children's Oncology Group - Operations Center Hospital Erasto Gaertner, Dept. of Surgery SDO Rua Dr Ovande do Amaral, 201 P.O. BOX 60012 Jardim das Americas 440 E. Huntington Drive, Suite 402 Curitiba - Parana 81520-060 Arcadia, CA 91066-6012 Brazil Phone: (626) 241-1583 Phone: 41 361-5000 Fax: (626) 445-4334 Fax: 41 266-1822 E-mail: [email protected] E-mail: [email protected]

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COG RESEARCH COORDINATOR Darlene Watson COG – Statistics and Data Center, Gainesville 104 North Main Street, Suite 600 Gainesville, Florida 32601-3330 Phone: (352) 273-0571 Fax: (352) 392-8162 E-mail: [email protected] COG PROTOCOL COORDINATOR Kesavan Radika, Ph.D. Children's Oncology Group - Operations Center Study Development Office 440 E. Huntington Drive P O Box 60012 Arcadia, CA 91066-6012 Phone: (626) 241-1588 Fax: (626) 445-4334 E-mail: [email protected] For Group Operations (GOC) and Statistics and Data Center (SDC) contacts see: http://members.childrensoncologygroup.org Telephone: (626) 447-0064 AGENT and NSC# Cisplatin #119875 Doxorubicin #123127 Etoposide #141540 Filgrastim (G-CSF) #614629 Mitotane #38721

SEE SECTIONS 7.2 and 7.3 FOR SPECIMEN SHIPPING ADDRESSES

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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. The Certificate protects against the involuntary release of information about your subjects collected during the course of our covered studies. The researchers involved in the studies cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to voluntarily disclose the protected information under certain circumstances. For example, if the subject or his/her guardian requests the release of information in writing, the Certificate does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or others ABSTRACT Adrenocortical tumors (ACT) constitute a rare but aggressive malignancy in children. There has been no unified approach in the treatment of these tumors. Treatment of ACT is mainly surgical, but a significant proportion of patients with early stage disease develop a locoregional recurrence, suggesting that a more radical approach needs to be undertaken. This study will investigate the benefit of performing a retroperitoneal lymph node dissection for patients with Stage II disease. Patients with more advanced locoregional disease and those with metastatic disease require systemic chemotherapy. The exact role of mitotane and other chemotherapeutic agents, as well as their different schedules and combinations is not well established. In this protocol patients with unresectable or metastatic disease will receive 8 cycles of cisplatin-based chemotherapy along with eight months of oral mitotane. Studies performed by investigators in Curitiba (Brazil) and at St Jude Children's Research Hospital have described a distinct germline TP53 mutation in Brazilian patients that appears to induce neoplastic transformation in a tissue-specific manner. This mutation is distinct from the wider spectrum of germline TP53 mutations observed in non-Brazilian ACT patients. Furthermore, the biological relevance of both the germline and somatic TP53 alterations in ACT is only partially understood. This study will compare the incidence and type of germline TP53 mutations in non-Brazilian children and Brazilian children.

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EXPERIMENTAL DESIGN SCHEMA

* Combination therapy with mitotane, cisplatin, etoposide and doxorubicin. ** If surgery cannot be scheduled immediately, Induction will continue for up to 2 more cycles.

FOLLOW

STUDY ENTRY

STRATUM 2 Stage II patients

STRATUM 1 Stage I patients

SURGERY – if necessary

STRATUM 3 Stage III and IV patients

FOLLOW

INDUCTION CHEMOTHERAPY* 2 cycles

EVALUATION

PR or SD PD

CONTINUATION THERAPY 4 or 5 cycles of combination

chemotherapy + up to a further 2 months of mitotane alone

INDUCTION CONTINUED**

1 or 2 cycles

OFF PROTOCOL THERAPY SURGERY

SURGERY

CONTINUATION THERAPY 6 cycles of combination

chemotherapy + up to a further 2 months of mitotane alone

STAGE III FOLLOW

STAGE IV EVALUATE

SURGERY if appropriate

STAGE III FOLLOW

STAGE IV EVALUATE

SURGERY if appropriate

FOLLOW

CR

CONTINUATION THERAPY

6 cycles of combination chemotherapy + up to a

further 2 months of mitotane alone

FOLLOW

FOLLOW

FOLLOW

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1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) Primary Objectives 1.1 To describe the outcome of patients with Stage I adrenocortical tumors (ACT) who are treated with surgery alone. 1.2 To describe the outcome of patients with Stage II ACT who are treated with radical adrenalectomy plus regional retroperitoneal lymph node dissection (RPLND). 1.3 To describe the outcome of patients with unresectable or metastatic adrenocortical carcinoma who are treated with mitotane and a cisplatin-based chemotherapy regimen. Secondary Objectives 1.4 To determine the feasibility and complications associated with the use of radical adrenalectomy and regional node dissection in patients with ACT. 1.5 To determine the toxicity of mitotane when administered in conjunction with cisplatin, etoposide and doxorubicin in patients with residual disease after surgery, inoperable tumors or metastatic disease at diagnosis. 1.6 To determine prospectively the frequency of tumor spillage during surgery in these patients. 1.7 To determine the frequency of lymph node involvement in these patients. 1.8 To determine and compare the incidence and type of germline p53 mutation in non-Brazilian children and children from Southern Brazil. 1.9 To characterize the cooperating molecular alterations associated with ACT. 1.10 To determine the presence of embryonal markers in children with ACT. 2.0 BACKGROUND 2.1 Epidemiology of Adrenocortical Tumors ACT are amongst the most rare and aggressive endocrine neoplasms. They appear to follow a bimodal distribution, with peaks during the first and fourth decades.1,2 In children, 25 new cases are expected to occur annually in the U.S., for an estimated annual incidence of 0.2-0.3 cases per million. Internationally, however, the incidence of ACT appears to vary substantially. The incidence of ACT is particularly high in

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southern Brazil, where it is approximately 10 to 15 times that observed in the U.S. Most cases occur in the contiguous states of Sao Paulo and Paraná. The cause of this higher rate has not been identified. Predisposing genetic factors have been implicated in > 50% of the cases in North America and Europe, and in 95% of the Brazilian cases. In all patients, germline TP53 mutations are almost always the predisposing factors. In the non-Brazilian cases, relatives of children with ACT often, though not invariably, have a high incidence of other non-ACT cancers (Li-Fraumeni syndrome), and germline mutations occur in the TP53 DNA-transactivation domain, nuclear localization signal or tetramerization domains (exons 2 to 8, primarily at highly conserved amino acid residues). In the Brazilian cases, in contrast, the patients’ families do not exhibit a high incidence of cancer, and a single, unique mutation at codon 337 in exon 10 of the TP53 gene is consistently observed. This inherited unique TP53 mutation represents a low-penetrance allele that contributes to the development of ACT in a tissue specific manner.3,4

ACT have also been reported in association with other genetic diseases such as congenital adrenal hyperplasia, and with the Li-Fraumeni, Beckwith-Wiedeman, McCune-Albright and MEN-1 syndromes.5 2.2 Biology of Adrenocortical Tumors The molecular biologic mechanisms of tumor formation in children with ACT are not well understood. A wide spectrum of germline TP53 alterations have been described in ACT, and these may contribute to the etiology of > 80% of childhood tumors. Outside of Brazil, predisposing genetic factors have been reported in greater than 50% of the cases. Although de novo cases are frequently observed, relatives of children with ACT often have a high incidence of cancer associated with the Li-Fraumeni syndrome.1,6 The spectrum of germline TP53 mutations, and the mechanisms of functional loss of heterozygosity in ACT in North American children, are quite diverse, although germline mutations occur primarily in the TP53 DNA-binding domains (exons 4 to 8).7 In the Brazilian cases, by contrast, the patients’ families do not have a high incidence of cancer, and a single mutation in exon 10 of the TP53 gene is consistently observed in these children. This mutation occurs within the tetramerization domain of TP53 (TP53-R337H). As a result, the conformation of the protein is less stable than the wild type epitope, and is highly sensitive to pH in the physiological range. This inherited unique TP53 mutation represents a low-penetrant allele that contributes to the development of ACT in a tissue specific manner.3,4 Additional genetic alterations, however, are necessary for transformation. The most plausible theory is that ACT arises as a result of a multistep process in which a combination of unchecked proliferation and dedifferentiation signals, such as the IGF-II/IGFR pathway, are combined.8 ACT is characterized by a high frequency of chromosomal gains and amplifications, and several chromosomal subregions containing candidate proto-oncogenes have been identified.9,10 In a series of 9 cases from Southern Brazil, the most consistent finding was copy number gain of chromosomal region 9q34, which was found in 8 of the cases.10 Also, preliminary data from BAC array analyses reveals a homozygous deletion of a region on chromosome 10p21 in 80% of the pediatric ACT samples. Through the combined approaches of microarray gene expression and BAC array analyses it may be possible to identify the factors and pathways that are corrupted during the development of ACT. Mining this data will identify specific targets that can then be further characterized for their potential biological role in ACT tumorigenesis, whether they be TP53-dependent or TP53-independent events. In addition, in vivo functional analyses of the ACT-associated TP53 alterations will be performed to determine the mechanisms by which disruption of TP53-mediated cell growth control might be modulated by epigenetic or environmental factors specific to the adrenal cortex. 2.3 Clinical Characteristics of Adrenocortical Tumors Patients with ACT typically present with signs and symptoms of increased production of androgens (virilization) and/or cortisol (hypercortisolism or Cushing syndrome). Rarely, hyperestrogenism

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(feminization) or aldosteronism (Conn syndrome) can be the presenting clinical manifestations. Mixed syndromes resulting from the secretion of several adrenocortical hormones are also very frequent. In general, the majority of the patients have functioning tumors,2,5,11-16 although up to 50% of tumors may produce mainly hormonal precursors of low bioactivity.14 Other presenting symptoms include abdominal pain in up to 50% of patients and, less frequently, weight loss.12 There appears to be a correlation between the degree and type of endocrine disturbance and the age of the patient.2,5 Older patients tend to have a much higher incidence of non-functioning tumors, whereas over 90% of children have functioning neoplasms.5,17-19 Adults usually have mixed virilization-hypercortisolism syndromes, whereas virilization syndromes are the most common presentation in children.5,17-19 The majority of patients (50-60%) present with large tumors and advanced regional or metastatic disease.5,11-16,20 Distant metastases usually develop to the liver, lungs, and bone, in that order. The diagnosis of ACT is straightforward. Because most of the patients have an endocrine syndrome, increased blood or urine concentration of adrenocortical hormones and a mass in the suprarenal region usually suggest a preoperative diagnosis of an adrenocortical tumor. However, the distinction between benign (adenomas) and malignant (carcinomas) tumors may not be easy. Several authors have proposed histologic criteria that may help in discriminating between both types of neoplasms.21,22 However, the morphologic criteria that are used to distinguish benign from malignant adrenocortical tumors may not be reliable, especially in cases of carcinoma. Specific biologic and histopathologic characteristics within individual tumors appear to dictate the clinical behavior. Mitotic rate has been consistently reported as the most important determinant of aggressive behavior.12,20,23,24 Other histopathologic variables are also important, and it is possible to establish different risk groups of recurrence based on a score that includes a combination of different histopathologic characteristics, such as venous, capsular or adjacent organ invasion, tumor necrosis, mitotic rate, and presence of atypical mitoses.20 Finally, the tumor size appears to have an independent prognostic value.20,24 Tumor size and weight, and mitotic activity are usually the best discriminating factors.22 2.4 Adrenocortical Tumors in Children Despite the rarity of the disease, the clinical and pathologic characteristics of ACT in children have been well characterized in recent years.17-19,25-27 A significant body of evidence derives from the data obtained by the International Pediatric Adrenocortical Tumor Registry (IPACTR) (www.stjude.org/ipactr). This registry was established in 1990 as part of the St Jude Children’s Research Hospital International Outreach Program, in a joint effort with the Hospital de Clinicas in Curitiba (Brazil), as an information-exchange website; more than 250 patients have been registered to date.28 Childhood ACT present typically during the first 5 years of life (median age 3 - 4 years), although there appears to be a biphasic age distribution, with a second smaller peak during adolescence.17,25,26,28 Female predominance is a constant in all series (female to male ratio 1.5:1); and it is even more significant after adolescence (female to male ration 6:1).25,26,28 In contrast to adult tumors, pediatric ACT are almost universally functioning, causing endocrine disturbances that lead to the diagnosis, usually 5 to 8 months after the first symptoms.18,25,28 Virilization syndromes are the most common, occurring alone or in combination with hypercortisolism in virtually 90% of the patients. Isolated Cushing syndrome is very rare, occurring in only 5% of the patients. Large numbers of patients have severe hypertension at presentation, and hypertensive crisis resulting in seizures is the presenting feature in 10% of the cases.17,25,26,28 Nonfunctional tumors are rare, although they appear to be more common in adolescents and young adults.28 At the time of diagnosis, two thirds of the pediatric patients have limited disease (completely resected tumors), and the remaining patients have either unresectable or metastatic disease. As with adult ACT, histologic differentiation between adenomas and carcinomas is not easy. However, approximately 10-20% of pediatric ACT are adenomas.25,28 In order to further analyze the pathologic features of pediatric

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ACT that would suggest malignancy, Bugg et al. evaluated the histology, ploidy, proliferative index, and tumor size of 54 cases.27 The histologic criteria for malignancy were the mitotic index, the presence of confluent necrosis and atypical mitoses, and the nuclear grade, as previously defined by Weiss.21,23 The most statistically significant predictor of outcome in this study was the histology of the tumor, followed by the tumor weight (< 100 vs. > 100 g). Tumor ploidy and the proliferative index were not predictive of outcome. Prognostic factors of malignant clinical behavior have been analyzed in three studies. In a retrospective review of 88 children, Wieneke et al. found that tumor size (defined as > 10.5 cm or > 400 g), local invasiveness (defined as infiltration to soft tissues and vena cava), and histologic features of malignancy (necrosis, atypia and increased mitotic rate) were predictors of malignancy, although only invasion of the vena cava and presence of necrosis and increased mitotic rate retained their prognostic value in a multivariate analysis.25 In an early analysis of 40 cases from Southern Brazil, Ribeiro et al. found that tumor volume (> 200 mL) or weight (> 80 g), and age > 3.5 years were associated with worse outcome, although tumor volume alone retained the prognostic significance on multivariate analysis. Of note, in this study it was also suggested that the pattern of hormone hyperproduction (defined by increased urinary levels of 17-OH-corticosteroids) might be associated with more aggressive disease.17 Similarly, the analysis of 254 patients registered in the IPACTR shows that the most important favorable prognostic factors are young age (< 3 yrs), small tumors (< 200 g), the presence of virilization, and limited stage (Stage I).28 Based on this data, tumor size appears to be especially important in children; small tumors have an excellent outcome with surgery alone, regardless of the histologic features.17,25,27-29 In fact, some authors have reported a better prognosis in children with non-metastatic ACT than in adults.5 On the basis of these studies, we have adopted a staging system which has been modified from Sandrini et al., and that is based on disease stage and tumor size26,28 (please see Appendix II for the complete modified staging system):

• Stage I patients are those with completely resected small tumors (volume < 200 cm3), and who normalize hormone levels after surgery.

• Stage II patients are those with tumor ≥ 200 cm3. • Stage III patients are those with residual disease or inoperable tumors. • Stage IV is defined by the presence of distant metastases.

Overall survival at 5 years for children with ACT is 54 to 74%.25,26,28 In the IPACTR, this staging system appears to be highly predictive of outcome in children with either Stage I or IV disease - that is, > 90% of patients with Stage I disease are long-term survivors, compared with 10% of those with Stage IV disease. Predicting outcome for patients with intermediate stages of disease is much more difficult. Despite presumed complete tumor resection, local recurrence is the most common adverse event in patients with Stage II disease, and it occurs in 30-50% of the cases. For patients with Stage III and IV disease, the outcome is extremely poor. The fact that childhood ACT are associated with the presence of constitutional mutations of TP53 (as discussed above), together with its distinctive clinical features, suggests that ACT arises from the fetal zone of the fetal adrenal cortex. The fetal zone represents 85% of the adrenal cortex during fetal development, and it is oriented toward dehydroepiandrosterone production. It is thus possible that the presence of a constitutional TP53 mutation increases the penetrance of ACT in the fetal adrenal cortex with lower risk for the remaining layers. Disruption of the p53 pathway under certain conditions of alkaline pH and/or supra-physiological temperature predicts a failure of the expected apoptosis in the fetal zone and/or lack of inhibition of the proliferative zone.3,8,9,11,12,17,27

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2.5 Treatment of Adrenocortical Tumors 2.5.1 Surgery in ACT Surgery is the mainstay of treatment for ACT. A curative, complete resection may be attempted in the 70-75% of patients with locoregional disease. In fact, low stages and the ability to perform a complete resection are the most important prognostic factors.11,12,14,15,20,23,25,30 ACT is a very aggressive malignancy, and despite the efforts at performing curative surgery, the 5-year survival in adults is not better than 30-40%.12,16,24,29 The outcome for patients with locoregionally advanced disease is very poor, and up to 70-80% of patients with localized primary will experience a recurrence.20 Recurrences are locoregional (15-25%), combined local and distant (25-30%), or distant alone (50%).12,20,31 However, with more widely available and higher quality imaging, diagnosis can be made at an earlier stage, and several authors have reported improved outcomes over the years in different cohorts in the same institutions, mainly due to an increase in the number of curative resections.11,12 Because of tumor friability, rupture of the capsule leading to tumor spillage is frequent (occurring in approximately 20% of the cases during the initial procedure and in 43% of the cases after recurrence).26,28 Moreover, infiltration of the vena cava with tumor thrombus may occur in an additional 20% of the patients, which may make radical surgery difficult.12,28 Often times, spillage cannot be avoided. Large tumors tend to adhere to adjacent structures (e.g., vena cava) and have large necrotic and friable areas that make a radical excision without capsule rupture very difficult. This is also true in the presence of tumor thrombus, which might contaminate the peritoneal cavity when the vessel is open and the thrombus removed. Data from the IPACTR suggests that tumor spillage is associated with worse prognosis.28 For this reason, in this study, patients with completely resected tumors that experience tumor spillage during the operative procedure will be upstaged to Stage III and will receive adjuvant chemotherapy. In the present study, data about intraoperative tumor spillage will be collected prospectively and will be correlated with the local recurrence rate. The lymph node drainage of the adrenal gland is complex. There is an extensive subserosal network of lymphatic channels around the gland, crossing several levels in different directions inside the fascia and connective tissue involving the adrenal gland. The incidence of lymph node involvement is not known, although some studies report it to be close to 40% in adults.15,32 The low frequency with which lymph nodes are resected reflects the standard surgical practice in which lymph node sampling is not routinely performed, except if there is obvious lymph node enlargement. However, based on the premise that residual tumor in lymph nodes may contribute to relapse, this protocol specifies that the regional lymph nodes be resected in patients with large tumors (Stage II). 2.5.2 Mitotane and Other Antineoplastic Agents in the Treatment of Adrenocortical Tumors (ACT) For those patients with advanced disease or with high risk of recurrence, the use of systemic therapy with mitotane or chemotherapy is indicated, although its impact in the overall outcome is minimal. The role of chemotherapy in the management of childhood ACT has not been well established. Mitotane [1,1-dichloro-2-(0-chlorophynyl)-2 (p-chlorophenyl)-ethane, or o,p'-DDD], an insecticide derivative that produces adrenocortical necrosis, has been used extensively in adult ACT. Mitotane both inhibits corticoid biosynthesis and destroys the adrenocortical cells. Mitotane acts on the adrenocortical mitochondria and inhibits the 11-β-hydroxylase and the cholesterol side chain cleavage enzymes, and also destroys the mitochondria resulting in necrosis of the adrenal cortex. At low plasma concentrations, mitotane suppresses the secretion of adrenal steroids, providing symptomatic improvement and regression of some of the endocrine dysfunction in patients with functioning tumors. However, higher levels are required for an adrenolytic effect.5,11 In patients with advanced disease objective responses may be obtained in approximately 20-30% of the cases using mitotane alone.5,11,14,33 However, these responses

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are transient and the effect on prolongation of survival is uncertain.5,14,34 In children, the use of mitotane for advanced ACT has not been evaluated systematically. There have been several reports of complete responses in children with advanced or metastatic ACT, but these appear to be rare events.35-37 In the Brazilian experience, there have been three patients who had locally unresectable tumors. They received mitotane for several months prior to undergoing a successful complete resection. They continued to receive mitotane for a total of 8 months, and all of them are alive without evidence of disease after 5+ years of follow-up. The pharmacokinetics of mitotane and the ability to maintain therapeutic levels during prolonged periods of time appear to impact the antitumor effect. Serum levels plateau after 8 weeks of treatment,37 and optimal antitumor responses occur when serum levels are maintained > 14 micrograms/mL for prolonged periods of time.30,33,38 A major problem, however, is the severe gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain) and neurologic (somnolence, lethargy, ataxia, depression, and vertigo) toxicity associated with the administration of mitotane, which limits patient compliance.5,14,33,39 An alternative approach to the administration of high doses of mitotane may be the administration of low doses for more prolonged periods of time. Some authors have recently reported good results with the use of low-dose mitotane (2 to 3 g/day). With the appropriate monitoring, therapeutic levels may still be achieved after 3 to 5 months of low-dose mitotane.38,40 The advantage of this approach is that the side effects, which are dependent on serum levels,33 are limited, improving the compliance significantly, and the therapeutic level can be reached with the lowest effective dose with stepwise increments.40 Another shortcoming of mitotane treatment is that it significantly alters steroid hormone metabolism, so that steroid measurements in blood and urine cannot be used as a marker of tumor relapse. However, sudden increases in the hormone levels should be strong indication of disease recurrence, even in the presence of mitotane. In the present protocol, a lower dosage of mitotane will be used aiming to keep blood levels between 14 and 20 micrograms/mL. Administration of mitotane in fatty vehicles results in better absorption and quicker saturation of the adipose tissue, resulting in earlier achievement of therapeutic levels.41,42 Chemotherapeutic agents other than mitotane have been less evaluated in ACT. Cisplatin as a single agent may induce responses in approximately 25% of patients with advanced disease,39 and cisplatin-based regimens have been evaluated by different authors. Combinations of cisplatin with doxorubicin and either cyclophosphamide43 or 5-fluorouracil44 have resulted in responses of 20-40%. Cisplatin has also been investigated in combination with etoposide (VP-16), with similar results.5,45 The combination of mitotane with cisplatin, etoposide, and doxorubicin has been extensively used in children with ACT by investigators of the IPACTR.28 Because of cisplatin renal dose-limiting toxicity, Ayass and co-workers substituted carboplatin for cisplatin in combination with VP-16. They used this combination to treat a 17-month-old boy with ACT metastatic to the brain and chest. Following complete resection of the primary tumor, the patient received eight cycles of VP-16 (250 mg/m2 /day) and carboplatin (470 mg/m2/day), with complete response of the metastatic disease, and long-term survival. The Curitiba group has also noted a complete response to cisplatin, VP-16 and mitotane in a patient who developed local recurrence and multiple pulmonary and hepatic metastases. The pulmonary metastases resolved after the third cycle and the hepatic lesion after the seventh cycle. Preclinical studies have shown that mitotane reverts the mdr phenotype in vitro,46 providing a rationale for the combination of mitotane with etoposide-containing regimens. Responses have been observed in 53% of patients using the combination of mitotane with cisplatin, etoposide, and doxorubicin.47,48 In this protocol, children with microscopic residual disease (including tumor spillage), inoperable tumors or metastatic disease at diagnosis will receive 8 monthly cycles of cisplatin, etoposide and doxorubicin. Mitotane will be used daily without interruption.

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2.5.3 Radiation Therapy The role of radiotherapy in pediatric ACT has not been consistently investigated. It is generally accepted that ACT is radioresistant.5 However, because many children with ACT carry cancer-predisposing germline p53 mutations that could potentiate genomic instability, there is a concern that radiation may increase the incidence of secondary tumors. Driver et al. reported that among 5 long-term survivors of pediatric ACT, 3 died because of secondary sarcoma arising within the radiation fields.19 Therefore radiation therapy will not be prescribed in this protocol. 2.6 Rationale for Current Protocol 2.6.1 Extended Surgery for Patients with Localized Disease In this trial, patients with Stage II disease will undergo extended surgery. Because there is evidence to suggest that locoregional recurrences may arise from the retroperitoneal lymph nodes, this protocol will explore the value of ipsilateral retroperitoneal lymph node dissection. 2.6.2 Cisplatin-Based Chemotherapy and Mitotane for Patients with Advanced Disease As discussed above, the prognosis for patients with unresectable or metastatic ACT is dismal. Although the response rate to mitotane and cisplatin-based chemotherapy is low, the role of this approach has not been investigated prospectively in children. In this study, we will be using a regimen that incorporates mitotane, cisplatin, etoposide, and doxorubicin. This is a well tolerated regimen that has been used by investigators of the IPACTR in a large number of children with ACT.28

2.6.2.1 Toxicity Considerations The proposed regimen has been widely used in the treatment of children with ACT, both in the U.S. and in Brazil; however, there is no published data on the toxicity experienced. In the experience of the investigators of this protocol, ACT in young children are very responsive to chemotherapy, and we expect that most children will complete the treatment plan with 8 cycles of the combination. In this study, patients are scheduled to receive cumulative doses of cisplatin of 800 mg/m2. Based on the results of the Intergroup study for patients with high-risk malignant germ cell tumors, POG 9049/CCG 8882, in which the same cumulative dose of cisplatin was administered to patients randomized to the high-dose arm, the incidences of cisplatin-related severe hearing loss and nephrotoxicity are expected to be 20% and 10%, respectively. 49 Strict guidelines for cisplatin dose modification in patients experiencing hearing loss and decreased glomerular filtration rate are provided in Sections 5.2 and 5.3. Also, the aggregate toxicity of this regimen will be closely monitored (see Section 10.3) 2.6.3 Rationale for the Biology Studies 2.6.3.1 Biology As discussed above, pediatric ACT appears to differ from its adult counterpart by its association with germline mutations of TP53. The type of mutation appears to have a geographic distribution, with most of the non-Brazilian cases reported to occur throughout the gene, and particularly within the DNA binding domain, whereas the Brazilian cases are confined to in the tetramerization domain. However, the incidence and type of mutation in childhood ACT outside of Brazil has not been completely defined. Furthermore, the functional relevance of these mutations (both Brazilian and non-Brazilian) to adrenocortical cell transformation has not been studied. In this study, all patients that consent will undergo a mutation analysis of the germline TP53, and the findings in the non-Brazilian and Brazilian cases will be compared. The cooperating alterations of genes that may contribute to neoplastic transformation in ACT are not yet known and the identification of these genetic alterations is a primary goal of the biology studies. In this study, a molecular characterization of childhood ACT will be determined. The molecular nature of ACT

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may provide insight into novel approaches to targeted therapy, particularly in the absence of currently widely effective cytotoxic approaches. 2.6.3.2 Cell of Origin Childhood ACT are typically tumors of the very young. Because of the many differences between adult and childhood cases, we believe that they are derived from different cells of origin. Our working hypothesis is that childhood ACT is an embryogenic (rather than epithelial, as in adults) carcinoma. A cell of fetal origin (probably from the fetal adrenocortical zone) may have undergone malignant transformation caused by the loss of function of TP53 during the cellular proliferative period or may have escaped the apoptotic process of the fetal zone that naturally occurs during the perinatal period. Investigators in Curitiba, Brazil, have found a high incidence of expression of placental alkaline phosphatase (PLAP) in childhood tumors. In this study, we will further evaluate the expression of PLAP by tumors. 2.6.4 Cooperation with Brazilian Institutions This protocol will be a collaborative effort between COG and Brazilian institutions. We believe that this collaboration is necessary for two reasons. First, both institutions in Southern Brazil have extensive experience in the management of these patients, have Federal Wide Assurances with the OHRP, and also have an excellent track record on clinical research. Given the rarity of the disease, a collaborative effort will guarantee good accrual. Second, these unique patterns of distribution appear to hold the key to the investigation of new oncogenic pathways. 2.6.5 Ethical Considerations Germline TP53 mutation analysis is a fundamental aspect of the correlative biology studies of this study. After the patient has been identified, but before study enrollment is performed, the parents/legal guardians will be approached by the primary oncologist who will indicate the propensity of this disease to have an underlying genetic etiology. In order to facilitate enrollment and initiate the RDE process, permission for obtaining blood from the child will be requested, and this sample will be sent to the Biopathology Center for DNA isolation. No analysis will be initiated at that time. Following study enrollment, the treating physician will contact the geneticist or genetic counselor at their institution for referral for genetic counseling for the family for TP53 screening. If the institution does not have an identified geneticist or genetic counselor then the treating physician will contact the Study Chair, who will communicate this information to Dr. Malkin in Toronto. Dr. Malkin will then communicate with the treating physician and arrange for genetic counseling at or near the treating institution, or through the cancer genetic counseling program at The Hospital for Sick Children (i.e. phone counseling). Following standard pre-test genetic counseling, the parents/guardians will be in a position to provide informed consent, in which case the biology laboratory will be notified and TP53 analysis can be initiated. If the parents/guardians refuse screening, they will be asked whether they wish the samples to be retained for potential future use, or to be destroyed. This information will be communicated back to the reference biology laboratory. For those samples for which TP53 mutation analysis is performed, once the result has been obtained in the laboratory, this information will be reported back to the genetic counselor and/or primary treating physician who will then counsel the parents as per standard practice. 3.0 STUDY ENROLLMENT AND PATIENT ELIGIBILITY 3.1 Study Enrollment 3.1.1 IRB Approval Upon receipt of local IRB approval for a COG study, fax the officially signed IRB approval to the Group Operations Center (GOC) at: (626) 445-6715. The COG IRB Approval Fax Cover Sheet is required to be

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faxed with the official approval. A copy of this cover memo can be obtained from the protocol links area of the COG website. After this approval is recorded by GOC staff, the institution will have access to the eRDE enrollment screens. 3.1.2 Patient Registration Prior to study enrollment, all patients must have been registered via the eRDE system into the COG Cancer Registry (Diagnosis/Registry). The patient registration application is available 24 hours a day, 7 days a week. The assigned COG patient identification number will be used to identify the patient in all future interactions with the COG. If you have problems with registration, please refer to the online help in the eRDE area of the COG website. A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will be assigned only one BPC number per COG Patient ID. Please use this number as part of the labeling information on all banking and biology specimens sent to the Biopathology Center or a COG Reference Laboratory. For clinical submissions (i.e. those which help determine patient treatment or diagnosis), the COG Patient ID takes precedence over the BPC Number as specimen labeling. The BPC Number should then be included as an identifier on the transmittal form rather than on the specimen. If you have a question about a patient’s BPC Number, please call the Biopathology Center at (800) 347-2486. 3.1.3 Study Enrollment Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study enrollment is accomplished by going to the Enrollment application in the eRDE system. If you have problems with enrollment, refer to online help in the Applications area of the COG website. 3.1.4 Timing Study enrollment must take place within five calendar days of beginning protocol therapy. If enrollment takes place before starting therapy, the date protocol therapy is projected to start must be no later than fifteen calendar days after enrollment. 3.1.5 Bilingual Services To allow non-English speaking patients to participate in the study, bilingual health care services will be provided in the appropriate language. 3.2 Patient Criteria Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per COG policy posted 5/11/01). All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must be available in the patient’s medical/research record which will serve as the source document for verification at the time of audit. 3.2.1 Age Patients must be less than 22 years of age at the time of diagnosis. 3.2.2 Diagnosis Newly diagnosed patients with histological diagnosis of adrenocortical carcinoma. 3.2.3 Performance Level (See Appendix I) Patients ≤ 16 years of age: Lansky ≥ 60% Patients > 16 years of age: Karnofsky ≥ 60%

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3.2.4 Prior Therapy The patient must have received no previous chemotherapy for adrenocortical carcinoma. Patients must be enrolled within 3 weeks of the date of original surgery. 3.2.5 Organ Function Requirements: 3.2.5.1 Adequate renal function defined as:

- Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73m2 or - A serum creatinine based on age/gender as follows:

Age

Maximum Serum

Creatinine (mg/dL) Male Female

1 month to < 6 months 0.4 0.4 6 months to < 1 year 0.5 0.5

1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1 1

10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

≥ 16 years 1.7 1.4 The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

3.2.5.2 Adequate liver function defined as:

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and - SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age.

3.2.5.3 Adequate cardiac function defined as:

- Shortening fraction of ≥ 27% by echocardiogram, or - Ejection fraction of ≥ 50% by radionuclide angiogram.

3.2.5.4 Patients must have an absolute neutrophil count ≥ 750/µl and platelet count ≥ 75,000/µl. 3.2.6 Other Criteria Since there is no available information, as yet, regarding human fetal or teratogenic toxicities, the following restrictions apply to patients receiving chemotherapy (Stratum 3):

• Female patients of childbearing potential must have a negative pregnancy test. • Lactating females must agree that they will not breastfeed a child while on this study. • Males and females of reproductive potential may not participate unless they have agreed to use an

effective contraceptive method. 3.2.7 Regulatory 3.2.7.1 All patients and/or their parents or legal guardians must sign a written informed consent. 3.2.7.2 All institutional, FDA, and NCI requirements for human studies must be met.

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4.0 TREATMENT PLAN 4.1 Overview of Treatment plan This protocol includes 3 strata. Stratum 1 consists of patients with Stage I tumors. Stratum 2 consists of patients with Stage II tumors. Stratum 3 consists of patients with Stage III or IV tumors (see Appendix II for a description of staging). Patients with Stage I disease (completely resected tumors < 100 g and < 200 cm3) will undergo primary tumor resection and retroperitoneal lymph node sampling. Patients with Stage I disease who have had surgery without nodal sampling before enrollment will be entered into the study and followed without any further intervention. Patients with Stage II disease (completely resected tumors ≥ 100 g or ≥ 200 cm3) will undergo extended regional lymph node dissection. Lymph node dissection should be performed, when possible, at the time of the initial surgery. Patients with Stage II disease who had surgery with simple resection of the primary tumor must have another exploratory surgery with extended regional lymph node dissection. Patients with inoperable primary tumors or tumors that were resected but where there is at least microscopic residual disease (including tumor spillage) at the time of study enrollment (Stage III) will receive 2 to 4 cycles of chemotherapy before attempting extended surgery and regional lymph node dissection. The chemotherapy will be continued post-surgery to complete 8 cycles of chemotherapy and 8 months of mitotane. Patients in whom hormonal levels fail to normalize 1 month after surgery and patients with positive retroperitoneal lymph nodes will also be considered to have residual disease, and thus will receive 8 cycles of postoperative chemotherapy and 8 months of mitotane. Patients with Stage IV disease will receive at least 2 to 4 cycles of chemotherapy before attempting resection of the primary tumor and regional lymph nodes, and surgical resection of the metastases. A total of 8 cycles of chemotherapy along with 8 months of mitotane will be given. 4.2 Surgical Guidelines See Section 14.0. 4.3 Administration of Chemotherapy Patients with Stage III and IV disease will receive 8 cycles of chemotherapy with cisplatin, etoposide and doxorubicin, as outlined below, and oral mitotane daily for 8 months. Response evaluation will be performed after 2 cycles of therapy for all patients. Patients with response or stable disease will continue therapy, and surgical resection of the primary tumor and the metastatic sites will be planned. Those patients receiving chemotherapy due to persistent elevated hormonal levels or positive retroperitoneal lymph nodes, for whom surgery is not necessary, will proceed to Continuation therapy. Patients with progressive disease will be removed from protocol therapy, and the Study Chair should be notified. All cycles of chemotherapy may begin as soon as the absolute neutrophil count (ANC) is ≥ 750/µl and the platelet count ≥ 75,000/µl.

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Reg # Accession # Reporting Period Page 1 of 4 4.4 Administration Schedule for Patients on Stratum 3 during Induction The Induction Phase consists of 2 to 4 cycles of chemotherapy given every 21 days or as soon thereafter as the ANC ≥ 750/µl and the platelet count ≥ 75, 000/µl. Each cycle of chemotherapy will last 21 days. A response evaluation will be performed after 2 cycles of therapy. If appropriate, surgery will be planned to occur following Cycle 2, 3 or 4 of Induction therapy. Therefore, this phase consists of a 3 week cycle repeated 2 to 4 times.

Drug Rte Dose Days Important Notes Mitotane PO, daily Dose will vary, see

Section 4.4.2 Days 1-21

See Sections 4.4.2 and 4.4.3

Cisplatin (CDDP)

IV over 6 hours

50 mg/m2/dose Hours 0-6 on Days 1 and 2

+ Mannitol 10 g/m2 in 125 mL/m2/hr of D5W1/2 NS

Hours -2 to 0: Prehydrate with D5W1/2 NS 500 mL/m2 + Mannitol 10 g/m2 (infuse over 2 hr at 250 mL/m2/hr). Hours 6-22: Posthydrate with D5W1/2 NS + KCl 20 mEq/L at 125 mL/m2/hr. Stop hydration at hour 22 on Day 2 to start prehydration with Mannitol (described above Hours -2 to 0). Etoposide (VP-16)

IV over 1 hour 100 mg/m2/dose Days 1, 2, 3

Hydration with D5W1/2 NS + KCl 20 mEq/L at 125 mL/m2/hr on Day 3

Doxorubicin (DOXO)

IV over 1 hour 25 mg/m2/dose Days 4, 5

Hydration with D5W1/2 NS + KCl 20 mEq/L at 125 mL/m2/hr x 24 hours

Filgrastim (G-CSF)

Sub-Q, daily 5 micrograms/kg/dose Starting on Day 6, 24 hours after the last dose of doxorubicin

Give daily until ANC > 5,000/µl post nadir. Do not administer closer than 24 hours prior to the next cycle of chemotherapy.

Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on the Therapy Delivery Map below.

4.4.1 Therapy Delivery Map – Induction.

Circle cycle: 1 2 3 4

Week 1 Note Patient’s: Wgt __________kg Hgt_________cm BSA __________m2 DATE DAY 1 2 3 4 5 6 7

Mitotane Cisplatin Etoposide Doxorubicin G-CSF

Enter date last dose of G-CSF given, if past Day 7: ______________

Patients receive Mitotane, with or without G-CSF, Days 6 through to 21 (see over the page).

The reporting period for therapy is every 2 cycles (42 days).

See Section 5.0 for Specific Dose Modifications for Toxicities.

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Reg # Accession # Reporting Period Page 2 of 4 Therapy Delivery Map – Induction, Continued. Patients receive Mitotane, with or without G-CSF, Days 6 through to 21

Circle cycle: 1 2 3 4

Week 2 DATE DAY 8 9 10 11 12 13 14

Mitotane

Week 3 DATE DAY 15 16 17 18 19 20 21

Mitotane

The reporting period for therapy is every 2 cycles (42 days).

See Section 5.0 for Specific Dose Modifications for Toxicities. A response evaluation will be performed after 2 cycles of therapy. If appropriate, surgery will be planned to occur following Cycle 2, 3 or 4 of Induction therapy.

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Reg # Accession # Reporting Period Page 3 of 4 4.4.2 Administration of Mitotane during Induction Initial Dose: 1-2 g/m2/day, divided 4 times a day. Increase dose weekly by 1-2 g/m2 to a maximum daily dose at 4 weeks of 4 g/m2/day. Monitor plasma levels of mitotane weekly beginning with the 4th week of dosing at 4 g/m2/day. Plasma levels are to be kept between 14 and 20 micrograms/mL. Therapeutic levels are usually achieved after approximately 14 weeks of therapy. *(Note: once plasma levels of > 14 micrograms/mL are achieved they tend to continue to increase for 1-2 additional weeks. Measure plasma levels weekly; readjust the mitotane dose to the lowest dose necessary to maintain therapeutic levels. When levels have been maintained within the therapeutic range for 4-6 weeks then monitoring can be reduced to once every 2 weeks.) To saturate the adipose tissue deposits as quickly as possible, it is recommended that for the first 30 days, powdered mitotane tablets be mixed with a liquid nutrition formula composed of vegetable fat (e.g. Pulmocare). Should Pulmocare (or equivalent) be unavailable, whole milk may be used instead. If interruption of mitotane occurs for toxicity, for example, severe gastrointestinal toxicity, it is recommended to reduce the dose of mitotane to 2/3rds of the previous dose, and attempt to increase to full dose subsequently (for example, if the previous daily dose was 9 grams, then 2/3rds of that dose would be 6 grams). If mitotane has reached saturation levels, with a half life of 152 days the levels of mitotane would not be expected to differ significantly. For those patients who have not yet reached saturation levels, plasma levels are expected to be only slightly diminished. If therapeutic plasma levels are not attained at a maximum dose of 4 g/m2/day notify the Study Chair or Vice Chair. See Section 8.2.2 for Supportive Care guidelines specific to Mitotane administration. 4.4.3 Guidelines for Monitoring of Mitotane Levels Begin weekly sampling of plasma levels at 2 months (4 weeks after a dose of 4 g/m2/day is attained), continue until plasma saturation levels are achieved. Once therapeutic levels have been achieved, the dose may need to be adjusted to maintain plasma levels in the range of 14-20 micrograms/mL. When levels have been maintained within the therapeutic range for 4-6 weeks then monitoring can take place every 2 weeks. Procedure: Prior to 1st and/or 2nd daily dose of Mitotane collect 3 to 4 mL of heparinized blood. Collect plasma sample the same day of the week every 1 or 2 weeks (as instructed above). Keep plasma samples at –85oC until used for evaluation.

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Reg # Accession # Reporting Period Page 4 of 4 4.4.4 Table of Required Observations

STUDIES TO BE OBTAINED Before each cycle**

After Cycle 2 and 4**

End of Therapy

History X__X__X__X__ X__X__ X__ Physical Exam (Ht, Wt, BSA, VS)1 X__X__X__X__ X__X__ X__ Performance Status X__X__X__X__ X__X__ X__ CBC, differential, platelets X__X__X__X__ X__X__ X__ Urinalysis X__X__X__X__ X__X__ X__ Electrolytes including Ca++, PO4, Mg++ X__X__X__X__ X__X__ X__ Creatinine, ALT, AST, Alkaline Phosphatase, bilirubin

X__X__X__X__ X__X__ X__

Total protein/albumin, Serum glucose, Uric acid X__X__X__X__ X__X__ X__ ECHO X__X__X__X__ MRI abdomen X__X__ X__ CT chest X__X__ X__ Bone Scan2 X__X__ X__ Audiogram/BAER3 X__X__ X__ Radioisotope GFR or Creatinine clearance4 X__X__ X__ Endocrine evaluation5 X__X__ X__ Mitotane levels6 X__X__X__X__

** Induction may consist of 2 to 4 cycles. 1 Document signs of endocrine dysfunction, such as virilization or signs of hypercortisolism. Document hypertension. A nutritional evaluation is recommended (see Section 8.4). 2 If positive at diagnosis. 3 Pure tone audiogram, or BAER if the patient is too young to cooperate for an audiogram. 4 For better monitoring of the renal toxicity, a baseline isotope GFR or creatinine clearance is strongly recommended for those patients with advanced disease that will receive chemotherapy. At institutions where GFR is unavailable, creatinine clearance is acceptable. 5 See Section 7.1.3, times will correspond approximately to months 1 and 3 in that table. 6 See Sections 4.4.2 and 4.4.3

OBTAIN ADDITIONAL STUDIES AS REQUIRED FOR GOOD PATIENT CARE

See Section 7.0 for complete list of observations. 4.4.5 COMMENTS For Institutional Use: COMMENTS (Must be dated; document any change from required therapy):

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Reg # Accession # Reporting Period Page 1 of 4 4.5 Administration Schedule for Patients on Stratum 3 during Continuation Therapy The Continuation Phase consists of 4 to 6 cycles of chemotherapy plus up to a further 2 months of mitotane alone. Each cycle will be given every 21 days or as soon thereafter as the ANC ≥ 750/µl and the platelet count ≥ 75, 000/µl. Each cycle of chemotherapy will last 21 days. The cycle will be repeated 4 to 6 times, depending on the length of Induction. Induction and Continuation Therapy should combine for a total of 8 cycles of chemotherapy and 8 months of mitotane.

Drug Rte Dose Days Important Notes Mitotane PO, daily Dose will vary, see

Section 4.5.2 Days 1-21 See Sections 4.5.2 and 4.5.3

Cisplatin (CDDP)

IV over 6 hours

50 mg/m2/dose Hours 0-6 on Days 1 and 2

+ Mannitol 10 g/m2 in 125 mL/m2/hr of D5W1/2 NS

Hours -2 to 0: Prehydrate with D5W1/2 NS 500 mL/m2 + Mannitol 10 g/m2 (infuse over 2 hr at 250 mL/m2/hr). Hours 6-22: Posthydrate with D5W1/2 NS + KCl 20 mEq/L at 125 mL/m2/hr. Stop hydration at hour 22 on Day 2 to start prehydration with Mannitol (described above Hours -2 to 0). Etoposide (VP-16)

IV over 1 hour 100 mg/m2/dose Days 1, 2, 3 Hydration with D5W1/2 NS + KCl 20 mEq/L at 125 mL/m2/hr on Day 3

Doxorubicin (DOXO)

IV over 1 hour 25 mg/m2/dose Days 4, 5 Hydration with D5W1/2 NS + KCl 20 mEq/L at 125 mL/m2/hr x 24 hours

Filgrastim G-CSF

Sub-Q, daily 5 micrograms/kg/dose Starting on Day 6, 24 hours after the last dose of doxorubicin

Give daily until ANC > 5,000/µl post nadir. Do not administer closer than 24 hours prior to the next cycle of chemotherapy.

Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on the Therapy Delivery Map below.

4.5.1 Therapy Delivery Map - Continuation Therapy

Circle cycle: 1 2 3 4 5 6

Week 1 Note Patient’s: Wgt __________kg Hgt_________cm BSA __________m2 DATE DAY 1 2 3 4 5 6 7

Mitotane Cisplatin Etoposide Doxorubicin G-CSF

Enter date last dose of G-CSF given, if past Day 7: ______________

Patients receive Mitotane, with or without G-CSF, Days 6 through to 21 (see over the page).

The reporting period for therapy is every 2 cycles (42 days).

See Section 5.0 for Specific Dose Modifications for Toxicities.

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Therapy Delivery Map – Continuation Therapy, Continued. Patients receive Mitotane, with or without G-CSF, Days 6 through to 21

Circle cycle: 1 2 3 4 5 6

Week 2 DATE DAY 8 9 10 11 12 13 14

Mitotane

Week 3 DATE DAY 15 16 17 18 19 20 21

Mitotane The reporting period for therapy is every 2 cycles (42 days).

See Section 5.0 for Specific Dose Modifications for Toxicities. Following a total of 8 cycles of chemotherapy, patients will continue with up to a further 8 weeks of mitotane alone, to receive a total of 8 months of mitotane.

Week ____ Note Patient’s: Wgt __________kg Hgt_________cm BSA __________m2 DATE DAY 1 2 3 4 5 6 7

Mitotane

The reporting period for this mitotane therapy will end at the completion of therapy.

See Section 5.0 for Specific Dose Modifications for Toxicities.

Reg # Accession # Reporting Period Page 2 of 4

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Reg # Accession # Reporting Period Page 3 of 4 4.5.2 Administration of Mitotane during Continuation Therapy During Continuation, patients will likely be dosed at or near 4 g/m2/day. Continue to monitor plasma levels of mitotane weekly beginning with the 4th week of dosing at 4 g/m2/day. Plasma levels are to be kept between 14 and 20 micrograms/mL. Therapeutic levels are usually achieved after approximately 14 weeks of therapy. *(Note: once plasma levels of > 14 micrograms/mL are achieved they tend to continue to increase for 1-2 additional weeks. Measure plasma levels weekly; readjust the mitotane dose to the lowest dose necessary to maintain therapeutic levels. Once levels have been maintained within the therapeutic range for 4-6 weeks then monitoring can be reduced to once every 2 weeks.) If interruption of mitotane occurs for toxicity, for example, severe gastrointestinal toxicity, it is recommended to reduce the dose of mitotane to 2/3rds of the previous dose, and attempt to increase to full dose subsequently (for example, if the previous daily dose was 9 grams, then 2/3rds of that dose would be 6 grams). If mitotane has reached saturation levels, with a half life of 152 days the levels of mitotane would not be expected to differ significantly. For those patients who have not yet reached saturation levels, plasma levels are expected to be only slightly diminished. If therapeutic plasma levels are not attained at a maximum dose of 4 g/m2/day notify the Study Chair or Vice Chair. See Section 8.2.2 for Supportive Care guidelines specific to Mitotane administration. 4.5.3 Guidelines for Monitoring of Mitotane Levels Begin weekly sampling of plasma levels at 2 months (4 weeks after a dose of 4 g/m2/day is attained), continue until plasma saturation levels are achieved. Once therapeutic levels have been achieved, the dose may need to be adjusted to maintain plasma levels in the range of 14-20 micrograms/mL. Once levels have been maintained within the therapeutic range for 4-6 weeks then monitoring can take place every 2 weeks. Procedure: Prior to 1st and/or 2nd daily dose of Mitotane collect 3 to 4 mL of heparinized blood. Collect plasma sample the same day of the week every 1 or 2 weeks (as instructed above). Keep plasma samples at –85oC until used for evaluation.

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Reg # Accession # Reporting Period Page 4 of 4 4.5.4 Table of Required Observations

STUDIES TO BE OBTAINED Before each cycle** After Cycle 4 and 6##

End of Therapy

History X__X__X__X__X__X__ X__X__ X__ Physical Exam (Ht, Wt, BSA, VS) 1 X__X__X__X__X__X__ X__X__ X__ Performance Status X__X__X__X__X__X__ X__X__ X__ CBC, differential, platelets X__X__X__X__X__X__ X__X__ X__ Urinalysis X__X__X__X__X__X__ X__X__ X__ Electrolytes including Ca++, PO4, Mg++ X__X__X__X__X__X__ X__X__ X__ Creatinine, ALT, AST, Alkaline Phosphatase, bilirubin

X__X__X__X__X__X__ X__X__ X__

Total protein/albumin, Serum glucose, Uric acid X__X__X__X__X__X__ X__X__ X__ ECHO X__X__X__X__X__X__ MRI abdomen X__X__ X__ CT chest X__X__ X__ Bone Scan2 X__X__ X__ Audiogram/BAER3 X__X__ X__ Radioisotope GFR or Creatinine clearance4 X__X__ X__ Endocrine evaluation5 X__X__ X__ Mitotane levels6 X__X__X__X__X__X__ ** Continuation may consist of 4 to 6 cycles. ## Out of the total 8 cycles of combination chemotherapy. 1 Document signs of endocrine dysfunction, such as virilization or signs of hypercortisolism. Document hypertension. A nutritional evaluation is recommended (see Section 8.4). 2 If positive at diagnosis. 3 Pure tone audiogram, or BAER if the patient is too young to cooperate for an audiogram. 4 For better monitoring of the renal toxicity, a baseline isotope GFR or creatinine clearance is strongly recommended for those patients with advanced disease that will receive chemotherapy. At institutions where GFR is unavailable, creatinine clearance is acceptable. 5 See Section 7.1.3, times will correspond approximately to months 3 and 6 in that table. 6 See Sections 4.5.2 and 4.5.3

OBTAIN ADDITIONAL STUDIES AS REQUIRED FOR GOOD PATIENT CARE

See Section 7.0 for complete list of observations. 4.5.5 COMMENTS For Institutional Use: COMMENTS (Must be dated; document any change from required therapy):

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5.0 DOSE MODIFICATIONS FOR TOXICITIES 5.1 Myelosuppression 5.1.1 Treatment may begin if ANC is ≥ 750/µl, and platelets ≥ 75,000/µl. G-CSF should be stopped once ANC > 5,000/µl post nadir. Chemotherapy can proceed even if the ANC has decreased after discontinuing G-CSF. G-CSF must be stopped for at least 24 hours before chemotherapy administration.

5.1.1.1 Delay chemotherapy, except mitotane, until above criteria are met. If delay is > 1 week, decrease the dose of all agents, except mitotane, by 20% for subsequent cycles (for example, if the full dose is 50 mg, then administer 40 mg for a 20% dose reduction).

5.2 Ototoxicity

5.2.1 A decrease in auditory acuity at frequencies above the normal hearing range (4000 – 8000 Hz) is expected. • For CTCAE version 3, Grade 1 or 2 ototoxicity, cisplatin dose will not be modified. • For CTCAE version 3, Grade 3 ototoxicity, reduce the dose of cisplatin by 50% for all subsequent

cycles (for example, if the full dose is 50 mg, then administer 25 mg for a 50% dose reduction). • For CTCAE version 3, Grade 4 ototoxicity, hold cisplatin dose and do not restart unless follow-up

audiograms show improvement in the hearing function. From CTCAE version 3:

Grade 1 Grade 2 Grade 3 Grade 4 Threshold shift or loss of 15-25 dB relative to baseline, averaged at 2 or more contiguous test frequencies in at least one ear; or subjective change in the absence of a Grade 1 threshold shift

Threshold shift or loss of > 25 – 90 dB, averaged at 2 contiguous test frequencies in at least one ear

Adults: Threshold shift of > 25 – 90 dB, averaged at 3 contiguous test frequencies in at least one ear. Children: Hearing loss sufficient to indicate therapeutic intervention, including hearing aids (e.g., ≥ 20 dB bilateral HL in the speech frequencies; ≥ 30 dB unilateral HL; and requiring additional speech-language related services)

Adults: Profound bilateral hearing loss (> 90 dB) Children: Audiologic indication for cochlear implant and requiring additional speech-language related services

5.3 Nephrotoxicity 5.3.1 Creatinine clearance or GFR < 50% of baseline value: withhold cisplatin until the creatinine clearance rises above 50% of the baseline value. If repeat GFR > 50% but < 75% of baseline, reduce dose of cisplatin by 50%, and repeat creatinine clearance after 2 cycles (for example, if the full dose is 50 mg, then administer 25 mg for a 50% dose reduction). If GFR rises to ≥ 75%, resume cisplatin at full dose.

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5.3.2 Creatinine clearance or GFR < 75% of baseline value: reduce the dose of cisplatin by 50% until GFR returns to ≥ 75% of baseline value, and then resume full dose (for example, if the full dose is 50 mg, then administer 25 mg for a 50% dose reduction). 5.4 Cardiac Toxicity An echocardiogram with determination of shortening fraction should be performed before treatment and before every course of chemotherapy. If a decrease in the shortening fraction to < 27% is observed, chemotherapy should be postponed one week, any existing malnutrition corrected and the test repeated. If the abnormality persists, doxorubicin should be permanently discontinued. 5.5 Mitotane Toxicity Sometimes it may be necessary to stop mitotane treatment for 4-5 days, for instance, in the event of severe gastrointestinal toxicity. However, it should be noted that gastrointestinal symptoms may be the result of inappropriate corticoid replacement leading to an Addisonian crisis (especially during stressful periods). If interruption in the treatment of mitotane occurs, then mitotane must be resumed at the same dose. Since mitotane has a very prolonged half-life (152 days), mitotane levels will not be significantly different from the last value if it has already reached the saturation level. For those patients that have not yet reached saturation, plasma levels will be only slightly diminished. If vomiting was caused by mitotane (and/or the fat vehicle), it is recommended to re-start with 2/3 of the previous daily dose (for example, if the previous daily dose was 9 grams, the recommended dose to re-start would be 6 grams), or even less. Sometimes, these side-effects are the result of not following the recommendation of splitting the dose to 4 times or the vehicle was not ideal (some nutritional oils may be better accepted than pulmocare by children).

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6.0 DRUG INFORMATION 6.1 CISPLATIN (Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ) NSC #119875

(032006)

Source and Pharmacology: Cisplatin is an inorganic, water-soluble complex containing a central platinum atom, 2 chlorine atoms and 2 ammonia molecules. In aqueous solution, the chloride ions are slowly displaced by water generating a positively charged aquated complex. This activated complex is then available to react with nucleophilic sites on DNA, RNA, or protein resulting in the formation of bi-functional covalent links, very similar to alkylating reactions. The intra-strand cross-links, in particular with guanine and cytosine, change DNA conformation and inhibit DNA synthesis leading to the cytotoxic and anti-tumor effects of cisplatin. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. Cisplatin has a rapid distribution phase of 25-80 minutes with a slower secondary elimination half-life of 60-70 hours. The platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more. Platinum is present in tissues for as long as 180 days after the last administration. Both cisplatin and platinum are excreted through the kidneys ranging from 10-50%. Fecal elimination is minimal. Cisplatin’s penetration into the CNS is poor. Toxicities

Common Happens to 21-100 children

out of every 100

Occasional Happens to 5-20

children out of every 100

Rare Happens to < 5 children

out of every 100 Immediate: Within 1-2 days of receiving drug

Nausea (L), vomiting (L)

Metallic taste (L) Anaphylactic reaction (facial edema, wheezing, tachycardia, and hypotension), phlebitis. Extravasation (rare) but if occurs = local ulceration (only in concentration ≥ 0.5mg/ml)

Prompt: Within 2-3 weeks, prior to the next course

Anorexia (L), myelosuppression, hypomagnesemia (L), high frequency hearing loss (L), nephrotoxicity (↑ Cr, BUN, Uric Acid) (L)

Electrolyte disturbances (L) (hypocalcemia, natremia, kalemia, & phosphatemia ), peripheral neuropathy (paresthesias in a stocking-glove distribution) (L)

Vestibular dysfunction, tinnitus (L), rash, seizure (L), elevated liver function tests(L),

Delayed: Any time later during therapy

Hearing loss in the normal hearing range

Areflexia, loss of proprioception and vibratory sensation, (very rarely loss of motor function) (L), optic neuritis, papilledema, cerebral blindness, blurred vision and altered color perception (improvement or total recovery usually occurs after discontinuing), chronic renal failure, deafness

Late: Any time after completion of treatment

Secondary malignancy

Unknown Frequency and Timing:

Fetal toxicities and teratogenic effects of cisplatin have been noted in animals and cisplatin can cause fetal harm in humans. Cisplatin is excreted into breast milk.

(L) Toxicity may also occur later.

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Formulation and Stability: Available as an aqueous solution containing 1 mg/ml of cisplatin and 9mg (1.54mEq)/ml of sodium chloride in 50 ml, 100 ml and 200 ml multi-dose non-preserved vials. Store at 15°C-25°C (68-77ºF). Do not refrigerate. Protect unopened container from light. The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light. Cisplatin removed from its amber container should be protected from light if not used within 6 hours. Guidelines for Administration: See the Treatment and Dose Modifications Sections of this protocol. Cisplatin may be further diluted in dextrose and saline solutions provided the solution contains ≥ 0.2% sodium chloride. Dextrose/saline/mannitol containing solutions, protected from light, are stable refrigerated or at room temperature for 24-72 hours but since such admixtures contain no preservative, use within 24 hours. Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not be used for preparation or administration. Aluminum reacts with cisplatin causing precipitate formation and a loss of potency. Supplier: Commercially available from various manufacturers. See package insert for more detailed information. 6.2 DOXORUBICIN (Adriamycin®) NSC #123127 (042006) Source and Pharmacology: An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of doxorubicin cytocidal activity. Doxorubicin cellular membrane binding may affect a variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases generate highly reactive species including the hydroxyl free radical OH•. Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both. Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 5 minutes suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours reflects a slow elimination from tissues. Steady-state distribution volumes exceed 20 to 30 L/kg and are indicative of extensive drug uptake into tissues. Plasma clearance is in the range of 8 to 20 ml/min/kg and is predominately by metabolism and biliary excretion. The P450 Cytochromes which appear to be involved with doxorubicin metabolism are CYP2D6 and CYP3A4. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. Binding of doxorubicin and its major metabolite, doxorubicinol to plasma proteins is about 74 to 76% and is independent of plasma concentration of doxorubicin.

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Toxicity:

Common Happens to 21-100 children out of

every 100

Occasional Happens to 5-20 children out of

every 100

Rare Happens to < 5 children out of

every 100 Immediate: Within 1-2 days of receiving drug

Nausea, vomiting, pink or red color to urine, sweat, tears and saliva

Hyperuricemia, facial flushing, sclerosis of the vein

Diarrhea, anorexia, erythematous streaking of the vein (flare reaction). Extravasation (rare) but if occurs = local ulceration, anaphylaxis, fever, chills, urticaria, acute arrhythmias

Prompt: Within 2-3 weeks, prior to the next course

Myelosuppression (leucopenia, thrombocytopenia, anemia), alopecia

Mucositis (stomatitis and esophagitis), hepatotoxicity

Radiation recall reactions, conjunctivitis and lacrimation

Delayed: Any time later during therapy

Cardiomyopathy1 (CHF occurs in 5-20% @ cumulative doses ≥ 450 mg/m²)(L)

Cardiomyopathy1 (CHF occurs in < 5% @ cumulative doses ≤ 400 mg/m²) (L), ulceration and necrosis of colon, hyper-pigmentation of nail bed and dermal crease, onycholysis

Late: Any time after completion of treatment

Subclinical cardiac dysfunction CHF (on long term follow up in pediatric patients)

Secondary malignancy (in combination regimens)

Unknown Frequency and Timing:

Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin have been noted in animal models. Doxorubicin is excreted into breast milk in humans.

1 Risk increases with chest radiation, exposure at a young or advanced age; (L) Toxicity may also occur later.

Formulation and Stability: Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 50 mg¹, 150 mg² vials and a preservative free 2 mg/ml solution in 10 mg¹, 20 mg¹, 50 mg¹, 75 mg¹, 200 mg² vials. ¹: Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF® (rapid dissolution formula) also contains methylparaben 1 mg per each 10 mg of Doxorubicin to enhance dissolution. ² Multiple dose vial contains lactose, 0.9%NS, HCl to adjust pH to 3. Aqueous Solution: Store refrigerated 2° to 8°C, (36° to 46°F). Protect from light. Retain in carton until contents are used. Powder for injection: Store unreconstituted vial at room temperature 15° to 30°C (59° to 86°F). Retain in carton until contents are used. Reconstitute with preservative-free normal saline to a final concentration of 2mg/ml. After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature under normal room light (100 footcandles) and 15 days under refrigeration 2° to 8°C (36° to 46°F). Protect from exposure to sunlight. Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. Administer by IV push; by IV side arm into a running infusion; or doxorubicin may be further diluted in saline or dextrose containing solutions and administered by infusion. Protect final preparation from light. Avoid extravasation. Supplier: Commercially available from various manufacturers. See package insert for further information.

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6.3 ETOPOSIDE (VePesid®, Etopophos®,VP-16) NSC #141540 (112005) Source and Pharmacology: A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase II and DNA which results in single and double strand DNA breaks. Its main effect appears to be in the S and G2 phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal half-life is 4 to 11 hours. It is primarily excreted in the urine. In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² or about 35% of the total body clearance over a dose range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and non renal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism accounts for most of the non renal clearance of etoposide. The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a high degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is related to toxicity. Preliminary data suggests that systemic exposure for unbound etoposide correlates better than total (bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. Cmax and AUC values for orally administered etoposide capsules consistently fall in the same range as the Cmax and AUC values for an intravenous dose of one-half the size of the oral dose. The overall mean value of oral capsule bioavailability is approximately 50% (range 25-75%). Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide phosphate is bioequivalent to etoposide when it is administered in molar equivalent doses. Toxicity:

Common Happens to 21-100 children out of

every 100

Occasional Happens to 5-20 children out of

every 100

Rare Happens to < 5 children out of every 100

Immediate: Within 1-2 days of receiving drug

Nausea, vomiting Anorexia Transient hypotension during infusion; anaphylaxis (chills, fever, tachycardia, dyspnea, bronchospasm, hypotension)

Prompt: Within 2-3 weeks, prior to next course

Myelosuppression (anemia, leukopenia), alopecia

Thrombocytopenia, diarrhea, abdominal pain, asthenia, malaise, rashes and urticaria

Peripheral neuropathy, mucositis, hepatotoxicity, chest pain, thrombophlebitis, congestive heart failure, Stevens-Johnson Syndrome, exfoliative dermatitis

Delayed: Any time later during therapy

Dystonia, ovarian failure, amenorrhea, anovulatory cycles, hypomenorrhea, onycholysis of nails

Late: Any time after completion of treatment

Secondary malignancy (preleukemic or leukemic syndromes)

Unknown Frequency and Timing:

Fetal toxicities and teratogenic effects of etoposide have been noted in animals at 1/20th of the human dose. It is unknown whether the drug is excreted in breast milk.

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Formulation and Stability: Etoposide for Injection is available in sterile multiple dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. Unopened vials of Etoposide are stable until expiration date on package at room temperature (25°C). Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized powder in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate must be stored under refrigeration 2°-8°C (36°- 46°F). Unopened vials of etoposide phosphate are stable until the expiration date on the package. Etoposide capsules must be stored under refrigeration 2°-8°C (36°- 46°F).The capsules are stable until the expiration date on the package. Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. Etoposide: Dilute Etoposide to a final concentration ≤ 0.4 mg/mL in Dextrose or Normal Saline containing IV solutions. Etoposide infusions are stable at room temperature for 96 hours when diluted to concentrations of 0.2 mg/ml; stability is 24 hours at room temperature with concentrations of 0.4 mg/mL. The time to precipitation is highly unpredictable at concentrations > 0.4 mg/mL. Administer over 60 minutes. Do not administer etoposide by rapid intravenous injection. To avoid leaching of DEHP from PVC bags and tubing, prepare the Etoposide solution as close as possible preferably within 4 hours to the time of administration or alternatively as per institutional policy, non-PVC containers and tubing may be used. Etoposide Phosphate: Dilute the 100 mg vial with 5 or l0 mL of Sterile Water for Injection, USP; 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; Bacteriostatic Water for Injection with Benzyl Alcohol; or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol for a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide (22.7 mg/mL or 11.4 mg/mL etoposide phosphate) respectively. When reconstituted with diluent containing a bacteriostat, etoposide phosphate solutions can be stored in glass or plastic containers under refrigeration at 2˚-8˚C (36˚-46˚F) for 7 days or at controlled room temperature 20˚-25˚C (68˚-77˚F) for 48 hours; following reconstitution with Sterile Water for Injection, USP, 5% Dextrose Injection, USP, or 0.9% Sodium Chloride USP store at controlled room temperature 20˚-25˚C (68˚-77˚F) for 24 hours. Following reconstitution, etoposide phosphate may be further diluted to concentrations as low as 0.1 mg/mL etoposide with Dextrose or Saline infusion solutions. Etoposide Phosphate may be administered as a bolus or by IV infusion at rates from 5 to 210 minutes. Supplier: Commercially available from various manufacturers. See package insert for more detailed information.

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6.4 FILGRASTIM (Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®) NSC #614629 (082006) Source and Pharmacology: Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by recombinant DNA technology. Filgrastim is a 175 amino acid protein with a molecular weight of 18,800 daltons manufactured by recombinant DNA technology utilizing E coli bacteria into which has been inserted the human granulocyte colony stimulating factor gene. It differs from the natural protein in that the N- amino acid is methionine and the protein is not glycosylated. G-CSF is a lineage specific colony-stimulating factor which regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory burst, antibody dependent killing, and the increased expression of some functions associated with cell surface antigens). The elimination half-life is similar for subcutaneous and intravenous administration, approximately 3.5 hours. The time to peak concentration when administered subcutaneously is 2 to 8 hours. Toxicity:

Common Happens to 21-100

children out of every 100

Occasional Happens to 5-20 children out of

every 100

Rare Happens to < 5 children out of every

100 Immediate: Within 1-2 days of receiving drug

Local irritation at the injection site, headache

Allergic reactions (more common with IV administration than subq):skin (rash, urticaria, facial edema), respiratory (wheezing, dyspnea) and cardiovascular (hypotension, tachycardia), low grade fever

Prompt: Within 2-3 weeks, prior to the next course

Mild to moderate medullary bone pain

Increased: alkaline phosphatase, lactate dehydrogenase and uric acid, thrombocytopenia

Splenomegaly, splenic rupture, exacerbation of pre-existing skin rashes, sickle cell crises in patients with SCD, excessive leukocytosis

Delayed: Anytime later during therapy

Cutaneous vasculitis, ARDS

Late: Anytime after completion of treatment

MDS or AML (confined to patients with severe chronic neutropenia and long term administration)

Unknown Frequency and Timing:

Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. Conflicting data exist in animal studies and filgrastim is known to pass the placental barrier. It is unknown whether the drug is excreted in breast milk.

Formulation and Stability: Supplied as a clear solution in 300 mcg/ml 1 ml or 1.6 ml vials and prefilled syringes containing 300 mcg/0.5 mL or 480 mcg/0.8 mL. Vials are preservative free single use vials. Discard unused portions of open vials. Store refrigerated at 2-8º C (36-46ºF). Prior to injection, filgrastim may be allowed to reach room temperature for a maximum of 24 hours. Avoid freezing and temperatures > 30ºC. For IV use, dilute in D5W only to concentrations >15 mcg/ml. At concentrations between 5 and 15 mcg/ml, human serum albumin should be added to make a final albumin concentration of 0.2% (2 mg/ml) in order to minimize the adsorption of filgrastim to infusion containers and equipment. Dilutions of 5 mcg/ml or less are not recommended. Diluted filgrastim should be stored at 2-8º C (36-46ºF) and used within 24 hours. Do not shake.

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Guidelines for Administration: See Treatment and Supportive Care sections of the protocol. Filgrastim should not be administered within 24 hours of chemotherapy. Supplier: Commercially available from various manufacturers. See package insert for further information. 6.5 MITOTANE (Lysodren®, o,p'DDD ) NSC# 38721 (082006) Source and Pharmacology: Mitotane, an isomer found in the insecticide DDD, causes focal degeneration in the zona fasciculata and zona reticularis of the adrenal cortex with resultant atrophy. The exact mechanism of action of mitotane is unclear. It appears to selectively inhibit adrenocortical function as well as functional and nonfunctional adrenocortical neoplasms by a direct cytotoxic effect. This effect may be mediated through covalent bonding of mitotane metabolites to mitochondrial proteins. Mitotane inhibits the production of corticosteroids and alters extra-adrenal metabolism of endogenous and exogenous steroids. The oral bioavailability of mitotane is 40%. It is extensively distributed into fatty tissues. The primary site of metabolism is the liver. 1% to 17% of the metabolite is excreted in the bile and up to 10% of the water soluble metabolite is excreted in the urine. Following discontinuation, the elimination half-life of mitotane ranges from 18 to 159 days. Following discontinuation, the blood levels become undetectable after 6 to 9 weeks. Toxicity:

Common Happens to 21-100

children out of every 100

Occasional Happens to 5-20 children

out of every 100

Rare Happens to <5 children out of every

100 Immediate: Within 1-2 days of receiving drug

Anorexia, nausea, vomiting, diarrhea

Orthostatic hypotension, hypertension, flushing, wheezing, shortness of breath, generalized aching, hyperpyrexia

Prompt: Within 2-3 weeks, prior to the next course

Depression, lethargy, somnolence, headache, irritability, confusion, mood changes, tremors, weakness, fatigue, decreased memory, Addisonian Crises if adrenal gluco and mineralocorticoids not replaced adequately

Prolonged bleeding times, dizziness, vertigo, gynecomastia, transient skin rash, leukopenia

Orthostatic hypotension, hypertension, hypersialorrhea

Delayed: Any time later during therapy

Hypothyroidism, hyperlipoprotenemia, elevated serum cholesterol and triglycerides

Elevated liver function tests

Orthostatic hypotension, hypertension, hematuria, hemorrhagic cystitis, albuminuria, renal impairment, blurred vision, diplopia, lenticular opacities, toxic retinopathy, hyperpigmentation, alopecia. Neurologic effects including permanent brain damage and functional impairment, speech difficulty, impaired memory, ataxia, neuropathy, myelopathy, hallucinations, psychosis.

Late: Any time after the completion of treatment

Long term adrenocortical dysfunction

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Formulation and Stability: Mitotane is available as a white, round, scored tablet available as 500 mgs. Inactive ingredients include: avicel, polyethylene glycol 3350, silicon dioxide and starch. Store at controlled room temperature between 15º-30ºC (59-86ºF). Guidelines for Administration: See Sections 4.4.2 and 4.5.2 of the protocol Supplier: Commercially available from various manufacturers. See package insert for more detailed information. 7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED All baseline studies must be performed prior to starting protocol therapy unless otherwise noted below. 7.1 Required and Optional Clinical, Laboratory and Disease Evaluations 7.1.1 Patients with Stage I and II disease (Strata 1 and 2, surgery only)

STUDIES TO BE OBTAINED Baseline History1 X Physical Exam (Ht, Wt, BSA, VS) X Performance Status X CBC, differential, platelets X Urinalysis X Electrolytes including Ca++, PO4, Mg++ X Creatinine, ALT, AST, Alkaline Phosphatase, bilirubin X Total protein/albumin, Serum glucose, Uric acid X MRI abdomen X CT chest X Bone Scan X Endocrine evaluation X Evaluation of TP53 germline status** X

1 Document ethnic background, place of birth, family history of cancer. Document signs of endocrine dysfunction, such as virilization or signs of hypercortisolism. Document hypertension. A nutritional evaluation is recommended (see Section 8.4). ** Optional biology study.

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7.1.2 Patients with Stage III and IV disease (Stratum 3)

STUDIES TO BE OBTAINED Baseline Before each cycle

After Cycles 2, 4 and 6

End of Therapy

History1 X X X X Physical Exam (Ht, Wt, BSA, VS) X X X X Performance Status X X X X CBC, differential, platelets X X X X Urinalysis X X X X Electrolytes including Ca++, PO4, Mg++ X X X X Creatinine, ALT, AST, Alkaline Phosphatase, bilirubin

X X X X

Total protein/albumin, Serum glucose, Uric acid X X X X Fasting Lipid Panel X X X ECHO X MRI abdomen X X X CT chest X X X Bone Scan2 X X X Audiogram/BAER3 X X X Radioisotope GFR or Creatinine clearance4 X X X Endocrine evaluation5 X X X Pregnancy test6 X Mitotane levels* X Evaluation of TP53 germline status** X 1 Document ethnic background, place of birth, family history of cancer. Document signs of endocrine dysfunction, such as virilization or signs of hypercortisolism. Document hypertension. A nutritional evaluation is recommended (see Section 8.4). 2 If positive at diagnosis. 3 Pure tone audiogram, or BAER if the patient is too young to cooperate for an audiogram. 4 For better monitoring of the renal toxicity, a baseline isotope GFR or creatinine clearance is strongly recommended for those patients with advanced disease that will receive chemotherapy. At institutions where GFR is unavailable, creatinine clearance is acceptable. 5 Will correspond approximately to months 1, 3, 6 in table 7.1.3 below. 6 Female patients of childbearing potential. * See Section 4.4.2 and 4.4.3. ** Optional biology study.

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7.1.3 Guidelines for Endocrinologic Evaluation

Labs Months Post surgery

H & P.E1

DHEA-S DHEA Andro-stenedione

Testosterone Cortisol ACTH2 Deoxycorticosterone Corticosterone Aldosterone3

Thyroid, Parathyroid

hormones and others4

7 days X X X X X X 1 X X X X X X X X 3 X X X X X X X 6 X X X X X X X X X 9 X X X X X X X 12 X X X X X X X X X 15 X X X X X X X 18 X X X X X X X X X 21 X X X X X X X 24 X X X X X X X X Every 6 months until 5th year

X X X X X X X

1 Accurate record of growth charts (height, weight, velocity, BMI), etc. 2 For control of cortisol replacement. 3 For patients diagnosed with hypertension. 4 Patients on mitotane and according to physical exam.

In general, the altered hormones found at diagnosis remain as the best hormonal markers of relapse, which may be in agreement with subtle changes in physical exam and imaging studies. For those patients on long-term treatment with mitotane, any sudden increase (1-3 months) in hormone levels (even within normal range) should be considered suspicious for recurrence. In these cases it may be necessary to monitor hormone levels and other diagnostic studies on a shorter interval.

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7.2 Specimen Submission

Please note: A Specimen Transmittal Form must be completed and submitted with all specimens sent to the Biopathology Center.

CENTRAL PATHOLOGY REVIEW - REQUIRED SPECIMEN/MATERIAL TIME POINTS SEND TO Slides: 1) 3 H&E slides from each tissue block submitted. 2) 20 unstained slides from 3 representative tissue blocks from the primary tumor site, and 20 slides from all tissue blocks from metastatic sites. Formalin-Fixed Tissue: 1) At least 1 representative formalin-fixed paraffin-embedded tissue block from both the primary tumor and metastatic sites. Report: 1) Institutional Surgical Pathology Report Recommended Reports: 1) Cytogenetics Report, when available. 2) Report from DNA Ploidy flow cytometry, when available.

At diagnosis. These specimens should be sent within 4 weeks of study enrollment.

Biopathology Center Attention: ARAR0332 Children’s Hospital of Columbus 700 Children’s Drive, WA1340 Columbus, OH 43205 Phone: (614) 722-2810 Fax: (614) 722-2897 See Section 15.2.4 for labeling requirements and shipping details.

BIOLOGY STUDIES AND BANKING - OPTIONAL SPECIMEN/MATERIAL TIME POINTS SEND TO Blood: 5 mL of blood in an EDTA (purple top) tube.

See Section 16.2 for details.

At diagnosis. Biopathology Center See Section 16.2 for labeling requirements. See Section 16.3 for packaging and shipping details.

Frozen Tissue: 10-15 grams of non-sterile tumor, frozen a.s.a.p. after surgery.

*This takes priority over the formalin-fixed tissue sample if there is insufficient material for both. In addition, if available: Snap frozen tissue Submit tissue from primary tumor site and all metastatic sites.

See Section 16.2 for details.

After diagnostic surgery. As above.

If available: Formalin-Fixed Tissue Submit either fixed tissue or 1 representative formalin-fixed paraffin-embedded tissue block from primary and metastatic tumor.

See Section 16.2 for details.

After diagnostic surgery. As above.

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7.3 Required Material for QARC Central Review 7.3.1 Imaging Studies

MATERIAL TIME POINTS SEND TO 1) MRI of abdomen 2) Chest CT 3) Bone scan 4) Other appropriate studies if a recurrence occurs 5) Corresponding radiology reports See Section 17.4 for details.

Send data within 30 days of completion of therapy.

QARC 272 West Exchange Street, Suite 101 Providence, Rhode Island 02903-1025 Phone: (401) 454-4301 Fax: (401) 454-4683

7.4 Evaluations during Follow-Up and After Completion of Therapy

Months Post Treatment

H & P, VS

Labs MRI 1o CT chest

Bone scan

Audiogram1 GFR1 Endo. ECHO1

3 X X X X X X 6 X X X X X X X X X 9 X X X X X X

12 X X X X X X X X X 15 X X X X X X 18 X X X X X X X 21 X X X X X X 24 X X X X X X X

Every 6 months until 5th year

X X X X X X

Annually until 5th year

X

1 Only for patients receiving chemotherapy

8.0 SUPPORTIVE CARE GUIDELINES These are provided for institutional consideration. Investigator discretion should be used, and individual considerations made for specific patient situations and institutional practices. 8.1 Pneumocystis Prophylaxis It is recommended that patients receiving chemotherapy receive trimethroprim/sulfamethoxazole. The schedule of b.i.d. dosing three days a week is recommended.

BSA (m2) Tablet* Liquid (mL)** < 0.3 - 2.5 0.3 – 0.79 ½ 5 0.8 – 1.39 1 10 1.4 – 1.89 1½ 15 > 1.89 2 20

* Single strength tablet (400 mg sulfamethoxazole / 80 mg trimethoprim) ** Suspension (200 mg sulfamethoxazole / 40 mg trimethoprim per 5 mL)

Patients with allergy to trimethroprim/sulfamethoxazole may be treated with dapsone or monthly pentamidine per investigator preference.

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8.2 Hormonal Replacement 8.2.1 Perioperative Management Patients with ACT usually require a steroid replacement. For those patients with localized disease, adrenal insufficiency is secondary to adrenal gland suppression by the hormone producing tumor. In these cases, adrenal insufficiency is temporary and the duration of hormone replacement required will vary. Patients should be followed by an endocrinologist. Guidelines for Corticoid Replacement Before and during surgery: Hydrocortisone 50 mg/m2 as a single injection 1hr before surgery, followed by 200 to 500 mg in D5W1/2NS as continuous infusion during surgery. After surgery: Initial corticoid replacement on Day 1 is hydrocortisone 60 mg/m2/day IV (divided in 4 doses/day). On Day 2 or 3 the dose is reduced to 40 mg/m2/day (divided in 4 doses/day) and it is then further decreased to 20 mg/m2/day. Those patients with Cushing’s syndrome at the time of diagnosis may have suppressed pituitary-adrenal axis, and the adrenal gland may fail to resume normal function. In these cases ACTH-stimulation is blunted and it is associated with elevated plasma ACTH-levels. Recovery of adrenal function is judged by plasma cortisol levels and periodic rapid ACTH testing. Some of these patients may require low dose hydrocortisone for some months after removal of the tumor. 8.2.2 Hormonal Replacement in Patients Receiving Mitotane Because mitotane is adrenolytic, all patients receiving this agent should be considered to have severe adrenal insufficiency. Adequate control of adrenal insufficiency increases mitotane tolerance. Sometimes nausea and vomiting are due to adrenal insufficiency and not due to mitotane. The cells in the zona fasciculata (which produce cortisol) are most affected, although the cells in the zona glomerulosa (which produce aldosterone) are also compromised. Corticoid replacement for patients on mitotane: One or two weeks after initiating mitotane it is necessary to start corticoid replacement: Prednisone 10-15 mg/m2/day (divided in 2 or 3 times a day) plus fludrocortisone 0.15 – 0.2 mg/day. Dexamethasone (2-3 mg/m2/day) can be used eventually to replace prednisone. In stress situations, prednisone may be increased to 30-45 mg/m2/day In addition to causing adrenal insufficiency, mitotane can also interfere with the metabolism of other hormones, including thyroid and parathyroid hormones. Thyroxine replacement may be necessary in these children. Another striking complication of mitotane is gynecomastia, which resolves after the medication is stopped. 8.3 Venous Access It is recommended that patients have a central line placed prior to starting chemotherapy.

8.4 Nutritional Management A very close monitoring of the nutritional status is necessary. Any patient with greater than 10% weight loss over pretreatment baseline should begin nutritional support. 8.5 Concomitant Medications Mitotane has been reported to accelerate the metabolism of warfarin by hepatic microsomal enzyme induction, leading to an increase in dosage requirement; therefore monitor such patients closely.

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9.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA

9.1 Criteria for Removal From Protocol Therapy

a) Progressive disease. b) Diagnosis of a second malignant neoplasm. c) Refusal of further protocol therapy by patient/parent/guardian. d) Completion of planned therapy. e) Physician determines it is in patient’s best interest.

Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below). Follow-up data will be required unless consent was withdrawn. 9.2 Off Study Criteria

a) Death. b) Lost to follow-up. c) Entry onto another COG therapeutic study. d) Withdrawal of consent for any further data submission. e) Tenth anniversary of study closure to accrual.

10.0 STATISTICAL CONSIDERATIONS 10.1 Statistical Design The study will be conducted as a single therapy trial with three strata. Stratum 1 consists of patients with Stage I tumors. Stratum 2 consists of patients with Stage II tumors. Stratum 3 consists of patients with Stage III or IV tumors. Stratum 1 and Stratum 2 patients will not receive any chemotherapy after surgical resection of the primary tumor. Stratum 3 patients will receive combination chemotherapy after surgical resection or biopsy.

10.2 Patient Accrual and Expected Duration of Trial We estimate the incidence of ACT in the United States in children 21 or less at diagnosis is estimated to be 27 cases annually. COG institutions recruit cases from Australia, New Zealand, Canada, The Netherlands and Switzerland as well as the United States. We consider the possibility of enrolling all patients in the United States unlikely. We estimate, therefore, the addition of cases from non-US sites will supplement this to provide 27 cases annually. The documentation provided by the sites in Brazil indicate approximately 20 cases are to be expected to be enrolled from those sites, providing for a maximum annual accrual of 47 patients per year for COG and the cooperating international institutions. Data provided by the St. Jude Children’s Research Hospital indicate the stage distribution of patients with adrenocortical carcinoma to be approximately: (1) Stage I – 35%; (2) Stage II – 35%; (3) Stage III – 15%; and (4) Stage IV – 15%. Most treatment failures will occur in the first two years following diagnosis. Patients will be enrolled for five years and the last patient enrolled will be followed for outcome for an additional two years. This is designated as the analytic point of the study for the descriptions in the next section. We estimate the distribution of patients by stage when the study closes to accrual to be: (1) Stratum 1 – 82 patients; (2) Stratum 2 – 82 patients; and (3) Stratum 3 - 71 patients.

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10.3 Statistical Analysis Methods Stratum 1: The background provided above indicates that 90% event-free survival can be obtained with surgery alone for disease of this extent. These data, however, were derived from a case series and not obtained in prospective setting in a cooperative group setting. Since Stratum 1 patients will have no further therapy after surgical intervention, we will determine whether the approach described from data derived from the IPACTR publication will yield equivalent results. We expect approximately 82 patients with Stage I disease to be enrolled in the proposed study. At the analytic point of the study, we will use the test statistic:

ln( ln( 2 )) ln( ln(0.90))

[ln( ln( 2 ))]Kaplan Meier Year EFS Estimate

Estimated SD Kaplan Meier Year EFS Estimate− − − − −

− − −

and compare this with a N(0,1) distribution. If this is +1.65 or greater (significant at the one-sided level of 0.10 or less) the therapy will be considered of insufficient efficacy. If the true 2-year EFS is 0.80, the probability the true regimen will be identified as of insufficient efficacy is approximately 0.90. Stratum 2: The background above indicates that 50% event-free survival can be obtained with surgery alone for disease of this extent. Since RPLND may be associated with significant surgical complications, we will recommend the approach proposed in the protocol with high probability only if the two-year EFS is consistent with 70%. We expect approximately 82 patients with Stage II disease to be enrolled in the proposed study. At the analytic endpoint of the study, we will use the test statistic:

ln( ln( 2 )) ln( ln(0.50))[ln( ln( 2 ))]

Kaplan Meier Year EFS EstimateEstimated SD Kaplan Meier Year EFS Estimate

− − − − −− − −

and compare this with a N(0,1) distribution. If this is -1.65 or less the therapy will be considered of sufficient efficacy to be considered the recommended approach for Stratum 2 patients; otherwise, the more aggressive surgery will not be considered to have provided significant benefit to be recommended. If the true 2-year EFS is 0.50, the probability the regimen will not be recommended as the new therapeutic guideline is approximately 0.95. If the true 2-year EFS is 0.7, the probability the regimen will be recommended as the new therapeutic guideline is approximately 0.98. Stratum 3: Patients staged as III or IV at diagnosis will receive combination chemotherapy, including cisplatin, doxorubicin, etoposide and mitotane. Little historical data are available for this group of patients, but it appears that with current approaches the long-term event-free survival for patients with either Stage III or IV disease is similar and is at most 15% at two years. We expect approximately 70 patients to be enrolled according to the study design described above. Since the proposed therapy may entail significant toxicity, we will recommend the approach proposed in the protocol with high probability only if the two-year EFS is consistent with 30%. At the analytic endpoint of the study, we will use the test statistic:

ln( ln( 2 )) ln( ln(0.15))

[ln( ln( 2 ))]Kaplan Meier Year EFS Estimate

Estimated SD Kaplan Meier Year EFS Estimate− − − − −

− − −

and compare this with a N(0,1) distribution. If this is -1.65 or less, the therapy will be considered of sufficient efficacy to be considered the recommended approach for Stage III or IV patients; otherwise, the aggressive chemotherapy will not be considered to have provided significant benefit to be recommended.

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If the true 2-year EFS is 0.15, the probability that the new regimen will not be recommended as the new therapeutic guideline is approximately 0.95. If the true 2-year EFS is 0.30, the probability that the new regimen will be recommended as the new therapeutic guideline is approximately 0.93. Interim Monitoring One year after the study has opened and at each successive DMC meeting, the study will be monitored to ensure that the outcome is consistent with the following target models:

Stage I: The model used for comparison will be an exponential model with a constant failure rate of 0.053 per year for the first two years and 0 after that. This corresponds to a model with 2-year failure probability of 0.10 with all failure observed during the first two years. Stage II: The model used for comparison will be an exponential model with a constant failure rate of 0.347 per year for the first two years and 0 after that. This corresponds to a model with 2-year failure probability of 0.50 with all failure observed during the first two years. Stage III or IV: The model used for comparison will be an exponential model with a constant failure rate of 0.602 per year for the first two years and 0 after that. This corresponds to a model with 2-year failure probability of 0.70 with all failure observed during the first two years.

The one-sample one-sided log-rank test comparing the observed data with the hypothesized model (Woolson, 1981) of size 0.05 will be used to assess whether the data are consistent with the target models.50 Since this test has independent increments, the method of Lan and DeMets will be used to derive the p-values for testing procedure. 51 Monitoring will take place after two years of enrollment when 24% of the expected information has been obtained, and annually after that time.

As an example, the following information times and nominal p-values for the stage III and IV analysis arise from this strategy:

Analysis Time (Years) Expected Information Time Value of Test Statistic

2 0.24 -2.76

3 0.44 -2.41

4 0.64 -2.15

5 0.84 -1.94

6 0.92 -1.91

7 1.0 -1.85 If the test statistic is smaller than the boundary value above, the study will be considered for closure. Because such a situation will indicate protocol therapy is superior to the historical baseline, the study may remain open to complete the evaluation of the secondary aims. At each time of interim monitoring, we will calculate the conditional probability that the test statistic will be less than the final monitoring boundary at the projected end of accrual and follow-up, given the true distribution of the data come from the target improvement, viz., 2-year EFS of 0.70 for patients in Stratum 2 or 2-year EFS of 0.30 for patients in Stratum 3. If the noted conditional probability is less than 0.10, the study will be considered for termination because there will be little chance of concluding that the protocol therapy is superior to historical outcome.

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The toxicities observed during protocol therapy for patients receiving chemotherapy will be summarized and presented for review by the DMC at every meeting. Monitoring for Toxicity Associated with Mitotane: All patients enrolled on protocol combination chemotherapy and who receive at least one cycle of therapy will be considered in the analysis for tolerability chemotherapy. Patients who have mitotane treatment stopped because of toxicity concerns will be considered to have experienced a toxicity-event. Patients who complete therapy or who are removed from protocol therapy for reasons not related to mitotane toxicity will be considered to have successfully tolerated treatment. If, at any time, 11 or more patients experience a toxicity-event, enrollment to the combination chemotherapy will be suspended and we will consider terminating further enrollment. If all 71 patients are evaluated and the true toxicity-event rate is 10%, the therapy will be considered tolerable with probability 0.91. If all 71 patients are evaluated and the true toxicity-event rate is 20%, the therapy will be considered tolerable with probability 0.13. Monitoring for Toxicity Associated with Chemotherapy: The study will be monitored to ensure the therapy can be delivered as planned (‘chemotherapy feasibility’). All eligible patients enrolled on protocol combination chemotherapy will be considered in the analysis for chemotherapy feasibility. Patients who have at least one agent of the combination stopped, regardless of reason, will be considered to have experienced a feasibility-event. Patients who complete therapy or who are removed from protocol therapy for reasons related to disease progression, second malignancy or death unrelated to protocol therapy will be considered to have successfully tolerated treatment. If, at any time, 19 or more patients experience a feasibility-event, enrollment to the combination chemotherapy will be suspended and we will consider terminating further enrollment. If all 71 patients are evaluated and the true feasibility-event rate is 20%, the therapy will be considered feasible with probability 0.90. If all 71 patients are evaluated and true feasibility-event rate is 35%, the therapy will be considered tolerable with probability 0.05. Determine the Feasibility and Complications Associated with Radical Adrenalectomy and Regional Lymph Node Dissection (RLND): All patients who have a RLND will be considered for the evaluation of this aim. Any patient who dies because of surgery or has a CTC Version 3 Grade 3 or 4 toxicity possibly, probably or likely related to surgery will be considered as having experienced a surgical complication. All patients who do not have such an event and who are followed for at least one month after surgery will be considered evaluable for the occurrence of complications. The complication rate will be estimated as the proportion of evaluable patients that have a complication. We expect all Stage II patients to have a RLND. We do not know how many Stage I patients will have a RLND. The evaluation rules for feasibility and their probabilistic characteristics as a function of the number of Stage I patients who have RLND, are given below.

Number of Stage II Patients

Number of Stage I Patients

with RLND

Total Largest Number with

Surgical Complications

For Which Conclusion is

RLND is Feasible

Probability Surgery is

Identified as Feasible if True Complication Rate is 10%

Probability Surgery is

Identified as Feasible if True Complication Rate is 20%

82 40 122 17 0.95 0.05 82 50 132 18 0.96 0.08 82 60 142 20 0.96 0.04 82 70 152 22 0.97 0.05

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Determine Prospectively the Frequency of Tumor Spillage and Lymph Node Involvement: All patients who undergo upfront surgery will be evaluated with respect to whether tumor spillage occurred. The percent of patients who have tumor spillage, and the associated 95% confidence interval, will be the indices of this outcome. Approximately 20% of patients in previous series were reported to have tumor spillage. The expected 95% confidence intervals as a function of the number of patients who have a RLND are given below: Number of Stage II

Patients Number of Stage I

Patients with RLND Total Expected 95% Confidence Interval if

the True Proportion of Patients with Tumor Spillage is 20%

82 40 122 13%-28% 82 50 132 14%-28% 82 60 142 14%-27% 82 70 152 15%-27%

Similar considerations apply for the determination of the proportion of patients with lymph node involvement. To Determine and Compare the Incidence and Type of Germline TP53 Mutations in Non-Brazilian Children and Children from Southern Brazil: Blood obtained prior to the start of chemotherapy will be used to determine the incidence and type of TP53 germline mutation (see Section 16). We project that, by the end of the study, we will have enrolled 135 non-Brazilian patients and 100 Brazilian patients. The proportion of patients in each subpopulation will be compared using the exact conditional test of proportions of size 0.05. The power of this test is dependent on the number of patients from whom blood can be obtained as well as the frequency of the relevant mutation in each group. The table gives some examples of the power of the proposed statistical tests as they relate to these factors.

Proportion of Patients Who Comply with

Protocol Specimen

Submission

Number – non-Brazilian Patients

Number – Brazilian Patients

Proportion of non-Brazilian Patients with

Factor Present

Proportion of Brazilian

Patients with Factor Present

Probability the Statistical Test Will Indicate a

Significant Difference Between

Subpopulations 100% 135 100 0.50 0.65 0.68 100% 135 100 0.50 0.70 0.85 100% 135 100 0.50 0.75 0.97 90% 121 90 0.50 0.65 0.53 90% 121 90 0.50 0.70 0.80 90% 121 90 0.50 0.75 0.95 80% 108 80 0.50 0.65 0.48 80% 108 80 0.50 0.70 0.75 80% 108 80 0.50 0.75 0.92

To Characterize Cooperating Molecular Alterations Associated With the Diagnosis of ACT and To Determine the Frequency of Embryonal Markers in Children with ACT: All patients for whom tumor is submitted will have that tissue evaluated for the presence of other genetic alterations and the presence of embryonal markers. These characteristics will be quantified by the proportion of patients who display the relevant marker divided by the total number of patients for whom this test is evaluable. The 95% confidence intervals for those proportions will also be calculated.

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10.4 Gender and Minority Accrual Estimates The gender and minority distribution of the study population is expected to be:

Accrual Targets

Sex/Gender Ethnic Category Females Males Total

Hispanic or Latino 23 15 38

Not Hispanic or Latino 119 78 197

Ethnic Category: Total of all subjects 142 93 235

Racial Category

American Indian or Alaskan Native 0 2 2

Asian 10 4 14

Black or African American 13 2 15

Native Hawaiian or other Pacific Islander 0 0 0

White 119 85 204

Racial Category: Total of all subjects 142 93 235

This distribution was derived from SEER incidence information. 11.0 EVALUATION CRITERIA 11.1 Common Terminology Criteria for Adverse Events v3.0 (CTCAE) This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and performance reporting. A copy of the current version of the CTCAE can be downloaded from the CTEP home page (http://ctep.info.nih.gov). Additionally, toxicities are to be reported on the appropriate data collection forms. 11.2 Response Criteria for Patients with Solid Tumors This study will use a modified version of the Response Evaluation Criteria in Solid Tumor (RECIST) from the NCI to evaluate disease response. The modifications will include volumetric measurement of the primary ACT and assessment of associated adenopathy. Measurable and non-measurable metastatic foci in the lungs, bones and liver will be evaluated as per RECIST. 11.2.1 Primary Tumor Measurement The primary tumor will be measured in the largest anterior-posterior, transverse and longitudinal dimensions and tumor volume will be estimated using the formula for an ellipsoid model: (AP X transverse X longitudinal) X 0.52.

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COG GUIDELINE: TUMOR SIZE MEASUREMENT

BASED ON CROSS-SECTIONAL IMAGING

• A, B, C. D, & E are contiguous parallel slices in the X-Y plane (usually axial) showing the tumor

• W and T are the maximal perpendicular diameters on the slice (C in this example) showing the largest surface area

• Tumor length in the Z-axis (L) (perpendicular to X-Y plane) can be obtained either by the [a] (difference in table position of the first and last slices showing the tumor + one slice thickness) or [b] the product of (slice thickness + gap) and the number of slices showing the tumor

11.2.1.1 Response of the Primary tumor: Complete Response (CR): Complete disappearance of the tumor confirmed at > 4 weeks. Partial Response (PR): At least 64% decrease in volume compared to the baseline. Progressive Disease (PD): At least 40% increase in tumor volume compared to the smallest measurement obtained since the beginning of therapy. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest disease measurement since the treatment started.

11.2.2 Measurable Metastatic Disease Target lesions: A lesion that can be accurately measured in at least one dimension with the longest diameter at least twice the thickness of the CT or MR slice (except lymph nodes, see below). The investigator will identify up to 10 measurable lesions total and up to 5 per organ to be followed for response. Lymph nodes will be included in target lesion measurements and the lymphatic system considered an organ system i.e. up to five enlarged nodes will be recorded. Any lymph node measuring ≥ 1.0 cm will be considered a target lesion regardless of CT or MR slice thickness. Therefore, target lesions will include pulmonary nodules, liver lesions and lymph nodes. If there are more than ten total target lesions, then those that are the most easily measured and amenable to reliable, reproducible, follow-up measurement should be chosen. Serial measurements of lesions are to be done with CT or MRI. The same method of assessment is to be used to characterize each identified and reported lesion at baseline and during follow-up. 11.2.3 Response of Target Metastatic Lesions Complete Response (CR): Disappearance of all target lesions. If immunocytology is available, no disease must be detected by that methodology. Partial Response (PR): At least a 30% decrease in the sum of the longest diameters of all target lesions, taking as reference the disease measurement done to confirm measurable disease at study entry.

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Progressive Disease (PD): At least a 20% increase in the sum of the longest diameters of all target lesions, taking as reference the smallest disease measurement recorded since the start of treatment, or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest disease measurement since the treatment started. 11.2.4 Non-measurable Metastatic Disease Non-target lesions: Includes all lesions that do not qualify as target lesions (all lesions < twice the slice thickness and truly non-measurable disease such as bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, lymphangitis cutis/pilmonis, abdominal masses not confirmed by biopsy and cystic lesions). These lesions should be noted and recorded and response indicated as improved, no change or worse. 11.2.5 Overall Response Assessment The overall response assessment takes into account response in the primary tumor, target and non-target lesions, and the appearance of new lesions, where applicable, according to the criteria described in the table below. The overall response assessment is shown in the last column, and depends on the assessments of the primary tumor, target, non-target, and new lesions in the preceding columns.

Primary Tumor

Metastatic Target lesions

Metastatic Non-Target Lesions

New Lesions

Overall Response

CR CR CR No CR CR PR/SD Non-PD No PR PR PR/SD Non-PD No PR SD Non-PD Non-PD No SD PD Any Any Any PD Any PD Any Any PD Any Any PD Any PD Any Any Any Yes PD

Two objective status determinations of CR before progression are required for best response of CR. Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. Two determinations of stable/no response or better before progression, but not qualifying as CR or PR, are required for a best response of stable/no response; if the first objective status is unknown, only one such determination is required. Patients with an objective status of progression on or before the second evaluations (the first evaluation is the first radiographic evaluation after treatment has been administered) will have a best response of increasing disease. Best response is unknown if the patient does not qualify for a best response of increasing disease and if all objective statuses after the first determination and before progression are unknown. 12.0 ADVERSE EVENT REPORTING REQUIREMENTS 12.1 Purpose Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents.

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12.2 Determination of Reporting Requirements Reporting requirements may include the following considerations: 1) the characteristics of the adverse event including the grade (severity); 2) the relationship to the study therapy (attribution); and 3) the prior experience (expectedness) of the adverse event. Commercial agents are those agents not provided under an IND but obtained instead from a commercial source. In some cases an agent obtained commercially may be used for indications not included in the package label. In addition, NCI may on some occasions distribute commercial supplies for a trial. Even in these cases, the agent is still considered to be a commercial agent and the procedures described below should be followed. Determine the prior experience Expected events are those that have been previously identified as resulting from administration of the agent. An adverse event is considered unexpected, for reporting purposes only, when either the type of event or the severity of the event is not listed in:

• the current NCI Agent-Specific Adverse Event List (provided in the Drug Information

Section of this protocol); or • the drug package insert (for treatments with commercially available agents).

12.3 Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway Commercial reporting requirements are provided in Table B. The commercial agent(s) used in this study are listed in the Drug Information Section of this protocol.

• COG requires the AdEERS report to be submitted within 5 calendar days of learning of the event.

• Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all reports.

Table B Reporting requirements for adverse events experienced by patients on study who have NOT received any doses of an investigational agent on this study. AdEERS Reporting Requirements for Adverse Events That Occur During Therapy With a Commercial Agent or Within 30 Days1

Attribution Grade 4 Grade 5 Unexpected Expected Unrelated or Unlikely

AdEERS

Possible, Probable, Definite

AdEERS AdEERS

1This includes all deaths within 30 days of the last dose of treatment with a commercial agent, regardless of attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial agent which can be attributed (possibly, probably, or definitely) to the agent and is not due to cancer recurrence must be reported via AdEERS.

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12.4 Reporting of Adverse Events Related to the Surgical Procedures Surgery is a primary component of the treatment of ACT, and adverse events secondary to the surgical procedures may occur. 12.4.1 Retroperitoneal Lymph Node Dissection (RPLND) RPLND is usually a very safe procedure. Complications of this procedure have been described in approximately 10% of patients, and include superficial wound infection (4.8%), small bowel obstruction (2.3%), loss of antegrade ejaculation (2%), lymphocele (< 1%), pancreatitis (< 1%), rectus sheath hematoma (< 1%), and ventral hernia (< 1%). 52

12.4.2 Resection of Primary ACT Tumor ACT are usually locally aggressive, and a curative procedure usually requires the resection of adjacent structures. The complications of this procedure have been reviewed recently. 53,54 Structures which may need to be concurrently resected at the time of surgery (41.5% of patients) and would have their respective associated complications, include the following: nephrectomy (29%), splenectomy (10%), partial hepatectomy (7.5%), partial pancreatectomy (3.6%), and less frequently cholecystectomy and diaphragmatic resection. Other complications include damage to the inferior vena cava, intraoperative spillage, wound dehiscence, and wound infection. 12.5 Reporting Secondary AML/MDS All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that occur in patients on NCI-sponsored trials following their chemotherapy for cancer must be reported to the Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation Program (CTEP) and included as part of the second malignant neoplasm reporting requirements for this protocol. Submit the following information within two weeks of an AML/MDS diagnosis occurring after treatment for cancer on NCI-sponsored trials:

• a completed NCI/CTEP Secondary AML/MDS Report Form (see http://ctep.cancer.gov/forms/index.html) do not use AdEERS; • a copy of the pathology report confirming the AML/MDS; and • a copy of the cytogenetics report (if available).

Submit the information via fax to: NCI (fax # 301-230-0159) and COG (fax # 626-445-6715; attention AE Coordinator) Note: If a patient has been enrolled in more than one NCI-sponsored study, the NCI/CTEP Secondary AML/MDS Report Form must be submitted for the most recent trial. The COG must also be provided with a copy of the report even if the study was not the patient’s most recent trial.

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13.0 RECORDS AND REPORTING 13.1 Categories of Research Records Research records for this study can be divided into three categories: 1. Non-computerized Information: Pathology Narrative Reports, Surgical Reports. These forms are

faxed to the Statistics and Data Center at (626) 445-4334. 2. Reference Labs’ required reports, and QARC data: These data accompany submissions to these

centers, which forward their review data electronically to the COG Statistics and Data Center. 3. Computerized Information Electronically Submitted: All other computerized data will be entered

in the COG Remote Data Entry System with the aid of schedules and worksheets (essentially paper copies of the RDE screens) provided in the data form packet.

See separate Data Form Packet posted on the COG web site, which includes submission schedule. 13.2 CDUS This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 31. This is not a responsibility of institutions participating in this trial. 14.0 SURGICAL GUIDELINES 14.1 Rationale for surgery The rationale and timing for surgery is based upon the stage of the disease. As noted in Appendix II, Stage I disease will be determined by a volume of tumor which is less than 200 cm3 (and < 100 g) and is completely resectable. Stage II patients will have a tumor volume equal to or more than 200 cm3 (or ≥ 100 g). The Stage I and II patients will undergo surgical resection upfront without need for pre-operative biopsy. Stage III patients will have inoperable tumors or have gross or microscopic residual disease (including tumor spillage) after an attempted upfront resection. Stage IV patients will have distant metastases. In those cases where the patients with Stage III disease did not undergo attempted resection and in cases where the Stage IV patients are identified, the diagnosis will be confirmed by biopsy of the primary tumor or metastasis (percutaneous or open routes as indicated). 14.2 Pre-operative Management It is important that once the diagnosis of an ACT is suspected that optimal imaging be obtained including ultrasound, CT scan and MRI as needed to precisely determine the resectability of the tumor. These tumors tend to invade adjacent structures, particularly the inferior vena cava. The involvement of the inferior vena cava can include the development of intravascular tumor thrombus, a relative contraindication to upfront surgical resection. As almost all ACT’s will be hormonally active with virilizing hormones and/or hypercortisolism, appropriate pre-operative steroids should be administered to avoid intra-operative adrenal insufficiency. In addition, a significant proportion of patients will also have severe hypertension, and should have their blood pressure aggressively treated pre-operatively to avoid intra-operative hypertensive crises and anesthetically-related blood pressure liability.

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14.3 Operative Management The operative management will be dictated by the treatment plan (see Section 4.1). It is strongly recommended that these cases be presented at a surgical tumor board or treatment planning conference prior to surgery. If a surgeon is unfamiliar with the requirements of lymph node dissection appropriate arrangements for intraoperative collaboration with a more experienced colleague should be obtained preoperatively. 14.3.1 Surgical Exposure As ACTs are generally friable, rupture easily and tend to invade adjacent structures, it is imperative that surgical exposure be optimized, maximizing the margin of intra-operative safety and optimizing the opportunity for a complete resection. To accomplish this, it is recommended that a thoracoabdominal approach be utilized. This is best accomplished by a seventh or eighth intercostal space incision extending onto the abdomen along the lateral edge of the abdominus rectus muscle on the ipsilateral side. The diaphragm is divided radially and the viscera are reflected medially.55 In certain circumstances, a median sternotomy with bilateral subcostal incisions (a “Mercedes-Benz” incision) may be indicated in the presence of obvious inferior vena caval involvement with either direct vessel wall involvement and/or documented intravascular tumor thrombus on imaging (see “Management of adjacent structures” below). Appropriate, preoperative consultation with other services (i.e. cardiothoracic surgery) is essential. 14.3.2 Management of Adjacent Structures If a complete surgical resection is feasible, all adjacent involved structures should be partially or completely resected (as indicated), including the ipsilateral kidney, the liver, pancreas, spleen and intestine. Good surgical judgment needs to be used to prevent the unnecessary resection of structures when a complete resection cannot be realistically accomplished, possibly leading to a prolonged period of post-operative convalescence and post-operative complications - such issues would also delay the initiation of chemotherapy. In addition, where feasible such involved structures may be able to be partially resected, preserving some organ function. In cases where the inferior vena cava is involved and there is no or little intravascular tumor thrombus, an attempt should be made to resect the involved vena cava with complete vascular isolation of the liver and adjacent organs as needed. 14.3.3 Lymph Node Dissection An ipsilateral retroperitoneal lymph node dissection (RPLND) is required in all Stage II patients and required in all Stage III and IV patients who are deemed resectable. Please see Appendix III for guideline diagrams for RPLND. The anatomical boundaries of the lymph node dissection are based upon the lymphatic drainage of the adrenal glands and indirectly upon the glands’ blood supplies. Lymph node involvement in adrenocortical carcinoma is stepwise and loco-regional lymph node dissection should identify any metastatic deposits. 1. Right-sided RPLND: The dissection will include the infra-renal lymph nodes beginning at the

level of the caval bifurcation. It will extend superiorly to include the perihilar lymph nodes of the right kidney and the suprarenal lymph nodes, ending at the insertion of the right hemidiaphram. In addition, it will extend medially to include the lymph nodes between the inferior vena cava and aorta at the infra-renal and supra-renal levels.

2. Left-sided RPLND: The dissection will include the infra-renal lymph nodes beginning at the level

of the aortic bifurcation. It will extend superiorly to include the perihilar lymph nodes of the left kidney and the suprarenal lymph nodes, ending at the insertion of the left hemidiaphram. In addition, it will extend medially to include the lymph nodes between the inferior vena cava and aorta at the infra-renal and supra renal levels.

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14.3.4 Overview 1 Stage I: Patients will undergo an upfront resection of the primary tumor with ipsilateral

retroperitoneal lymph node sampling. In cases where an ipsilateral lymph node sampling was not performed at the time of the initial surgery, a second laparotomy is not indicated.

2. Stage II: Patients will undergo an upfront resection of the primary tumor with ipsilateral RPLND. In cases where an ipsilateral RPLND was not performed, a second-look laparotomy with ipsilateral RPLND must be performed.

3. Stage III: Patients may have undergone an attempted upfront resection with residual gross tumor left behind or been designated as unresectable. A biopsy of the tumor will be obtained as needed (percutaneous or open routes as indicated). Patients will be considered for surgery any time after the second cycle of chemotherapy. If feasible, an attempted resection (or re-resection) of the primary tumor with ipsilateral RPLND should be undertaken after 2-4 cycles of chemotherapy. Thereafter, 4-6 more cycles of chemotherapy will be given to complete a total of 8 cycles of chemotherapy. Mitotane will be given alone for up to a further 2 months in order to complete a total of 8 months of mitotane therapy.

4. Stage IV: Patients with metastatic disease will undergo resection of the primary with ipsilateral RPLND and resection of metastases, where feasible. Patients will be considered for surgery any time after the second cycle of chemotherapy. If indicated and feasible, an attempted resection (or re-resection) of the primary tumor with ipsilateral RPLND and resection of metastases should be undertaken after 2-4 cycles of chemotherapy. Thereafter, 4-6 more cycles will be given to complete a total of 8 cycles of chemotherapy. Mitotane will be given alone for up to a further 2 months in order to complete a total of 8 months of mitotane therapy. Following chemotherapy, the patient will be reimaged to assess for resectability of the primary lesion and metastases. If indicated and feasible, an attempted resection (or re-resection) of the primary tumor with ipsilateral RPLND and resection of metastases should be undertaken.

14.4 Post-operative Management It should be anticipated that there will be a period of adrenal insufficiency following resection of the primary tumor. Stress doses of hydrocortisone should be administered in the post-operative period. These doses can be tapered over several weeks. An ACTH-stimulation test can be performed to determine the appropriate timing of the cessation of steroid replacement therapy56 (see Section 8.2.1). 15.0 PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 15.1 Pathology Guidelines for Diagnosis As discussed above (see Section 2.3), the criteria for malignancy include a combination of histologic characteristics, including the mitotic index, the presence of confluent necrosis and atypical mitoses, the nuclear grade, local invasiveness and tumor weight, as previously defined by Weiss21,23 and the AFIP.25 Immunocytochemical staining for p53 and mib-1 (Ki-67) will be performed. Expression of p53 and increased mib-1 labeling have been associated with recurrence and aggressive behavior. Mib-1 labeling index will be determined for the tumors (low index > 5% of cells, intermediate index 5-15% of cells, and high index > 15% of cells). Correlation with proliferative index from DNA ploidy analysis will also be performed. Once the diagnosis of adrenocortical carcinoma along with AFIP criteria assessment and exclusion of any other diagnosis has been made, the patient will be eligible for the study.

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15.2 Pathology Review Requirements 15.2.1 Central Review Central pathology review is required on this study. The aim of the central pathology review is to: 1) provide confirmation of the originating institutional diagnosis; 2) provide systematic staging and risk assessment of the tumor; 3) ensure accuracy and fidelity of the data; 4) generate tissue arrays for future studies (see below). All patients enrolling on this protocol require Central Review of their diagnostic tissue. However, treatment assignment will occur at study entry based on institutional pathology. If immediate consultation is desired please contact the Study Pathologist, Dr. John Hicks. 15.2.2 Required Material Please send the following required material within 4 weeks of enrollment on study, or soon thereafter:

1) 3 H&E slides from each tissue block submitted on the entire case, including lymph nodes, vessel biopsies, distant organ biopsies and periadrenal tissues.

2) At least 1 representative formalin-fixed paraffin-embedded tissue block from both the primary tumor and metastatic sites.

3) 20 unstained slides, on coated slides for immunocytochemical studies, from 3 representative tissue blocks from the primary tumor site and 20 slides from all tissue blocks from metastatic sites, also coated for immunocytochemistry.

4) Institutional Surgical Pathology report. 5) Transmittal Form.

15.2.3 Recommended Material 1) Cytogenetic analysis is encouraged and should be performed by the originating institution and results, when available, forwarded to COG Biopathology Center. 2) DNA ploidy flow cytometry is encouraged and should be performed by the originating institution and the results, when available, should be forwarded to COG Biopathology Center.

15.2.4 Specimen Shipping Label pathology review materials with the patient’s COG patient ID number and the surgical pathology ID (SPID) number from the corresponding pathology report. Material must be sent by OVERNIGHT carrier for next day delivery. If material is sent by Federal Express use account 2504-6481-9. Send all pathology central review materials to:

Biopathology Center Attention: ARAR0332 Children’s Hospital of Columbus 700 Children’s Drive, WA 1340 Columbus, OH 43205 Phone: (614) 722-2810 Fax: (614) 722-2897

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16.0 SPECIAL STUDIES SPECIMEN REQUIREMENTS 16.1 Specimen Submission To facilitate collection of biologic samples, the Biopathology Center (BPC) will provide a Specimen Procurement Kit. The kit allows both frozen and ambient temperature specimens to be sent in a single shipment. The kit provides foil for the frozen tissue, instructions, packaging materials, a pre-printed Federal Express air bill and required biohazard and dry-ice labels. For further information, or to obtain a kit please contact the BPC at (800) 347-2486. A completed copy of the COG Specimen Transmittal Form must be sent with every shipment of specimens. 16.2 Specimens Requested for Biologic Studies Patient Blood At diagnosis a blood sample will be drawn from every patient that provides consent. Each sample will consist of 5 ml of whole blood, drawn in an EDTA tube. Label tubes with patient’s BPC number, collection date and the specimen type. Specimens will be shipped on the day of collection at room temperature by overnight mail to the BPC. If blood can not be shipped on the day of collection, store at 4° C (refrigerator) and ship on the next business day. Personnel at The Hospital for Sick Children will process specimens for the preparation of genomic DNA using a commercially available kit (e.g., Gentra Pure Gene Whole Blood DNA kit) according to the manufacturer’s recommendation. DNA will be stored at 4oC. Samples will be screened for genetic alterations by DNA sequencing and Affymetrix Gene Chip analysis. If consent has been obtained DNA samples will be banked for future use. Frozen Tissue at diagnosis 10-15 grams of non-sterile tumor should be frozen as soon as possible after surgery. Wrap specimen in aluminum foil, freeze in liquid nitrogen or isopentane and then place in the plastic zip-lock bag provided in the Specimen Procurement Kit. Write the patient’s BPC number, collection date and the specimen type on the outside of the bag. Store at – 70oC until shipped. Personnel at St. Jude Children’s Research Hospital will process specimens for the preparation of genomic DNA and total cellular RNA by established protocols and commercially available kits (e.g., Qiagen RNeasy Midi Kit). Samples will be analyzed by DNA sequencing and Affymetrix Gene Chip analysis. If available, additional tissue not used for diagnostic purposes at originating institution should be equally divided between formalin-fixation and cryopreservation at -70oC. This tissue will be banked for future research if consent has been obtained. Representative primary and metastatic tumor tissue should be prepared as follows:

1) Fix primary and metastatic tissue with 10% buffered formalin. Submit either fixed tissue or a representative formalin-fixed paraffin-embedded tissue block from primary and metastatic tumor to the COG Biopathology Center (BPC). Tissue sections from formalin-fixed paraffin-embedded tissue block should be 3-5µm in thickness and placed on coated slides for immunocytochemical study. 2) Snap freeze tissue from primary tumor site and all metastatic sites and store at -70oC. Submit representative tissue to the BPC.

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Tissue Microarrays In order to facilitate future study of ACT, a tissue microarray will be generated. Tissue microarrays of the tumor samples will be prepared using formalin-fixed paraffin-embedded tissue blocks of the biopsy material and a tissue arrayer (Beecher Instruments, Silver Spring, MD). One hematoxylin and eosin (H&E)-stained section will be obtained from each tumor sample block (“donor” block). After microscopic examination by a pathologist the area/areas of the section to be sampled for the tissue microarray will be outlined with a permanent slide marker. Subsequently, 2 to 3 1 mm tissue cores will be removed from each tumor sample block from areas corresponding to those areas outlined on the H&E-stained sections. These cores will be embedded into a single “recipient” paraffin block. Samples from each tumor will be embedded at distance from each other, to compensate for variability in staining that may occur across the histologic sections obtained from the recipient block. Each recipient block prepared in the laboratory includes approximately 25-30 tissue cores (i.e. approximately 10-15 tumor samples). For smaller samples, the method may be adapted by using fewer or smaller (0.6 mm) cores. Histologic sections, 3-5 µm in thickness, will then be obtained from the final recipient blocks. 16.3 Specimen Shipping Biology specimens are shipped to the BPC in a dual-chambered Specimen Procurement Kit. The Specimen Procurement Kit is constructed to allow shipment of frozen (on dry ice) and ambient (room temperature) specimens in the same container. Dry ice may be placed in either compartment of the kit, but should not be put in both. 1. Before specimens are placed into the Specimen Procurement Kit, they first need to be placed in three

separate layers of packaging. Package the frozen tissue and the blood separately since they will be placed in separate compartments of the kit. a. The specimens should all be stored in individual zip lock bags (keep frozen and room temperature

specimens separate). b. Place the zip lock bags in the plastic watertight biohazard diagnostic envelope along with the

absorbent material (both are provided in the kit) and seal the envelope securely. c. Place the clear plastic biohazard diagnostic envelope inside the pressure-proof Tyvek diagnostic

envelope (also provided in the kit) and seal securely. 2. Snap frozen tissue should be placed in one of the kit compartments filled with dry ice. Layer the

bottom of the compartment with dry ice until it is approximately one-third full. Place the frozen specimens on top of the dry ice. Cover the specimens with the dry ice until the compartment is almost completely full. Place the Styrofoam lid on top to secure specimens during shipment.

3. Blood should be shipped in the other kit compartment at room temperature. Remember to replace the Styrofoam lid on top of the kit compartment to secure specimens during shipment.

4. Place the transmittal form into the plastic bag that contained the kit instructions. Place the bag in the space between the Styrofoam container and the cardboard shipping box.

5. Close the outer lid of the Specimen Procurement Box and seal it with filament or other durable sealing tape.

6. Complete the pre-printed Federal Express air-bill and insert it into the plastic pouch. Attach the pouch to the top of the kit. Complete the dry ice label (UN 1845) and stick this label and the Biohazard label to the side of the box.

Specimens should be shipped to the BPC via Federal Express Priority Overnight using the account number on the pre-printed air-bill (1290-2562-0). Arrange for Federal Express pick-up per your usual institutional procedure or by calling 1-800-238-5355. When requesting pick-up, be sure to give the appropriate FedEx account number, but stress that pick-up is at your institutional address. The Specimen Procurement Kit may be shipped to the BPC on Monday-Thursday for Tuesday-Friday delivery. Saturday delivery is not available.

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Biopathology Center Address: Biopathology Center Attention: ARAR0332 Children’s Hospital of Columbus 700 Children’s Drive, WA 1340 Columbus, OH 43205 Phone: (614) 722-2810 Fax: (614) 722-2897

17.0 IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 17.1 Timing of Imaging Studies:

Study to be obtained Pre-study After Cycle 2, 4, and 61

End of therapy

Follow-up At Recurrence

MRI abdomen X X X X CT chest X X X X Bone Scan X X2 X

See Section 7.4

X 1 For patients receiving chemotherapy 2 If positive at diagnosis 17.2 Imaging of the Primary Tumor MR imaging of the abdomen must include non-enhanced coronal T1W and STIR and axial fat-saturated T2 weighted images of the primary tumor. All coronal images should be obtained with a field of view that includes the area from the diaphragms to the symphysis pubis. Post contrast imaging should include axial T1W images and either sagittal or coronal T1W images depending on which plane best demonstrated the tumor on the pre-contrast imaging. The area covered on the post contrast axial imaging should be determined by reviewing the pre-contrast imaging and including all suspected abnormal areas. The slice thickness should be 4.0 or 5.0 mm with no skip between slices. 17.3 Imaging of Metastatic Disease 17.3.1 Chest CT of the chest must be performed with IV contrast in order to evaluate for possible supraclavicular or mediastinal adenopathy. It is strongly recommended that imaging be obtained in the bone algorithm which incorporates edge-enhancement and improves the visibility of pulmonary nodules. Imaging must be performed utilizing a 5 mm slice thickness regardless of the type of scanner used (helical vs. non-helical) for all patients weighing more than 9.4 kg. Slice thickness for patients weighing ≤ 9.4 kg should be no more than 3.75 mm. Images must be reviewed in both the mediastinal and lung windows. 17.3.2 Bone disease Single phase nuclear bone scanning must be performed using Technetium 99 labelled methyl-diphosphonate. Whole body planar imaging should be performed within 2 to 3 hours after the injection and should include anterior and posterior images of the entire skeleton including the digits of the hands and feet. 17.4 Submitting Imaging for Central Review The imaging review will be performed as a retrospective review. Therefore, the data may be batched and must be submitted within 30 days of completion of therapy.

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Submission of Diagnostic Imaging data in digital format is preferred over hard copies of films. Digital files must be in DiCom format. These files can be burned to a CD and mailed to QARC. Multiple studies for the same patient may be submitted on one CD; however, please submit only one patient per CD. Institutions with PACS systems can contact QARC regarding installation of the COG DiCommunicator software that manages e-mailing studies securely to QARC. Contact [email protected] for further information. Imaging studies for central review should be sent to:

Quality Assurance Review Center 272 West Exchange Street, Suite 101 Providence, Rhode Island 02903-1025 Phone: (401) 454-4301 Fax: (401) 454-4683

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REFERENCES

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2. Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72:3145-55, 1993

3. DiGiammarino EL, Lee AS, Cadwell C, et al: A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9:12-6, 2001

4. Ribeiro RC, Sandrini F, Figueiredo B, et al: An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98:9330-5, 2001

5. Wajchenberg BL, Pereira MAA, Medonca BB, et al: Adrenocortical carcinoma: clinical and laboratory observations. Cancer 88:711-36, 2000

6. Wagner J, Portwine C, Rabin K, et al: High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86:1707-1710, 1994

7. Reincke M, Karl M, Travis WH, et al: p53 mutations in human adrenocortical neoplasms: Immunohistochemical and molecular studies. J Clin Endocrinol Metab 78:790-4, 1994

8. Kirschner LS: Signaling pathways in adrenocortical cancer. Ann NY Acad Sci 968:222-239, 2002 9. Dohna M, Reincke M, Mincheva A, et al: Adrenocortical carcinoma is characterized by a high

frequency of chromosomal gains and high-level amplifications. Genes Chromosomes Cancer 28:145-152, 2000

10. Figueiredo BC, Stratakis CA, Sandrini R, et al: Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab 84:1116-1121, 1999

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12. Kendrick ML, Lloyd R, Erickson L, et al: Adrenocortical carcinoma: Surgical progress or status quo? Arch Surg 136:543-9, 2001

13. Schulick RD, Brennan MF: Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol 6:719-26, 1999

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15. Crucitti F, Bellantone R, Ferrante A, et al: the Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119:161-70, 1996

16. Icard P, Chapuis Y, Andreassian B, et al: Adrenocortical carcinoma in surgically treated patents: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112:972-9, 1992

17. Ribeiro RC, Sandrini Neto R, Schell MJ, et al: Adrenocortical carcinoma in children: A study of 40 cases. J Clin Oncol 8:67-74, 1990

18. Ciftci AO, Senocak ME, Tanyel FC, et al: Adrenocortical tumors in children. J Pediatr Surg 36:549-54, 2001

19. Driver CP, Birch J, Gough DCS, et al: Adrenal cortical tumors in childhood. Pediatr Hematol Oncol 15:527-32, 1998

20. Stojadinovic A, Ghossein RA, Hoos A, et al: Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20:941-50, 2002

21. Weiss LM: Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8:163-9, 1984

22. Slooten HV, Schaberg A, Smeenk D, et al: Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55:766-73, 1985

23. Weiss LM, Medeiros LJ, Vickery AL: Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13:202-6, 1989

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24. Harrison LE, Gaudin PB, Brennan MF: Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection. Arch Surg 134:181-5, 1999

25. Wieneke JA, Thompson LDR, Heffess CS: Adrenal cortical neoplasms in the pediatric population: A clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27:867-881, 2003

26. Sandrini R, Ribeiro RC, DeLacerda L: Childhood adrenocortical tumors. J Clin Endocrinol Metab 7:2027-2031, 1997

27. Bugg MF, Ribeiro RC, Roberson PK, et al: Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. Am J Clin Pathol 101:625-9, 1994

28. Michalkiewicz E, Sandrini R, Figueiredo B, et al: Clinical and outcome characteristics of children with adrenocortical tumors. An analysis of 254 cases from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 22:838-845, 2004

29. Michalkiewicz EL, Sandrini R, Bugg MF, et al: Clinical characteristics of small functioning adrenocortical tumors in children. Med Pediatr Oncol 28:175-8, 1997

30. Haak HR, Hermans J, van de Velde CJ, et al: Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 69:947-51, 1994

31. Bellantone R, Ferrante A, Boscherini M, et al: Role of reoperation in recurrence of adrenal cortical carcinoma: Results from 188 cases collected in the Italian national registry for adrenal cortical carcinoma. Surgery 122:1212-8, 1997

32. Lee JE, Berger DH, el-Naggar AK, et al: Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118:1090-8, 1995

33. Van Slooten H, Moolenaar AJ, Van Seters AP, et al: The treatment of adrenocortical carcinoma with o,p' -DDD: Prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol 20:47-53, 1984

34. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71:3119-23, 1993

35. Coelho Netto AS, Wajchenberg BL, Ravaglia C, et al: Treatment of adrenocortical cancer with mitotane (o,p' -DDD). Ann Intern Med 59:74-8, 1963

36. Fisher DA, Panos TC, Melby JC: Therapy of adrenocortical cancer with mitotane (o-p' -DDD) in two children. J Clin Endocrinol Metab 23:218-21, 1963

37. Ostuni JA, Roginsky MS: Metastatic adrenal cortical carcinoma: documented cure with combined chemotherapy. Arch Intern Med 135:1257-8, 1975

38. Dickstein G, Shechner C, Arad E, et al: Is there a role for low doses of mitotane (o,p' -DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 83:3100-3, 1998

39. Chun HG, Yogoda A, Kemeny N: Cisplatinum for adrenal cortical carcinoma. Cancer Treat Rep 76:513-4, 1983

40. Terzolo M, Pia A, Berruti A, et al: Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer. J Clin Endocrinol Metab 85:2234-8, 2000

41. Moolenar AJ, van Slooten H, van Seters AP, et al: Blood levels of o,p’-DDD following administration in various vehicles after a single dose and during long-term treatment. Cancer Chemother Pharmacol 7:51-54, 1981

42. Watson AD, Rijnberk A, Moolenaar AJ: Systemic availability of o,p’-DDD in normal dogs, fasted and fed, and in dogs with hyperadrenocorticism. Res Vet Sci 43:160-165, 1987

43. Van Slooten H, Van Oosterom AT: CAP (cyclophosphamide, doxorubicin and cisplatinum) regimen in adrenal cortical carcinoma. Cancer Treat Rep 67:377-9, 1983

44. Schlumberger M, Brugieres L, Gicquel C, et al: Fluorouracil, doxorubicin and cisplatin as treatment for adrenal cortical carcinoma. Cancer 67:2997-3000, 1991

45. Williamson SK, Lew D, Miller GJ, et al: Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma. Cancer 88:1159-65, 2000

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46. Bates SE, Shieh CY, Mickley LA, et al: Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (MDR-1/P-Glycoprotein) which is also expressed by adrenocortical carcinoma. J Clin Endocrinol Metab 73:18-29, 1991

47. Bonacci R, Gigliotti A, Baudin E, et al: Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma. Br J Cancer 78:546-9, 1998

48. Berruti A, Terzolo M, Pia A, et al: Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Cancer 83:2194-200, 1998

49. Cushing B, Giller R, Cullen JW, et al: Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: A Pediatric Intergroup Study – Pediatric Oncology Group 9049 and Children’s Cancer Group 8882. J Clin Oncol 22:2691-2700, 2004

50. Woolson RF: Rank Tests and one-sample logrank test for comparing observed survival data to a standard population. Biometrics 37:687-696, 1981

51. Lan KKG and DeMets DL: Group Sequential procedures: calendar versus information time. Stat Med 8: 1191-1198, 1989.

52. Baniel J, Foster RS, Rowland RG, et al: Complications of primary retroperitoneal lymph node dissection. J Urol 152:242-247, 1994

53. Icard P, Goudet P, Charpenay C, et al: Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 25:891-897, 2001

54. Meyer A, Niemann U, Behrend M: Experience with surgical treatment of adrenal cortical carcinoma. Eur J Surg Oncol 30:444-449, 2004

55. Tsuchida Y, La Quaglia MP: Surgery for neuroblastoma. In: Neuroblastoma (Brodeur GM, Sawada T, Tsuchida Y, and Voute RA, eds.), 497-517, Elsevier Science, The Netherlands: 2000

56. Doski JJ, Robertson FM, Cheu HV: Endocrine tumours. In: Pediatric Surgical Oncology (Andrassy RJ, ed.), WB Saunders Company, Philadelphia:365-403, 1998

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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES Performance Status Criteria Karnofsky and Lansky performance scores are intended to be multiples of 10

ECOG (Zubrod) Karnofsky Lansky*

Score Description Score Description Score Description

100 Normal, no complaints, no evidence of disease

100 Fully active, normal.

0 Fully active, able to carry on all pre-disease performance without restriction. 90 Able to carry on normal

activity, minor signs or symptoms of disease.

90 Minor restrictions in physically strenuous activity.

80 Normal activity with effort; some signs or symptoms of disease.

80 Active, but tires more quickly

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.

70 Cares for self, unable to carry on normal activity or do active work.

70 Both greater restriction of and less time spent in play activity.

60 Required occasional assistance but is able to care for most of his/her needs.

60 Up and around, but minimal active play; keeps busy with quieter activities.

2

Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

50 Requires considerable assistance and frequent medical care.

50 Gets dressed, but lies around much of the day; no active play, able to participate in all quiet play and activities.

40 Disabled, requires special care and assistance.

40 Mostly in bed; participates in quiet activities.

3

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.

30 Severely disabled, hospitalization indicated. Death not imminent.

30 In bed; needs assistance even for quiet play.

20 Very sick, hospitalization indicated. Death not imminent.

20 Often sleeping; play entirely limited to very passive activities.

4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 10 Moribund, fatal processes

progressing rapidly. 10 No play; does not get out of bed.

*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.

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APPENDIX II: STAGING SYSTEM OF ADRENOCORTICAL TUMORS

• STAGE I – o Completely resected, small tumors (< 100 g and < 200 cm3) with normal post-

operative hormone levels • STAGE II –

o Completely resected, large tumors (≥ 100 g or ≥ 200 cm3) with normal post-operative hormone levels

• STAGE III – o Unresectable, gross or microscopic residual disease o Tumor spillage o Patients with Stage I and II tumors who fail to normalize hormone levels after

surgery o Patients with retroperitoneal lymph node involvement

• STAGE IV – o Presence of distant metastases

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APPENDIX III: GUIDELINE DIAGRAMS FOR RETROPERITONEAL LYMPH NODE DISSECTION

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SAMPLE INFORMED CONSENT FORM / PARENTAL PERMISSION FOR PARTICIPATION IN RESEARCH ARAR0332, Treatment of Adrenocortical Tumors with Surgery plus Lymph Node Dissection and Multiagent Chemotherapy If you are a parent or legal guardian of a child who may take part in this study, permission from you is required and the assent (agreement) of your child may be required. When the word “you” appears in this consent from, it refers to your son or daughter. This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends and family. You can also discuss it with your health care team. If you have any questions, you can ask your study doctor for more explanation. You are being asked to take part in this study because you have a rare and aggressive type of tumor in the adrenal gland next to one of your kidneys. This type of tumor is called an adrenocortical tumor (ACT). Since ACT is rare there is no well accepted standard (usual) treatment. Surgery is the most common treatment but it does not always remove all of the cancer, and it can return. This happens most often in people with advanced disease who cannot have surgery at the time of diagnosis. These people are also treated with chemotherapy. WHY IS THIS STUDY BEING DONE? Subjects will be treated according to the stage of their disease (how advanced the disease is; the size of the tumor and whether the disease has spread). Each subject will be placed into 1 of 3 possible treatment groups. The main goals of this study are: 1) To see how effective surgery alone is for subjects with early stages of ACT (Treatment Groups 1 and 2). 2) To find out if it is better to do a larger surgery than usual (and remove more lymph nodes) in some subjects (Treatment Group 2). 3) To find out how well a combination of mitotane with cisplatin, etoposide and doxorubicin works for subjects with more advanced stages of ACT (Treatment Group 3). The other goals of this study are: 1) To find out if the larger surgery is better for some subjects with an early stage of disease. (We want to make sure that the benefits outweigh the added risks.); 2) To find out how common it is for lymph nodes to be affected by ACT; 3) To find out what the risks (toxicities) of mitotane are when it is combined with certain other chemotherapy drugs.

This model informed consent form has been reviewed by the DCT/NCI and is the official consent document for this study. Institutions should use the sections of this document which are in bold type in their entirety. Editorial changes to these sections may be made as long as they do not change information or intent. If the institutional IRB insists on making deletions or more substantive modifications to any of the sections in bold type, they must be justified in writing by the investigator at the time of the institutional audit.

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Treating ACT requires that the tumor be totally removed. Because of this, surgery is likely the most important part of standard treatment for ACT. The scale of the surgery will depend on the stage of the disease. Surgery often requires that some surrounding tissues and even parts of other organs be removed too. ACT may return or spread to other parts of the body even after surgery. We think that some disease may remain in the lymph nodes nearby after the tumor has been removed. It is common for patients with early stages of ACT to have some of the lymph nodes near the tumor removed. We would like to remove all of the lymph nodes nearby for those subjects with an early stage of ACT who have a large tumor. We want to find out if this larger surgery than usual will offer a better cure rate. If ACT is at an early stage and the tumor can be totally removed by surgery, then no other treatment is needed. However, for people with advanced disease, chemotherapy has to be used. The drug mitotane is effective against ACT but at high doses it also causes many side effects. Most of our current information about the effects of this drug (both good and bad) has come from treatment on adults rather than children. Giving mitotane at lower doses in children may avoid some of the side effects and still help fight the tumor. When mitotane is given at a lower dose it needs to be taken for a longer period of time. It may have to be taken for several months for it to work. Combinations of different chemotherapy drugs are used to treat cancers. Recent studies have shown that adding the drug mitotane to a combination of the drugs cisplatin, etoposide and doxorubicin can be effective. By giving mitotane with other drugs, instead of alone, we may improve the treatment for ACT. HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? About 235 people worldwide will take part in this study. WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? Before you start the study You will need to have the following exams, tests or procedures to find out if you can be in the study. These are part of regular cancer care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.

• Physical exam • Blood tests, including measuring levels of different hormones • Urine tests • Kidney function tests • Liver function tests • Bone scan • MRI of the abdomen (MRI is Magnetic Resonance Imaging, the use of magnetic waves

to look at soft tissues of the body) • CT scan of the chest (CT is Computed Tomography, a scan that takes a picture of the

inside of your body) • Surgery (biopsy or removal of tumor)

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If you will get chemotherapy, you will also have these tests: • Hearing test • Pregnancy test (if you are a female of childbearing potential) • ECHO (Echocardiogram – heart function test)

During the study You will need the tests and procedures listed below if: - you will get chemotherapy, and - the exams, tests and procedures show that you can be in the study, and - you choose to take part. They are part of regular cancer care.

• Physical exam • Blood tests, including measuring levels of different hormones • Urine tests • Kidney function tests • Liver function tests • Bone scan • MRI of the abdomen • CT scan of the chest • Surgery • ECHO

The following is also part of standard cancer care but will be done more often because you are in this study.

• Measurement of blood hormone levels If you get chemotherapy you will have these tests and procedures that are either being tested in this study or being done to see how the study is affecting your body.

• Hearing test • Measurement of mitotane levels in the blood

Some of the tissue already taken and copies of the films used to make the diagnosis of your disease will be sent to central review centers as part of COG quality control. The central review of tissue and films to confirm a diagnosis helps to make sure that an acceptable standard of expertise is maintained at each institution that is a member of the COG. You will not get any information from these reviews. TREATMENT The treatment that you get will depend upon how advanced the cancer is. If doctors think that the disease was totally removed by surgery then you may not need any more treatment. We will keep a close eye on you to make sure the cancer does not come back. Some subjects will need another surgery to see if the cancer has spread. Other subjects will need both surgery and chemotherapy. You will be treated in 1 of 3 ways according to the stage of your disease.

• Stage 1: Subjects that had a small tumor (about the size of a small apple, less than a quarter of a pound in weight) removed by surgery will get Study Treatment 1 (see below).

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• Stage 2: Subjects that had a larger tumor removed by surgery will get Study Treatment 2 (see below).

• Stage 3 or 4: Subjects with a tumor that could not be totally removed by surgery, and

those whose disease that has spread, will get Study Treatment 3 (see below). Each treatment plan is described below: Study Treatment 1: You will have no more treatment but you will be watched closely to make sure the cancer does not come back. Study Treatment 2: If you did not have all of the lymph nodes closest to the tumor taken out during the surgery used to make your diagnosis then you will have a second surgery to remove those lymph nodes. This second surgery would not always be done as standard care, but we think it may lower the chance of the cancer coming back. If you have this second surgery, it will be the only difference between standard care for ACT and treatment on this study. You will have no more treatment but you will be watched closely to make sure the cancer does not come back. Study Treatment 3: You will get chemotherapy, and if there is a good response you may have another surgery. Surgery will include removing the tumor and also all of the lymph nodes nearby. If the cancer has spread, then any other tumors in other parts of the body will also be removed, when possible. The chemotherapy will last about 8 months (32 weeks). If you also have surgery then the total treatment time may be longer. If you choose not to take part in this study you will likely still get the same chemotherapy drugs and similar surgery. Chemotherapy Schedule You will get Induction therapy over a period of 6 to 12 weeks in order to shrink the tumor. You might then have another surgery. If the tumor shows a good response to Induction therapy, then you will go on to Continuation therapy. Continuation therapy will last about 20 to 26 weeks. Induction therapy is the use of chemotherapy to reduce/get rid of the cancer. If the cancer goes away then the disease will be “in remission”. Continuation therapy is treatment intended to make the cancer stay in remission. Induction therapy: Induction therapy consists of 2 to 4 cycles of chemotherapy with the drugs mitotane, cisplatin, etoposide and doxorubicin. Each cycle will last 21 days. After 2 cycles you will be evaluated and if surgery is right for you it will be scheduled as soon as possible.

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Drugs will be given in the following way. One cycle is described. Drug Route Dose Days Mitotane

By mouth The dose will vary as needed to remain effective.

Every day

Cisplatin (CDDP)

IV over 6 hours 50 mg/m2 Days 1 and 2

Etoposide (VP-16)

IV over 1 hour 100 mg/m2 Days 1, 2 and 3

Doxorubicin (DOXO)

IV over 1 hour 25 mg/m2 Days 4 and 5

IV means the drug will be given by a needle or tubing inserted into a vein. To help get Mitotane into your system as quickly as possible, it is likely that the Mitotane tablets will be ground into powder and mixed with a liquid nutrition formula for the first 30 days of treatment. Other drugs will be given to help prevent or manage the side effects of chemotherapy, like nausea and vomiting. Also, you will get the drug filgrastim (G-CSF) to help blood cells return to a level that will allow more chemotherapy to be given. This drug will be given by an injection under the skin. Continuation therapy: You will have 4 to 6 more cycles of chemotherapy with the same drugs used during Induction. The drugs will be given in the same way. Once you have finished a total of 8 cycles of chemotherapy, you will continue to get mitotane alone every day, for up to 8 more weeks. The total time that you will get mitotane will be 8 months. WHEN I AM DONE WITH THE STUDY TREATMENT All Treatment Groups (Groups 1-3) You will have a number of tests and procedures as part of your follow up to treatment. We will use these tests to watch for improvements, monitor side effects, and look for any signs that the cancer has come back. ACT often causes an increase in hormone levels. Once the tumor has been removed, or after chemotherapy has started, these hormone levels should go down. We will measure your hormone levels very closely in order to monitor the tumor response and look for any signs that the cancer has come back. We will need to take about 1 teaspoon of blood to test your hormone levels at each of the following times:

• 1 week after surgery • 1 month after surgery • Every 3 months up until 2 years after surgery • Every 6 months between the second and fifth years after surgery

In addition to tests of your hormone levels, you will also have a physical exam and standard lab tests, including blood tests, plus MRI, CT and bone scans regularly for the first 2 years after

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treatment (every 3 months). These tests will be done less often for years 3 to 5 after treatment (every 6 months). Treatment Group 3 Only In addition, you will have a heart function test and a kidney function test at 6 and 12 months after treatment has ended. You will have a hearing test every 6 months for the first 2 years after treatment has ended, and then every year until 5 years have passed. A treatment plan for this study is provided on the following page.

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TREATMENT PLAN

FOLLOW UP

STUDY ENTRY

GROUP 2 Stage II patients

GROUP 1 Stage I patients

SURGERY – if necessary

GROUP 3 Stage III and IV patients

FOLLOW

INDUCTION CHEMOTHERAPY* 2 cycles

EVALUATION

Response to therapy Disease worsens

CONTINUATION THERAPY#

INDUCTION CONTINUED**

1 or 2 cycles

OFF PROTOCOL THERAPY SURGERY

SURGERY

CONTINUATION THERAPY#

EVALUATE

SURGERY - if appropriate

EVALUATE

SURGERY - if appropriate

FOLLOW UP

* Combination therapy with mitotane, cisplatin, etoposide and doxorubicin. ** If surgery cannot be scheduled immediately, Induction will continue for up to 2 more cycles. # Continuation therapy will consist of 4 to 6 cycles of combination chemotherapy + up to a further 2 months of mitotane alone.

No evidence of disease

CONTINUATION THERAPY#

FOLLOW UP FOLLOW UP

FOLLOW

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HOW LONG WILL I BE IN THE STUDY? Study Treatment Group 1 or 2 Your study doctor will ask you to come back for follow-up exams for at least 5 years. Study Treatment Group 3 You will take drugs for about 8 months. If you need more surgery you may be in the study for longer. After you are done taking the drugs, you will need to come back for follow-up exams for at least 5 years. All Study Treatment Groups We would like to continue to find out about your health for about 10 years after the study closes to new patients. We would like to do this by calling you on the telephone once a year to see how you are doing. Keeping in touch with you and checking on how your health is every year for a while after the study closes helps us understand the long-term effects of the study. CAN I STOP BEING IN THE STUDY? Yes. You can stop at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely. The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest or if the study is stopped. Study Treatment Group 3: It is important to tell the study doctor if you are thinking about stopping so any risks from the chemotherapy drugs can be reviewed by your doctor. Another reason to tell your doctor that you are thinking about stopping is so that you talk about what follow-up care and testing could be most helpful for you. WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? Study Treatment Group 1: If you choose not take part in this study you may still be treated with surgery and then watched closely to make sure the cancer has not come back. There are no extra risks as a result of taking part in this study. Study Treatment Group 2: If you choose not take part in this study you may still be treated with surgery and then watched closely to make sure the cancer has not come back. The difference is that subjects with Stage II cancer may have more surgery than is usual if they take part in this study. Therefore, the risks of taking part in this study are linked to the surgery you have. Surgical risks: The surgery you have may be more aggressive than usual because you may have to have a second surgery to remove all of the lymph nodes close to your tumor. Serious complications from this surgery are rare but can happen. Known complications include: In 2-5% of subjects:

• infection of the surgical site • a blockage of the bowel • problems with ejaculation

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In less than 1% of subjects: • build up of fluid in the abdomen • inflammation of the pancreas • blood collection in the muscles of the abdominal wall • hernia of the bowel (A hernia is a weakness or opening in the muscle wall or lining

that normally holds an organ in place. With a bowel hernia, part of the intestines may poke through the opening in the abdominal wall.)

Having a second surgery will increase your recovery time and you may need more pain medication. If you have surgery, you will sign a separate consent form for that surgery. The planned surgery will be explained to you and your questions about it will be answered by your surgeon. Study Treatment Group 3: You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know all the side effects that may happen. Side effects may be mild or very serious. You may get medicines to help lower side effects. Many side effects go away soon after you stop taking the chemotherapy drugs. In some cases, side effects can be serious, long lasting, or may never go away. There also is a risk of death. One of the most common side effects of chemotherapy is lowered blood cell counts.

• A lowered red blood cell count will make you feel weak and tired (anemia). • A lowered white blood cell count will lower your resistance to infection. • A lowered platelet count will cause an increased risk of bleeding.

You should talk to your study doctor about any side effects that you have while taking part in the study. Possible side effects of the chemotherapy drugs used in this study are listed on the following pages.

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The following kinds of side effects may result from the drugs used in this study: Risks and side effects related to cisplatin include:

Likely Less Likely Rare but serious • Nausea and vomiting • fewer red blood cells

and white blood cells and platelets in the blood o a low number of red

blood cells can make you feel tired and weak

o a low number of white blood cells can make it easier to get infections

o a low number of platelets causes you to bruise and bleed more easily

• Abnormal levels of magnesium in the body which may require that you take extra magnesium by mouth or in the vein

• Loss of appetite • Damage to the ear

causing difficulty in hearing high pitched sounds

• Temporary and mild increases in levels of certain chemicals in the blood because the kidney is not working as well as normal

• Abnormal levels of certain salts in the body like sodium, calcium, potassium and phosphate

• Metallic taste • Rash • Numbness and tingling

in the fingers and toes • Temporary changes in

vision • Damage to the ear

causing hearing loss, balance problems and ringing in the ears

• Elevation in the blood of certain enzymes found in the liver

• Inflammation and discomfort in the vein through which the medicine was given

• Allergic reactions which may be severe and life-threatening, causing difficulty in breathing, rapid heart rate, facial swelling and or a drop in blood pressure

• Damage to the kidney which may be permanent

• Deafness • Seizures • Damage to the vision

which could lead to blurred vision, blue-green color blindness and to loss of vision which usually goes away after stopping the drug

• Decrease in muscle and nerve reflexes that may affect normal functions such as walking

• Leukemia later in life

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Risks and side effects related to doxorubicin include:

Likely Less Likely Rare but serious • Nausea • Vomiting • Temporary hair loss • Pink or red color to

urine, sweat, tears, saliva

• Fewer white blood cells, red blood cells and platelets in the blood. ○ A low number of

red blood cells can make you feel tired and weak

○ A low number of white blood cells can make it easier to get infections

○ A low number of platelets causes you to bruise and bleed more easily

• Slight damage to the heart muscle that is unlikely to have any noticeable effects on your heart function

• Inflammation and/or sores in the mouth (and/or throat and/or esophagus, the tube that leads from the mouth to the stomach) that may make swallowing difficult and are painful (painful mouth sores)

• Damage to the heart muscle which may make you tired, weak, feel short of breath, and retain fluid

• Facial Flushing • Fever/chills • Hives • High levels of uric acid in

the blood which could damage the kidneys

• Dark discoloration of the hands, feet and under the fingernails with possible separation of the nail from the nail bed

• Damage to the skin if the medication leaks from a vein

• Thickening and hardening of the veins through which the medication is given

• Reddening reaction of the vein through which the drug is given

• Elevation in the blood of certain enzymes found in the liver

• Tearing and inflammation of the eyes

• Loss of appetite • Redness and burning at

sites which have received radiation in the past

• Diarrhea

• Severe allergic reaction which can be life threatening with shortness of breath, low blood pressure and a rapid heart rate

• Ulceration of the lower intestinal tract

• An irregular heart beat which can be life-threatening

• Severe damage to the heart muscle which may lead to severe heart failure

• A new cancer or leukemia resulting from this treatment.

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Risks and side effects related to etoposide include:

Likely Less Likely Rare but serious • Nausea and vomiting • Hair Loss • A feeling of weakness

or tiredness • Fewer red and white

blood cells and platelets in the blood o a low number of

red blood cells can make you feel tired and weak

o a low number of white blood cells can make it easier to get infections

o a low number of platelets causes you to bruise and bleed more easily

• Loss of appetite • Decreased blood

pressure during the infusion which may require treatment

• rashes • Diarrhea • Pain in the abdomen • Mouth sores • Tingling sensation or

loss of sensation in fingers or toes

• A feeling of extreme tiredness or weakness

• The finger or toe nails may loosen from their nail beds

• Inflammation of the vein through which the medication was given

• Chest pain

• Damage to the liver • Severe allergic reaction

which can be life threatening with shortness of breath, low blood pressure, rapid heart rate chills and fever

• A new cancer or leukemia resulting from this treatment

• Severe rashes which can result in loss of skin and damage to mucous membranes

• Absence or decrease monthly periods which may be temporary or permanent and which may decrease the ability to have children

• Damage to the heart muscle which may make you feel tired, weak, feel short of breath, and retain fluid

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Risks and side effects related to filgrastim (G-CSF) include:

Likely Less Likely Rare but serious • Aching or pain

in the bones

• Local irritation at the site of the injection

• Headache • Higher than normal levels

of liver enzymes which may indicate liver irritation or damage and uric acid in the blood

• A low number of platelets in the blood which may cause you to bruise and bleed more easily

• Low fever • Enlargement of the spleen

which may cause pain in the abdomen or left shoulder

• Worsening of skin rashes • Inflammation of a blood

vessel in the skin leading to a raised purple rash and bruising

• Higher than normal white blood count

• Allergic reactions which can be life threatening with shortness of breath, low blood pressure, rapid heart rate, hives and facial swelling. This reaction is very rare and has been associated mainly with intravenous administration.

• If you are known to have sickle cell disease, filgrastim may cause a sickle cell crisis.

• Severe damage to the spleen (an organ in the abdomen/belly which stores blood cells) which could lead to pain and loss of blood into the abdomen (belly) and may be life threatening

• Difficulty breathing and lung damage that may be due to the white blood cells that are stimulated by filgrastim traveling to the lungs when they are inflamed or infected.

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Risks and side effects related to mitotane include:

Likely Less Likely Rare but serious • Nausea and Vomiting • Diarrhea • Confusion • Sleepiness and

tiredness • Blood triglycerides

and cholesterol may be elevated which could lead to heart problems later in life

• The hormones that maintain blood pressure and prevent shock in stressful situations will be decreased and will require replacement with prednisone and fludrocortisone pills

• Thyroid hormone levels may be decreased requiring replacement with thyroid hormone pills

• Loss of desire to eat • Mood changes

including depression, irritability

• Feeling of weakness

• Dizziness • Breast enlargement • Low blood pressure on

standing • High blood pressure • The time to clot the blood

may take longer, which may make it more likely to bleed

• Temporary skin rash that may go away even while receiving the drug

• Memory may not be as good as it was previously

• Low white blood cell count which may make infections more likely

• Fever • Produce extra saliva (fluid) in

the mouth • Reddening of the face with

feelings of warmth • Hair loss • A problem in nerve function

that may cause pain, numbness, tingling, and muscle weakness in various parts of the body

• The liver does not work as well which leads to an increase in the blood of enzymes found in the liver

• Wheezing and shortness of breath

• Changes in mood which may include severe depression, feelings of suicide, feelings of aggressiveness and violent behavior

• Mental changes such as hallucinations (seeing or hearing things that are not there)

• Permanent brain damage with difficulty in carrying out daily tasks

• Damage to the nerves of the spinal cord which may make muscular actions such as walking more difficult

• May require replacement hormones (prednisone and fludrocortisone) even after stopping mitotane

• Vision changes including blurred vision and seeing double

• Damage to the bladder that may cause blood in the urine

• Kidney damage which could result in protein (albumin) in the urine

Reproductive risks: You should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important you understand that you need to use birth control while on this study. Check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study. Some of the drugs used in the study may make you unable to have children in the future. Female subjects of childbearing potential will be required to have a negative pregnancy test result before starting chemotherapy on this study. Surgical risks: The surgery may be very aggressive. In almost half of the study subjects, complete removal of the tumor will require the removal of other organs or parts of them.

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In close to 30% of the cases: • one of the kidneys will have to be removed

In 10% of the cases: • the spleen will have to be removed with the tumor

In less than 10% of the cases: • it will be necessary to remove small portions of the liver, the pancreas or the

gallbladder Much less often complications include:

• damage to a large vein that returns blood to the heart • a tear in the tumor and spillage into the abdominal area • problems with healing of the surgical wound • infection

If you have surgery you will sign a separate consent form for that surgery. The planned surgery will be explained to you and your questions about it will be answered by your surgeon. For more information about risks and side effects, ask your study doctor. ARE THERE BENEFITS TO TAKING PART IN THE STUDY? Taking part in this study may or may not make your health better. While doctors hope the surgery, or combination of surgery and drugs used, will be useful against ACT, there is no proof of this yet. We do know that the information from this study will help doctors learn more about surgery and the combination of drugs used as a treatment for ACT. This information could help future cancer patients. We don’t know the reasons why cancer returns in some people after surgery. It is possible that the tumor has spread to the lymph nodes that surround the kidney(s) and the adrenal gland. In this study, we will do more aggressive surgery than usual on Stage II subjects and remove those lymph nodes. It is possible that removing those lymph nodes will lower the chance of the cancer coming back. One of the important parts of the study treatment for subjects with advanced ACT is the use of mitotane. Mitotane is quite toxic but we think that if we give it at lower doses it will have the same anti-tumor effects but with less side effects. WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? Your other choices may include:

• Getting treatment or care for your cancer without being in a study • Taking part in another study • Getting no treatment • Getting comfort care, also called palliative care. This type of care helps reduce pain,

tiredness, appetite problems and other problems caused by the cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.

Talk to your doctor about your choices before you decide if you will take part in this study.

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WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. It is very unlikely that the research testing might uncover important information about you or your child’s current or future health. If this unlikely event occurs, the researchers may contact your child’s doctor through COG’s Data Center about what the research test results might mean. Only the doctor will be notified and the information will remain confidential. Your child’s doctor may discuss this unexpected finding with you, and may recommend consultation with a genetic counselor and/or repeat testing in a clinical (not research) laboratory if necessary. It is possible that your child’s doctor may recommend that no additional action is necessary. The Children’s Oncology Group has a Certificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. Information about the certificate is attached at end of this consent. Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:

• The Children’s Oncology Group • Representatives of the National Cancer Institute (NCI), Food and Drug

Administration (FDA), and • other U.S. and international governmental regulatory agencies involved in keeping

research safe for people • The Institutional Review Board of this hospital (IRB) • The Pediatric Central Institutional Review Board (CIRB) of the National Cancer

Institute WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment. You will not be paid for taking part in this study. For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web site at http://cancer.gov/clinicaltrials/learning/insurance-coverage . You can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.

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WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ [telephone number]. You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment. WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ [name(s)] at __________________ [telephone number]. For questions about your rights while taking part in this study, call the ________________________ [name of center] Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number). [Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.] WHERE CAN I GET MORE INFORMATION? The COG Family Handbook for Children with Cancer has information about specific cancers, tests, treatment side effects and their management, adjusting to cancer, and resources. Your doctor can get you this Handbook, or you can get it at www.curesearch.org If you are in the United States, you may call the National Cancer Institute's Cancer Information Service at:

• 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 You may also visit the NCI Web site at http://cancer.gov/

• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ • For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/

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You will get a copy of this form. You will be given a copy of the protocol (full study plan) upon request. If you want more information about this study, ask your study doctor. SIGNATURE I have been given a copy of all _____ [insert total number of pages] pages of this form. The form includes one (1) attachment. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study. SUBJECT ________________________________ DATE __________________ PARENT/LEGAL GUARDIAN ________________________________ DATE __________________

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OPTIONAL BIOLOGY STUDIES Please note: This section of the informed consent form is about additional research studies that are being done with people who are taking part in the main study. You may take part in these additional studies if you want to. You can still be a part of the main study even if you say ‘No’ to taking part in any of these additional studies. Please read the information below and think about your choices. After making your decisions, circle “Yes” or “No”, then add your initials and the date after your answer. No matter what you decide to do, it will not affect your care. If you have any questions, please talk to your doctor or nurse, or call our research review board at the IRB’s phone number included in this consent. We believe that ACT starts with cells during the fetal development (while a baby is growing in the womb). The development of the tumor is not well understood but some changes that happen inside the body’s cells have been linked to ACT. In order to help with our research, we are asking your permission to use some of the leftover tumor tissue taken during your diagnosis and treatment for some laboratory studies. We hope to learn more about the cells which become cancerous and also the steps involved in the development of the tumor. The research aims are: 1) To look for signs that ACT comes from cells present during fetal development. 2) To learn more about the process that makes a normal cell become a cancerous ACT cell. These tests will be performed at a COG laboratory. The results of these studies will not directly affect your cancer therapy. Therefore the results of the tests will not become part of your health records. 1. I agree to allow leftover tissue from my diagnostic and treatment procedures to be used for research to study the cells of origin of ACT, and the changes inside cells that cause the development of ACT.

#1: Yes No ________ / _______ Initials Date

We are also asking your permission to save leftover tumor tissue samples from your diagnosis and treatment in a special tumor bank. A tumor bank is a lab where of tumor and blood specimens are kept for use in future research studies.

Consent Form for Use of Tissue for Research About Using Tissue for Research You are going to have a biopsy (or surgery) to see if you have cancer. Your doctor will remove some body tissue to do some tests. The results of these tests will be given to you by your doctor and will be used to plan your care. We would like to keep some of the tissue that is leftover from your surgery for future research. If you agree, this tissue will be kept and may be used in research to learn more about cancer and

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other diseases. Please read the information sheet called "How is Tissue Used for Research?" to learn more about tissue research. [Note to Local Investigator: This information sheet is available on the COG web site at: https://members.childrensoncologygroup.org/prot/reference_materials.asp under CONSENTS AND IRB FORMS] Your tissue may be helpful for research whether you do or do not have cancer. The research that may be done with your tissue is not specifically to help you. It might help people who have cancer and other diseases in the future. Reports about research done with your tissue will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an effect on your care. Things to Think About The choice to let us keep the leftover tissue for future research is up to you. No matter what you decide to do, it will not affect your care. If you decide now that your tissue can be kept for research, you can change your mind at any time. Just contact us and let us know that you do not want us to use your tissue. Then any tissue that is left will no longer be used for research. In the future, people who do research may need to know more about your health. While this institution may give them reports about your health, it will not give them your name, address, phone number, or any other information that will let the researchers know who you are. Sometimes tissue is used for genetic research (about diseases that are passed on in families). Even if your tissue is used for this kind of research, the results will not be put in your health records. Your tissue will be used only for research and will not be sold. The research done with your tissue may help to develop new products in the future. Benefits The research studies will not benefit you. However, the benefits of research using tissue include learning more about what causes cancer and other diseases, how to prevent them, and how to treat them. Subjects will not profit from any new product developed from research done on their specimens. Risks The only risk to you is the release of information from your health records. We will do our best to make sure that your personal information will be kept private. The chance that this information will be given to someone else is very small. Making Your Choice Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or "No" and write your initials in the space provided. No matter what you decide to do, it will not affect your care.

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If you have any questions, please talk to your doctor or nurse, or call our research review board at IRB's phone number. 1. My tissue may be kept for use in cancer research.

YES NO Initials ___________ 2. My tissue may be kept for use in research to learn about other health problems (for example: diabetes, Alzheimer's disease, or heart disease).

YES NO Initials ___________ 3. Someone may contact me in the future to ask me to take part in more research.

YES NO Initials ___________

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Attachment #1: Information about the Certificate of Confidentiality The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. The Certificate protects against the involuntary release of information about subjects collected during the course of our covered studies. The researchers involved in the studies cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to voluntarily disclose the protected information under certain circumstances. For example, if the subject or his/her guardian requests the release of information in writing, the Certificate does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against the required reporting by hospital staff of information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or others.

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SAMPLE INFORMED CONSENT FORM / PARENTAL PERMISSION FOR PARTICIPATION IN RESEARCH ARAR0332, Treatment of Adrenocortical Tumors with Surgery plus Lymph Node Dissection and Multiagent Chemotherapy Optional Biology Study, Part 1: Consent for Additional Blood Sample The study doctors would like to take a 1-teaspoon sample of blood before you start treatment. The blood will be studied to look at a gene (p53) which normally helps protect the body’s cells from damage. Mutations (changes) in this gene can cause cells to become cancerous, and have been linked to the type of cancer that you have. This is an optional test and whatever you decide will not affect your taking part in the rest of this research study. The sample will not be studied right away. First, if you agree to let the blood be taken, you will get to talk to a person called a genetic counselor. You and/or your family will get information about your genes which may help you make good medical decisions. The genetic counseling is provided at no cost to you. After you have the genetic counseling, you will then have a better understanding of the risks and benefits of knowing the results of the blood test. At that time you will be able to decide whether or not to allow the study doctors to do the test on the blood sample. If you do not agree to have the test done on the blood sample you will be asked if we should destroy the specimen or save it for future use. There are no medical risks to the blood draw except that there may be a small amount of bleeding afterwards and there may be some slight discomfort. Please read the sentence below and think about your choice. Then circle "Yes" or "No" and sign your name in the space provided. I agree to give a blood sample for genetic testing. I understand that the p53 mutation analysis on the blood will not be done until I have had pre-test genetic counseling and sign an additional consent form for the test. YES NO SIGNATURE I understand the information and have had my questions answered. SUBJECT ________________________________ DATE __________________ PARENT/LEGAL GUARDIAN ________________________________ DATE __________________

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[Note to Local Investigator: Please verify this Informed Consent is in compliance with the genetic testing notification rules for your state, and make any necessary alterations.] SAMPLE INFORMED CONSENT FORM / PARENTAL PERMISSION FOR PARTICIPATION IN RESEARCH ARAR0332, Treatment of Adrenocortical Tumors with Surgery plus Lymph Node Dissection and Multiagent Chemotherapy Optional Biology Study, Part 2: Consent for p53 Testing When you enrolled on this study you agreed to provide some extra blood that might be tested for a certain genetic feature (the p53 mutation). Since then you have had genetic counseling to explain the reason for the test and any consequences that the results might have. This form will record your decision whether or not take part in this research. Please note: You can still be a part of the main study even if you say ‘no’ to taking part in this research study. WHY IS THIS STUDY BEING DONE? The molecular biology that controls the development of the adrenocortical tumor (ACT) is not well understood but a certain genetic feature (the p53 mutation) has been linked to ACT. ACT occurs more often in some countries than in others. For example, a child in Southern Brazil is 10 to 15 times more likely to develop ACT than a child in the U.S. The purpose of this research is to study the DNA of subjects with ACT and try to better understand the development of the tumor. We would also like to compare the frequency and type of the p53 mutation in children in North America and other countries with children in Southern Brazil. Benefits Cancer patients in general may benefit from this study because it will help us to better understand the influence of genetic changes on the development of different forms of the disease. With our present knowledge, we do not know that every person who carries a mutation of the p53 gene in their blood will develop cancer. We also do not know that the absence of a mutation means that the person is not genetically predisposed. (To be genetically predisposed to a condition means that you may be more likely to develop that condition because of the nature of your genetic structure.) The identification of a genetic mutation in the blood test will provide clues to a possible factor that made the development of your tumor more likely. Risks The greatest risk to you is the release of information from your health records. We will do our best to make sure that your personal information is kept private but we cannot guarantee total privacy. When you signed the consent form for the treatment portion of this research study, you were told that the Children’s Oncology Group has a Certificate of Confidentiality which is given by the Federal Government to help keep research records private. That certificate also applies to this

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optional research study. Your personal information may be given out if required by law. However, the chance that this information will be given to someone else is very small. The result of this genetic test will be kept separate from your regular medical record that contains information on the treatment of your disease. This means that the result of the test will not be available to your insurance company. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:

• The Children’s Oncology Group • Representatives of the National Cancer Institute (NCI), Food and Drug

Administration (FDA), and • other U.S. and international governmental regulatory agencies involved in keeping

research safe for people • The Institutional Review Board of this hospital (IRB) • The Pediatric Central Institutional Review Board (CIRB) of the National Cancer

Institute WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? You will not be charged for taking part in this optional research study. You will not be paid for taking part in this study. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ [name(s)] at __________________ [telephone number]. For questions about your rights while taking part in this study, call the ________________________ [name of center] Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number). [Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.] MAKING YOUR CHOICE This section will record 2 things: 1) Your decision whether or not to allow the test for the p53 mutation to be done on the blood sample you gave. 2) Your decision whether or not to receive the result of the test. Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or "No" and write your initials in the space provided. If you have any questions, please talk to your doctor or nurse, or call our research review board at [IRB's phone number]. No matter what you decide to do, it will not affect your care.

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1. I agree to allow the blood sample taken at the time of my diagnosis to be used for research to study the occurrence and type of p53 mutation that is present in children with ACT.

YES NO Initials ___________ If your answer is YES, please go on to question 2. Also, we would like you to consider the request below to have any DNA that is leftover banked for future research. If your decision was NO, please ignore question 2 but we would like you to consider the request below to have the DNA from your sample of blood banked for future research. 2. I would like to be given the result of the test and know whether I carry the p53 mutation.

YES NO Initials ___________

Banking of DNA for Future Research DNA that is banked will be frozen and stored in a deep freezer at a COG laboratory. The DNA will be identified only by an anonymous code number. There is no way to predict exactly what tests will be performed with the banked samples in the future. You can still be a part of the p53 mutation study even if you say ‘No’ to banking for future research. The future research that may be done with your DNA is not specifically to help you. The DNA taken from your sample of blood will be stored in such a way that it will be usable in the future when new genes are identified that are thought to be important in cancer formation. The research might help people who have cancer and other diseases in the future. Reports about research done with your DNA will not be put in your health record. The research will not have an effect on your care. Generally these reports will not be given to you or your doctor. It is very unlikely that the research testing might uncover important information about you or your child’s current or future health. If this unlikely event occurs, the researchers may contact your child’s doctor through COG’s Data Center about what the research test results might mean. Only the doctor will be notified and the information will remain confidential. Your child’s doctor may discuss this unexpected finding with you, and may recommend consultation with a genetic counselor and/or repeat testing in a clinical (not research) laboratory if necessary. It is possible that your child’s doctor may recommend that no additional action is necessary. In the future, people who do research may need to know more about your health. While this institution may give them reports about your health, it will not give them your name, address, phone number, or any other information that will let the researchers know who you are. Your DNA will be used only for research and will not be sold. The research done with your tissue may help to develop new products in the future.

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Benefits The benefits of research using DNA include learning more about what causes cancer and other diseases, how to prevent them, and how to treat them. Subjects will not profit from any new product developed from research done on their specimens. Risks The greatest risk to you is the release of information from your health records. We will do our best to make sure that your personal information will be kept private. The chance that this information will be given to someone else is very small. Making Your Choice Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or "No" and write your initials in the space provided. If you have any questions, please talk to your doctor or nurse, or call our research review board at IRB's phone number. No matter what you decide to do, it will not affect your care. 1. My DNA may be kept for use in future cancer research.

YES NO Initials ___________ 2. My DNA may be kept for use in future research to learn about other health problems (for example: diabetes, Alzheimer disease, or heart disease).

YES NO Initials ___________ SIGNATURE I have been given a copy of all _____ [insert total number of pages] pages of this form. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study. SUBJECT ________________________________ DATE __________________ PARENT/LEGAL GUARDIAN ________________________________ DATE __________________