Cancer of the testis is a relatively uncommon disease, accountingfor approximately 1% of all cancers in males.1 However, it is an impor-tant disease in the field of oncology, as it represents a highly curableneoplasm, and the incidence of which is focused on young patients attheir peak of productivity. Despite the rarity of the diagnosis, the impactof cure in this population is enormous. It was the subject of a recentcost-benefit analysis, suggesting that the annual economic value of suc-cessful treatment of this disease can be estimated at $150 million.2

Effective therapy, which can now cure the majority of patients evenwhen disseminated disease is present, is a product of careful applica-tion of the principles of surgical oncology and radiation therapy, as wellas of several decades of rational drug development, well-planned clin-ical trials, and a small measure of serendipity. As a result, testicular can-cer has truly become a model for the treatment of other cancers.3

EPIDEMIOLOGY

INCIDENCE An age-related incidence curve of testicular cancerreveals a bimodal distribution. The major peak occurs between ages 15and 35 years, due almost exclusively to tumors of germ cell origin,which account for approximately 95% of all testicular cancer. Withinthe subclass of germ cell neoplasms is another bimodal distribution,with embryonal carcinoma representing the predominant histopatho-logic diagnosis up to the age of 35 years, after which seminoma ismore common up to the age of 75 years. The incidence of testicularcancer declines steadily beyond the age of 40 years, but a small risebeyond the age of 75 years can be attributed primarily to an increasein the incidence of testicular lymphoma.

Demographic analysis of testicular cancer worldwide reveals anumber of interesting trends. The incidence of the disease variesmarkedly on the basis of geographic distribution, with the highest inci-dence in northern Europe and North America, and the lowest in Asiaand Africa. There is also a striking influence of race, with the inci-dence among black and Hispanic males worldwide far less than thatfor their Caucasian counterparts.4,5 The incidence of testicular cancerrises with increasing socioeconomic status,6 but even when stratifiedby this parameter, the racial differences persist, with blacks having alower incidence than Caucasians in each class.

The incidence of testicular cancer is increasing among young Cau-casian males in the Scandinavian countries, the United Kingdom, andthe United States. In Denmark, from 1945 to 1970, the age-adjustedincidence for testicular cancer nearly doubled to 6.4 per 100,000. Dur-ing that period, the percentage of malignant neoplasms in the 15- to34-year age range attributable to testicular cancer increased from 17 to29%.7,8 A similar doubling in incidence in younger age groups in Eng-land and Wales over the same period has also been observed.9,10 In theUnited States, from 1937 to 1976, the age-adjusted incidence for tes-ticular cancer in Caucasian males rose from 2 to 3.8 per 100,000, whilethe rate for African American males remained constant at 0.9 per100,000.9,1113 The American Cancer Society projected that in 1999,6,900 cases of testicular cancer would be diagnosed in the UnitedStates, with approximately 300 persons dying of the disease. RISK FACTORS Cryptorchidism is the major identifiable risk factorassociated with the development of testicular cancer, with a risk ratiovariably reported between 2.5 and 14 in case-control studies.1417 Thelocation of the maldescended testicle appears to be an importantcofactor in the subsequent development of cancer, since those patientswith intra-abdominal retention have a four-fold higher incidence of

malignancy than do those with the testicle retained in the inguinalcanal. For a number of reasons, it seems unlikely that maldescent, inand of itself, represents the initiating event in the development of germcell tumors: only 10% of testicular tumors are associated with cryp-torchidism; at least 25% of the malignancies in patients with cryp-torchidism occur in the contralateral, normally descended testicle; pre-pubertal orchiopexy fails to prevent the subsequent development ofmalignancy in the undescended testicle;18 and first-degree male rela-tives of patients with testicular cancer exhibit an increased incidenceof cryptorchidism, hydroceles, and inguinal hernias, as well as testic-ular cancer.19 These data suggest that some genetic predispositionand/or in utero environmental event may result in several urothelialdevelopmental abnormalities, including maldescent and germ cellneoplasia. Interestingly, an increase in the frequency of cryp-torchidism has been observed and appears to parallel the timing andmagnitude of the increase in incidence of testicular cancer.20

The use of exogenous estrogens during pregnancy in the mothersof testicular cancer patients has been analyzed by a number of investi-gators. Interest in this as a possible etiologic factor is based on a seriesof observations: murine testicular tumors can be produced experimen-tally by administration of estrogen,21 male offspring of mothers treatedwith diethylstilbesterol (DES), a synthetic, nonsteroidal estrogen,exhibit a number of urogenital developmental abnormalities, includ-ing testicular hypoplasia and maldescent,2224 female offspring ofmothers using DES during the first 2 months of gestation have shownan increased frequency of clear cell adenocarcinoma of the vagina,with a peak incidence in the middle to late teens;25 use of exogenousestrogens by pregnant women was a common practice from 1940 to1960 for a number of conditions, including threatened abortion; andthe risk of testicular cancer is increased 40-fold in testicular feminiza-tion syndromes.26 Three case control studies have been performed, andshow a relative risk of 2.8 to 5.3 in the offspring of mothers who wereadministered exogenous sex steroids during gestation,8,14,23 althoughdifferences between index and control cases have, in general, failed toreach statistical significance. It is unlikely that exogenous steroidscontribute to a major degree to the incidence of testicular cancer in theUnited States. Their lack of use in other endemic areas with rising inci-dence rates (Denmark) underscores their relatively minor role (if any)in the etiology of this disease.

Carcinoma in situ of the testis (intratubular germ cell neoplasia)appears to represent a true premalignant condition for the develop-ment of invasive germ cell tumors. On the basis of observations bySkakkebaek and colleagues, the appearance of these cytologicallyabnormal cells can be detected in a small percentage of men undergo-ing infertility work-ups, and a significant number of those individualssubsequently develop invasive germinal malignancies.27,28 Carcinomain situ may appear in up to 10% of contralateral testes in patients witha prior germ cell malignancy.29,30 Although the premalignant potentialof such lesions is no longer in doubt, general agreement on the clini-cal approach to this histopathologic finding has not been established.

Patients with a history of unilateral testicular cancer are at risk fordeveloping cancer in the other testicle. In a large Danish series, 2.7%of 2,338 patients developed a contralateral testicular tumor during theperiod of follow-up.31 Patients with nonseminoma had a higher over-all relative risk of developing contralateral tumors than did those withseminoma. Investigators at the Royal Marsden Hospital reported asimilar rate of 2.75% for developing contralateral tumors among 760men in an interval as long as 15 years. (248). These observationsunderscore the importance of continued follow-up after treatment.Recommendations for the investigation and management of carci-noma in situ in patients with a diagnosis of testicular cancer rangesfrom close clinical observation to biopsy of the contralateral testicleand, if carcinoma in situ is identified, radiation therapy to the testicle.

PATHOLOGY

An understanding of the pathologic classification of germinal neo-plasms must be based on knowledge of the embryologic development oftesticular tissue, as well as on recognition of the totipotent nature of the

110 NEOPLASMS OF THE TESTISCRAIG R. NICHOLS, MDROBERT TIMMERMAN, MDRICHARD S. FOSTER, MDBRUCE J. ROTH, MDLAWRENCE H. EINHORN, MD

primordial germ cell. This stem cell normally retains the ability to formboth extraembryonic tissues (yolk sac, trophoblast) and true embryonicderivatives (endoderm, mesoderm, and ectoderm), which ultimatelygive rise to mature somatic structures. Not surprisingly, the malignantanalogue of the primordial germ cell maintains at least a pluripotentnature, and pathologic variants of germ cell neoplasms appear to reca-pitulate the normal pattern of embryonic segregation and differentiation.One can envision seminoma as continued differentiation along germ celllines, choriocarcinoma and yolk sac tumor as differentiation intoextraembryonic structures, and mature teratoma as terminal differentia-tion into somatic structures, some of which are indistinguishable fromnormal adult tissue. To extend this hypothesis, embryonal carcinomamay represent an intermediary form, derived from the totipotent germcell and able to convert to all other variants, although the factors gov-erning this conversion remain unknown. The possibility of such inter-conversion would help explain the frequent appearance of mixed tumorscontaining any or all of these pathologic variants.

In the United States, the classification of testicular cancers isbased on the system described initially by Dixon and Moore in 1952.32

Approximately 95% of all testicular neoplasms are of germinal origin(Table 110.1). Classification of germ cell tumors has been an ongoingprocess since the mid-1940s, and two major systems have remained inuse. The American system is based on the work of Teilum,33 Friedmanand Moore,34 Dixon and Moore,32 Melicow,35 Mostofi,36 and Mostofiand Price,37 and evolved into the current system proposed by theWorld Health Organization in 1977.38 This system is based on the con-cepts of histogenesis as described above, and this germ cell theory issupported by the bulk of clinical and experimental evidence to date.The British classification is based on a different conceptual model ofhistogenesis, and differs from the American system, in that it com-pletely separates seminomas from teratomas, and it fails to recognizethe malignant transformation of the primordial germ cell as the etiol-ogy of teratoid lesions. The system proposed by Collins and Pugh in1964 was updated in 1976 and became the basis for the current systemproposed by the British Testicular Tumour Panel.39,40 Comparison ofthese two systems has been the subject of several reviews, and despitetheir differences, they are remarkably interchangeable.41,42 These twosystems are outlined in Table 110.2.

SEMINOMA Overall, the diagnosis of pure seminoma accounts forapproximately 47% of all testicular cancers, but interestingly, its inci-dence is increased in cryptorchid testes, where it accounts for more than60% of neoplasms.43,44 Currently, seminoma is subclassified as eitherclassic or spermatocytic. Formerly, a third category of anaplastic semi-noma was distinguished histologically, on the basis of a large number ofmitoses per high-power field, an absence of trophoblastic elements, anda tumor appearing less well organized on low-power examination thanits classic counterpart. Although patients with this anaplastic variantmay present with more advanced disease, when stratified by stage ofdisease, survival rates are no different than those for patients with clas-sic seminoma, and ultrastructural characteristics are identical.4547 Onthe basis of these findings, an international panel in 1980 suggested thatthis term be deleted from pathologic classification.48

Classic Seminoma. This subtype accounts for approximately 93%of all seminomas. On gross examination, the tumor is generally roundedand well demarcated, although no formal capsule exists. On cut sections,distinct lobulation is apparent, with nodules separated by dense fibrousbands. Areas of necrosis and hemorrhage may also be observed but, typ-ically, are neither numerous nor large.

Microscopically, there is a monotonous distribution of uniform,rounded cells with large, centralized nuclei and nucleoli. The cyto-plasm may be either clear or granular and will frequently stain posi-tively for glycogen, lipid, and/or alkaline phosphatase. Stromal ele-ments are equally characteristic, with a lymphocytic infiltration thatcan proceed to granuloma formation containing Langerhans-likegiant cells (Plate 23, Fig. 110.1). These areas may predominate histo-logically and mimic granulomatous orchitis. Approximately 7% ofclassic seminomas contain true syncytial trophoblastic giant cells (asdistinct from Langerhans cells) that stain positively for human chori-onic gonadotropin (hCG), and that may account for the low-level ele-vation of serum hCG in some patients with pure seminoma.

Clinically, classic seminoma presents in the fourth or fifth decade,most commonly as an enlarging, painless testicular mass. Only onequarter of seminomas present with metastatic disease; in a review ofover 2,300 cases, Smith documented that 74.7% of patients presentedwith stage I disease, 19.5% with stage II, and only 5.8% with stagesIII and IV.43 Lymphatic spread is to the para-aortic lymph nodes, thento the mediastinal or supraclavicular lymph nodes, usually only afterthe development of significant infradiaphragmatic disease.Hematogenous dissemination to the lung, liver, bone, or adrenal is alate occurrence in the natural history of this disease. Low-level hCG

CHAPTER 110 / Neoplasms of the Testis 1597

Table 110.1. Pathologic Classification of Testicular Malignancies

Primary malignancies

Germinal neoplasms (containing one or more of the following types)1. Seminoma

a. Classicb. Anaplastica

2. Embryonal carcinoma3. Teratoma

a. Matureb. Immature

4. Choriocarcinoma5. Yolk sac tumor (formerly endodermal-sinus tumor)

Nongerminal neoplasms1. Neoplasms of specialized gonadal stroma

a. Leydigs cell tumorsb. Other stromal tumors (androblastoma, Sertolis cells tumor,

granulosa-thecal cell tumor)2. Gonadoblastoma3. Miscellaneous

a. Adenomatoid tumorsb. Adenocarcinoma of the rete testisc. Adrenal rest tumorsd. Mesenchymal tumors

Secondary malignanciesMetastatic carcinomasLymphoeticular malignancies

*The term anaplastic seminoma has been discarded in an updated classification sys-

tem. (Garnick M. Treatment and surgical staging of testicular and primary extrago-

nadal germ cell cancer. JAMA 1983;250:1733-1740.

Table 110.2. WHO* and TTP Classifications of Germ Cell Tumors ofthe Testis

WHO TTP

Tumors of one histologic type

Seminoma SerminomaSpermatocytic seminoma Spermatocytocytic seminomaEmbryonal carcinoma Malignant teratoma, Polyembryoma undifferentiated (MTU)Teratoma Teratoma, differentiatedMatureImmatureWith malignant transformationYolk sac tumor (endodermal sinus tumor) Yolk sac tumorChoriocarcinoma

Tumors of more than one histologic type

Embryonal carcinoma with teratoma Malignant teratoma,(teratocarcinoma) intermediate (MTI)

Choriocarcinoma and any other types Malignant teratoma, (specify) trophoblastic (MTT)

Other combinations (specify) Combined tumor when seminoma present

*WHO, World Health Organization TTP, Testicular Tumour Panel (British)

1598 SECTION 30 / Neoplasms of the Genitourinary Tract tumor is variable because of the common appearance of other germcell elements. In pure form, however, choriocarcinoma is character-ized on cut sections by frequent focal hemorrhages.

Microscopically, the diagnosis requires close proximity of cytotro-phoblasts (ovoid cells with well-defined borders, and with hyperchro-matic or vacuolated nuclei) with the more easily recognizable syncy-tiotrophoblasts (larger, multi-nucleated cells with indistinct bordersand a large amount of eosinophilic cytoplasm). Stroma is sparse, buttends to be highly vascular (Plate 24, Fig. 110.5).

Choriocarcinoma of the testis represents the most aggressivepathologic variant of germ cell tumors in adults, characteristically withearly hematogenous and lymphatic spread. Large-volume visceralmetastases may be observed at presentation with an occult primarylesion. A poorer prognosis in these patients may result from the aver-age volume of disease at presentation, rather than as an inherent resis-tance to therapy with this pathologic pattern. These patients character-istically have extreme elevations of serum levels of hCG, with anormal serum level of AFP.TERATOCARCINOMA The term teratocarcinoma refers to a germcell tumor containing elements of mature teratoma mixed with othergerm cell elements. Macroscopically, there is a variegated appearance,with cystic areas of the mature teratoma admixed with areas of solidtumor representing the malignant elements. Microscopically, separateareas of obviously malignant germinal elements (i.e., embryonal car-cinoma) are in proximity to mature, adult-like structures. Clinically,the aggressiveness of this tumor lies somewhere in between that ofmature teratoma and pure embryonal carcinoma.TERATOMA The term teratoma refers to a germ cell tumor thatcontains elements of all three germ layers (endoderm, mesoderm, andectoderm), present with varying degrees of differentiation. Althoughtechnically no malignant tissue exists in these terminally differentiatedtumors, metastases can occur, and death can result from slowly pro-gressive, unresectable disease. Therefore, the label benign is mis-leading and should be avoided when referring to these tumors. Ter-atoma does not secrete either -hCG or AFP and is not responsive tochemotherapy. Subcategories include mature teratoma, immature ter-atoma, and teratoma with malignant transformation. Surgical extirpa-tion represents the only known therapeutic option.

Macroscopically, primary lesions in the testicle tend to be large,replacing normal epithelium. Cut surfaces show large multi-loculatedcystic areas, with cysts containing serosanguinous fluid. If solid areasare noted grossly, they should be analyzed histologically, as othermalignant germinal elements may be present.

Mature Teratoma. Microscopically, mature (adult) teratoma iseasily distinguished, with obvious epithelial-lined structures, as well asmature cartilage, and striated or smooth muscle (Plate 24, Fig. 110.6).Although each component is histologically mature, the distribution ofthe elements appears haphazard. Overall, testicular teratomas are muchless well organized at an organ level than are their ovarian counterparts.

Immature Teratoma. Several histologic features may result in ateratoma being labeled as immature. The presence of a highly cellularstroma exhibiting mitotic figures is sufficient to make this diagnosis(Plate 24, Fig. 110.7). More commonly, immature teratoma has areasof primitive mesoderm, endoderm, or ectoderm mixed with the moremature elements.

Teratoma with Malignant Transformation. A relatively recentobservation has been of a variant of teratoma that contains malignantnongerm cell elements, presumably derived from somatic tissues withinthe teratoma.57,58 It is unclear whether these elements represent partialdifferentiation along somatic lines of the malignant totipotent germ cell,or malignant degeneration of a mature somatic element of the teratoma.This histopathologic entity may include areas of adenosquamous carci-noma, multiple varieties of soft tissue sarcomas, neuroblastoma, ornephroblastoma. The presence of these malignant somatic tissues, eitherat the time of diagnosis or following induction chemotherapy, is a poorprognostic sign in terms of relapse and overall survival.59

GONADAL STROMAL TUMORS Tumors arising from stromal tissueaccount for only 4% of all adult testicular tumors but represent almost20% of childhood testicular tumors.60 These tumors are thought toarise from primitive gonadal mesenchyme and have been subcatego-

elevation can be seen in 5 to 10% of pure seminomas and is likely aresult of the presence of syncytial trophoblastic elements within thetumor.49 The presence of such hCG elevation, however, does notappear to negatively influence prognosis.4951 Seminoma does notsecrete alpha-fetoprotein (AFP), however, and elevation of this serummarker denotes the presence of nonseminomatous elements.

Spermatocytic Seminoma. Spermatocytic seminoma accountsfor approximately 7% of all seminomas. On gross examination, thisvariant has a grayish appearance and tends to be softer than the classicvariety, containing cystic areas without necrosis or hemorrhage. Micro-scopically, these tumors tend to form tubular clusters and are composedof round cells of highly variable size that are closely related morpho-logically to the three types of cells in the normal spermatocytic series(Plate 24, Fig. 110.2). In contrast to classic seminoma, stromal lym-phocytic infiltration does not occur in spermatocytic seminomas. Clin-ically, this variant tends to occur in an older population than does clas-sic seminoma, with a median age of 65 years. The prognosis isexcellent, as this tumor grows extremely slowly. The appearance ofmetastases is anecdotal, and orchiectomy alone may be the only treat-ment necessary when this diagnosis is made.52

EMBRYONAL CARCINOMA Embryonal carcinoma accounts for 20%of all testicular tumors. Macroscopically, pure embryonal carcinomastend to be small (even in the presence of widespread metastases),although larger tumors can efface the normal testicular tissue. The cutsurface is less homogeneous than seminoma, with frequent areas ofnecrosis and hemorrhage. Direct invasion of the spermatic cord, epi-didymis, and tunica albuginea is common.

The microscopic appearance is extremely variable, a testament to theability of embryonal carcinoma to differentiate into other pathologic vari-ants (Plate 24, Fig. 110.3). Areas of solid neoplasm, tubular or glandularstructures, and hemorrhage or necrosis can exist side by side. Largepolygonal cells with indistinct cytoplasmic borders (unlike seminoma)are the rule, with pale granular cytoplasm, large nuclei, and one or morecentrally placed nucleoli. Mitotic figures and multi-nucleated cells arecommon. In a subset of embryonal carcinomas, spherical structuresresembling embryos of 1 to 2 weeksgestation appear and are referred toas embryoid bodies. The appearance of this as the dominant pattern in thetumor has been given the designation polyembryoma.37

Clinically, these are aggressive tumors with a high metastaticpotential. Embryonal carcinoma may contain differentiated compo-nents of extraembryonic structures, such as trophoblastic or yolk sacelements, with corresponding elevation of the serum levels of hCG orAFP, respectively.YOLK SAC CARCINOMA While yolk sac elements are frequentlyfound in embryonal carcinoma, this pattern can also appear in a pureform. Formerly referred to as endodermal sinus tumor, it is the mostcommon testicular malignancy in infants and young children.37,53,54 Inchildren, it is occasionally designated as infantile embryonal carci-noma or orchidoblastoma and carries an excellent prognosis.55 Macro-scopically, lesions may be large and on cut sections appear yellowish,with areas of cystic degeneration.

Microscopically, patterns show great variety, but commonly,lesions contain cystic areas lined by ovoid or flattened cells that pro-trude into the lumen of the cyst (Plate 24, Fig. 110.4). The appearanceof the endodermal sinus, is pathognomonic; its structure in many waysresembles the mature glomerulus. Clustering of these cells around asmall central blood vessel results in a structure referred to as aSchiller-Duval body.

In adults, pure yolk sac tumor is a virulent neoplasm with earlyhematogenous dissemination and a particular affinity for the develop-ment of hepatic metastases. Primary mediastinal germ cell tumors areespecially prone to exhibiting this type of extraembryonic differentia-tion, with the incidence in one series approaching 50%.56 Serologi-cally, patients with pure yolk sac tumors have elevated serum levels ofAFP, usually with a normal serum level of hCG.CHORIOCARCINOMA Although trophoblastic components are com-mon components of mixed germ cell tumors, pure choriocarcinoma ofthe adult testis is rare. On gross examination, the appearance of the

rized as Leydigs cell tumor, Sertolis cell tumor, gonadoblastoma, andgranulosa-theca cell tumor.61

Leydigs (Interstitial) Cell Tumor. These tumors account for 1to 3% of testicular tumors,32,37,62 and while they may be seen in chil-dren, the median age of appearance is 60 years. Histologically, polyg-onal cells with vacuolated cytoplasm and indistinct cell borders pre-dominate, although fusiform cells may be present. Destruction oftubular structures by malignant cells must be demonstrated to distin-guish this from benign Leydigs cell hyperplasia.

Clinically, symptoms are usually related to the endocrinologicabnormalities induced by this tumor. Leydigs cells synthesize bothandrogens and estrogens, and presenting symptoms may include pre-cocious puberty in a child or gynecomastia in the adult male. Approx-imately 7 to 10% of Leydigs cell tumors metastasize, and this occursonly in the postpubertal patient.6365 In patients with distant metastaticdisease, treatment with radiation therapy or standard chemotherapeu-tic agents has generally been ineffective.

Sertolis Cell Tumor. There is no age predilection for this stro-mal tumor, and the patient may present with a testicular mass; one-thirdof patients present with gynecomastia secondary to tumor estrogen pro-duction. Microscopically, these lesions are composed of rounded cells.The cells have distinct cytoplasmic borders, and large nuclei arrangedin sheets or tubules. As with other stromal tumors, therapy is primarilydirected at resection of the primary lesion, with a staging work-up toinclude abdominal computed tomography (CT) scan and chest radiog-raphy, and no further intervention if these tests are negative.

CLINICAL PRESENTATION

Most patients with testicular cancer seek medical attentionbecause of the development of a painless, swollen testis. Accompany-ing symptoms include a sensation of heaviness or aching in theaffected gonad. Severe pain is quite rare, unless there is associated epi-didymitis or bleeding in the tumor. On occasion, since testicular can-cer is commonly associated with low sperm counts, patients may pre-sent during the course of an infertility work-up.

About 25% of patients with disseminated disease present withsymptoms arising from metastatic disease.66 Severe back pain frommetastasis to the retroperitoneum is the most frequent symptom frommetastatic disease of the testis and is the presenting symptom inpatients with primary retroperitoneal germ cell tumors. Pulmonarycomplaints, such as shortness of breath, chest pain, or hemoptysis, areusually manifestations of far-advanced lung metastases. Primarymediastinal germ cell tumors are an exception, in that these tumors (ifmalignant) present with symptoms of mediastinal compression withpain, dysphagia, shortness of breath, and superior vena cava syn-drome. Benign teratomas of the mediastinum produce few symptomsand are commonly discovered on routine chest film obtained for minorchest complaints.DIAGNOSIS The diagnostic process begins with the physical exami-nation. The examination of the testis is performed by grasping thegonad between the thumb and first two fingers and carefully palpatingthe testis, epididymis, and cord. Tumors of the testis can present witha discrete nodular density or as diffuse infiltration of the entire testis(particularly seminoma and lymphoma). The other testis serves as auseful reference standard to make comparisons.

On occasion, it is difficult to distinguish between a mass within thebody of the testis and a small tense hydrocele; a large hydrocele mayobscure complete palpation. In such instances, trans-scrotal ultra-sound may be useful in discriminating the diagnostic possibilities.Inguinal orchiectomy remains the standard approach for definitivepathologic diagnosis, as well as for ensuring local control of a primarytesticular cancer.

Extragonadal germ cell tumors arising within the retroperitoneumor mediastinum require specialized management. At institutions withexperienced cytopathologists, fine-needle aspiration coupled with ele-vated tumor markers is sufficient. If there is no marker elevation or thecytology is insufficient, a formal biopsy is required. For mediastinalgerm cell tumors, an anterior median sternotomy is favored for diagno-sis. Since chemotherapy is the primary modality of treatment, attemptsat debulking or total removal of mediastinal germ cell tumors as initial

management are inappropriate. Primary retroperitoneal germ celltumors are more commonly associated with an occult testicular primary.Such patients should have a thorough evaluation of the gonads, includ-ing the use of testicular ultrasonography. If a previously unsuspected tes-ticular tumor is found, orchiectomy can serve as the diagnostic proce-dure. Otherwise, fine-needle aspiration of the abdominal mass orexploratory laparotomy is required to provide tissue for diagnosis.

Management of patients who have had a scrotal violation dependson the procedure performed and the anticipated treatment of the malig-nancy. If, at the time of scrotal orchiectomy, the surgeon identified thetumor and removed the testis in toto, then the only additional proce-dure that need be accomplished is removal of the inguinal portion ofthe spermatic cord. This can be done at the time of the retroperitoneallymphadenectomy or through a separate inguinal incision. If a testicu-lar biopsy was performed, management of the hemiscrotum dependson the primary treatment modality. Patients who are receiving primarychemotherapy do not need hemiscrotectomy. Patients managed withsurgery alone should have a hemiscrotectomy performed at the time ofretroperitoneal lymphadenectomy. Inguinal lymphadenectomy isreserved for patients with palpable inguinal lymphadenopathy. Forpatients with early-stage seminoma who have had a scrotal violation,about 5 to 10% will experience local failure. Extending the field toinclude the groin and scrotum diminishes these prospects but is asso-ciated with increased infertility. Such patients should be managed ona case-by-case basis, depending on such issues as the desire to have afamily and compliance with follow-up.TUMOR MARKERS Management of testicular cancer has come todepend on the accurate determination of levels of serum tumor mark-ers and the interpretation of these values in the clinical context. Themost sensitive and specific markers are AFP and the beta subunit ofhCG. AFP is a glycoprotein normally produced by the fetal yolk sacand is derived from the yolk sac or embryonal carcinoma elements ofgerm cell cancers. Levels of AFP are not detectable in normal adults.The half-life of this protein in the serum is about 5 days. hCG is asmaller glycoprotein that is normally produced by trophoblastic tis-sues. In germ cell cancers, syncytiotrophoblastic components elabo-rate hCG. The protein comprises an alpha subunit and a beta subunit,each of which is antigenically distinct. The serum half-life of the entireprotein is 18 to 24 hours.

Clinical decisions in patients with germ cell cancer frequentlydepend on precise measurement of serum tumor markers: beta subunithCG, AFP, and lactate dehydrogenase (LDH). Overall, hCG and/orAFP is elevated in 85% of patients with disseminated testicular andprimary retroperitoneal nonseminomatous germ cell tumors. AFPalone is elevated in 40% of patients, and hCG alone is elevated, whichis somewhat more common, in 50 to 60% of patients with dissemi-nated testicular cancer. Elevated LDH is a less specific marker and isprobably a correlate of disease bulk. Mediastinal nonseminomatousgerm cell tumors more commonly have elevation of AFP (80%) andless commonly of hCG (40%).

Pure seminoma is most frequently associated with normal AFPand hCG, but about 10% of all cases, and up to 30 to 50% of patientswith advanced disease, may have low-level elevation of hCG (usuallyless than 100 mIU/mL).67 Any elevation of AFP in patients with semi-noma must be viewed as evidence of nonseminomatous disease andmanagement should proceed as such.

The role of preorchiectomy determination of markers is limited,particularly since as many as one-third of patients with early-stage dis-ease have normal markers.68 AFP and hCG should be determinedbefore and after orchiectomy, but the absence of marker elevationshould not influence the decision to undertake the procedure. Like-wise, normalization of serum markers after orchiectomy does notensure that all disease has been removed, although persistence ofmarker elevation implies residual disease.

The rate of disappearance of elevated tumor markers is very usefulin determining response to treatment. hCG is the most useful in thisregard; the most clinically helpful guideline is that a 10-fold decreasein the hCG level over a 3-week period is consistent with disease eradi-

CHAPTER 110 / Neoplasms of the Testis 1599

1600 SECTION 30 / Neoplasms of the Genitourinary Tract Several staging systems have been proposed for seminomatousgerm cell tumors. The majority of stage groupings define stage I asdisease limited to the testicle or scrotum with no metastases to lymphnodes or distant sites. Discrepancies occur in defining stage II, whichgenerally implies evidence of nodal dissemination occurring belowthe diaphragm (Table 110.4). While all recognize tumor burden asprognostically important, differences relate to the perceived relativeimportance of multi-centricity, small tumor burden, and large tumorburden. In assigning categories for identifying tumor bulk, some stag-ing systems remain vague (e.g., those of the Massachusetts GeneralHospital and the Princess Margaret Hospital), whereas others disagreeas to the proper dimension cut-offs (e.g., The Royal Marsden Hospitaland The M.D. Anderson Cancer Center). The different criteria used todefine stage II make comparisons of reported outcomes between insti-tutions using different staging systems open to misinterpretation.Stage III typically indicates nodal disease above the diaphragm. StageIV identifies patients with extranodal disseminated disease.

Recently, the American Joint Committee on Cancer (AJCC) hasrefined the classification system and included the important aspect ofelevated tumor markers into the classification system. This TNM-based system adds important local prognostic parameters, such as vas-cular invasion; more regional nodal information, including size; andvisceral versus nonvisceral metastasis and markers levels. This newAJCC and World Health Organization classification should be the newinternational standard (Table 110.5).69

Standard procedures to establish clinical stage include abdominaland chest CT, with other studies (e.g., bone scan, brain CT) performedonly as warranted by clinical symptoms. With CT-based staging, 25%of patients will be understaged, and 10 to 20% will be overstaged.These limitations in clinical staging have led to a policy of surgicalstaging that provides accurate pathologic parameters of disease extentand simplifies follow-up.

Historically, bipedal lymphangiography has been a standard stag-ing study for seminoma. Its role has been challenged with the adventof modern CT scanning, since nonpalpable disease > 1.0 cm can beeasily identified without the risk of a moderately invasive procedure.Moreover, fewer radiologists are being trained in the United States toperform the study and interpret its results. Nonetheless, recent studieshave demonstrated the utility of lymphangiograms in detecting abnor-mal lymph node architecture in 13 to 22% of patients with negativeabdominal CT scans.7072 As expected, institutions where lymphan-giography has not been routinely used report stage distributions withrelatively more patients classified as stage I and fewer with stage II.73

cation. Less steep declines of hCG levels may correlate with the emer-gence of drug-resistant disease in the case of chemotherapy, or residualdisease in the case of surgery. Likewise, the reappearance of markerelevation often predates the radiographic appearance of recurrent dis-ease and, as such, is an invaluable method of detecting early relapse.

While the presence of tumor markers and their accurate determi-nation serve as a luxury in the management of patients with germ cellcancer, the presence of these markers also can lead to errors in clini-cal management, if not interpreted with caution. First, hCG determi-nation can be nonspecific, and there is some cross-reactivity in theradioimmunoassay with luteinizing hormone. Also, hCG can befalsely elevated in patients who use marijuana. Low levels of hCG ele-vation consequently are difficult to interpret. A conservative approachto this dilemma is to repeat the hCG determination to ensure that theelevation is not a laboratory error. If the level is still high, the patientshould be queried regarding drug usage. Testosterone should be givento ensure that a hypogonadal state with resultant high levels ofluteinizing hormone is not interfering with the determination of hCG.If the level remains increased, restaging procedures and investigationof sanctuary sites are in order.

A recent example of how blind dependence on predicted hCGdeclines can lead to treatment errors was demonstrated at Indiana Uni-versity in the retrospective review of management strategies in patientswith very high hCG levels. Forty-one patients with an hCG greater than50,000 mIU/mL were included. All patients received modern cisplatin-based chemotherapy. As expected 40 of 41 had advanced disease by theIndiana prognostic classification system. The overall results reveal that22 patients (54%) are continuously free of disease, and 8 more are cur-rently free of disease with additional therapies. Only 2 of these 41patients had normal hCG levels at the time of the fourth course ofchemotherapy. Eight additional patients had normalized the hCGwithin 1 month of the fourth course of therapy. Of these patients, 7remain continuously free of disease, and 3 are currently disease freewith salvage therapy. Thirty-one patients had an abnormal hCG > 1month after completing the fourth course of primary chemotherapy.Fifteen of these patients are continuously disease free, despite no fur-ther treatments. An additional 5 patients are currently disease free withsalvage treatments. The median level of hCG for these 15 patients at 1month was 24 mIU/mL (range 277). The median time to normaliza-tion was 149 days (range 114230 days). This review highlights a sub-set of patients with very high hCG levels that do not have a consistentpredictable decline of hCG with treatment. Absolute dependence onpredicted patterns of decline in these patients would have resulted inovertreatment or inappropriate initiation of salvage therapy.

False-positive elevation of AFP is quite rare. Differential consider-ations include laboratory error, other tumor types (such as hepatocel-lular carcinoma), and liver inflammation from cirrhosis or hepatitis.

STAGING

Nonseminomatous germ cell tumors are typically catagorized asstage I (or A), referring to tumors confined to the testis; stage II (or B),indicating metastatic disease to the nodes of the periaortic or venacaval zone without pulmonary or visceral involvement; and stage III(or C), which denotes metastasis above the diaphragm or involvingother viscera (Table 110.3).

Table 110.3. Memorial Sloan-Kettering Staging System for Nonseminomatous Germ Cell Tumors

Stage A: Tumor confined to the testisStage B: Minimal nodal spread, microscopic only and with fewer

than six nodes involved, none more than 2 cmStage B2: Grossly positive nodes, or more than six nodes positive in

the retroperitoneumStage B3: Bulky retroperitoneal involvement, unresectableStage C: Metastases above the diaphragm or involvement of the solid

visceral organs, brain, or bone

Table 110.4. Stage II Seminoma: Variations in Definitions

Stage IIClinical or radiographic evidence of involvement of femoral, para-aortic,iliac, or inguinal nodes with no demonstrable metastases to visceral organs orabove the diaphragm

Princess Margaret HospitalStage IIA No palpable massStage IIB Palpable mass

Royal Marsden HospitalStage IIA Lymph node metastasis less than 2 cmStage IIB Lymph node metastasis 2 to 5 cmStage IIC Lymph node metastasis more than 5 cm

Massachusetts General HospitalStage IIA Minimal retroperitoneal diseaseStage IIB Bulky retroperitoneal metastasis

M.D. AndersonStage IIA Lymph node metastasis less than 10 cmStage IIB Lymph node metastasis equal to or more than 10 cm

American Joint Commission on CancerStage II (T3, N1, M0) Single homolateral regional lymph nodeStage III (Any T, N2, M0) Contralateral, bilateral or multiple lymph

nodesStage IV (Any T, N3, M0) Palpable abdominal mass present or fixed

inguinal lymph nodes

Of course, outcome data from such series must be interpreted accord-ingly. In addition, the pattern of dye uptake allows for accurate radia-tion therapy portal design that maximizes nodal coverage, while min-imizing normal tissue exposure.

The role of newer imaging technologies such as positron emis-sion tomography (PET) are being investigated. To date, there hasbeen little evidence that routine PET adds to classic imaging with CTand has been unreliable in distinguishing viable malignancy fromnecrosis or teratoma.74

THERAPY

NONSEMINOMA: EARLY STAGE There is an ongoing controversyregarding the management of early-stage nonseminomatous germ celltumors. This controversy has been spurred, in part, by the phenomenalsuccess of chemotherapy in disseminated disease and increasing con-cern regarding the acute and long-term toxicities of curative therapy.

Knowledge of the natural history of testicular primary lesions andtheir lymphatic drainage patterns is key to understanding the thera-peutic options available. Testicular lymphatics arise in proximity to theembryonic origin of the testicle, in the genital ridge in the high lumbarregion. Although the afferent lymphatic channels accompany testicu-lar descent into the scrotum, draining lymph nodes remain in theretroperitoneum, including first-echelon lumbar nodes and second-echelon iliac chain nodes.

The specific patterns of lymphatic drainage for testicular tumorshave been known for over 80 years. In 1910, Jamieson and Dobsondemonstrated that the drainage pattern differed according to the sideof the primary lesion, with right-sided lesions draining to the para-caval, interaortocaval, and preaortic nodes, and left-sided lesions tothe paraaortic and preaortic nodes.75

RETROPERITONEAL LYMPH NODE DISSECTION On the basis of theknowledge of a predictable pattern of spread of testicular tumors, mul-tiple reports of retroperitoneal lymph node dissections (RPLND) sur-faced from 1907 through 1950,7678 with a significant improvement inthe 5-year survival to 46%. A number of surgical techniques have beendescribed to expose and resect retroperitoneal lymph nodes. Radicallymphadenectomy via a thoracoabdominal (extraperitoneal) approachwas described in 1950,79 while reports of pure abdominal (anterior)approaches dominated the 1970s,8082 with each approach havingintrinsic advantages. The extraperitoneal approach allows easy expo-sure on the ipsilateral side, whereas the anterior approach is preferablewhen bilateral dissections are undertaken. An extension of the anteriorapproach, which included bilateral renal suprahilar dissection, waspioneered by Donohue.83

In experienced hands, the classic, bilateral RPLND, as described, isassociated with minimal perioperative morbidity and virtually no mor-tality.84 A major side effect of this approach, however, is the loss ofantegrade ejaculation, with resultant infertility in over 90% of patients,a significant factor in young men in the 15- to 34-year age group. Sev-eral nerve-sparing modifications of the classic node dissection havebeen described, in an attempt to minimize ejaculatory dysfunction andmaintain the staging and/or therapeutic benefit of the procedure. Ananatomic basis for such modified procedures has been provided by sev-eral meticulous mapping studies of retroperitoneal node involvement inearly-stage disease.8587 In the study by Donohue and colleagues,patients with grossly negative, microscopically involved nodes (stageB1) were analyzed separately.85 In right-sided primary lesions, nopatient had involvement of the suprahilar regions, and only 4% had leftpara-aortic (contralateral) node involvement. Similarly, in left-sided B1disease, no patient exhibited right paracaval or precaval involvement.These studies suggested that full bilateral dissection is unnecessary inpatients with grossly negative nodes at the time of surgery.

Unilateral lymph node dissections have, therefore, become popu-lar for treating early-stage disease, both in the United States88,89 andin Europe.87,90,91 Modifications to the classic dissection have gener-ally involved complete dissection of lymph nodes on the same side asthe primary lesion, with limited (if any) intervention on the contralat-eral side, thus preserving the contralateral sympathetic efferents andejaculatory function in 75 to 90% of patients. Particular emphasis isgiven to avoidance of the region anterior to the aortic bifurcation, as

nerves exiting the thoracolumbar sympathetic trunk cross this regionand become the hypogastric plexus. Preservation of these fibersappears to be particularly important in the maintenance of ejaculatoryfunction. In a more recently described procedure by Donohue and col-leagues, postganglionic sympathetic fibers from lumbar ganglia areprospectively identified and preserved prior to lymphadenectomy.92

Of 75 patients treated in this manner, all are alive and disease free at 2years, and 100% have preservation of antegrade ejaculation.Retroperitoneal recurrences occurred in 3 of 14 stage B patients, andin none of the 61 pathologic stage A patients. An updated experience

CHAPTER 110 / Neoplasms of the Testis 1601

Table 110.5. AJCC Staging

TNM Clinical Classification

T-Primary TumorThe extent of the primary tumor is classified after radical orchiectomy (see pT). If no radical orchiectomy has been performed, TX is used.

N-Regional Lymph NodesNX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis with a lymph node mass 2 cm in greatest dimension

or multiple lymph nodes, not > 2 cm in greatest dimensionN2 Metastasis with a lymph node mass > 2 cm but not > 5 cm in

greatest dimension, or multiple lymph nodes, any one mass > 2 cmbut not > 5 cm in greatest dimension

N3 Metastasis with a lymph node mass > 5 cm in greatest dimension

M-Distant MetastasisMX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

M1a Nonregional lymph node or pulmonary metastasisM1b Distant metastasis other than to nonregional lymph node and lungs

pTNM Pathological Classification

pT-Primary TumorpTX Primary tumor cannot be assessed (if no radical orchiectomy has

been performed TX is used) pT0 No evidence of primary tumor (e.g. histologic scar in testis)pTis Intratubular germ cell neoplasia (carcinoma in situ)pT1 Tumor limited to testis and epididymis without vascular/lymphatic

invasion, tumor may invade tunica albuginea but not tunica vaginalispT2 Tumor limited to testis and epididymis with vascular/lymphatic

invasion, or tumor extending through tunica albuginea withinvolvement of tunica vaginalis

pT3 Tumor invades spermatic cord with or without vascular/lymphaticinvasion

pT4 Tumor invades scrotum with or without vascular/lymphatic invasion

pN-Regional Lymph NodespNX Regional lymph nodes cannot be assessedpN0 No regional lymph node metastasispN1 Metastasis with a lymph node mass 2 cm in greatest dimension

and 5 positive nodes, none > 2 cm in greatest dimensionpN2 Metastasis with w lymph node mass > 2 cm but not > 5 cm in

greatest dimension; or > 5 nodes positive, non > 5 cm; or evidenceof extranodal extension of tumor

pN3 Metastasis with a lymph node mass > 5 cm in greatest dimension

pM-Distant MetastasisThe pM category corresponds to the M category

S-Serum Tumor MarkersSX Serum marker studies not available or not performedS0 Serum marker study levels within normal limits

LDH hCG(mIU/L) AFP (ng/mL)S1 50,000 or >10,000

N = the upper limit of normal for the LDH assay; LDH = ; hCG = human chorionic

gonadotropin.

1602 SECTION 30 / Neoplasms of the Genitourinary Tract The current recommendation for patients with pathologic stage Anonseminomatous disease is for no further therapy to be administeredfollowing RPLND. This recommendation is based on the high surgicalcure rate with orchiectomy and RPLND alone (90%), the favorablerelapse pattern in patients who recur (lung only), and the effectiveness ofchemotherapy for small-volume metastatic disease in relapsing patients.CLINICAL STAGE A As the vast majority of testicular cancer patientsare cured today even in the presence of minimal to moderate distantmetastatic disease, attention has been focused on a reduction in thetoxicity of curative therapy. For nonseminomatous disease clinicallylimited to the testicle, this has resulted in a reconsideration of the needfor RPLND and its attendant morbidity. This type of surveillance pol-icy has been quickly accepted but must be considered in the context ofits effect on the natural history of the disease, the implications forpatient follow-up, fertility, the potential need for chemotherapy, andultimately patient survival.

The accurate diagnosis of clinical stage A disease is critical to theconsideration of less interventional therapy. Following inguinal orchiec-tomy and the diagnosis of nonseminoma, serum levels of -hCG andAFP must return to normal (if elevated before orchiectomy), andabdominal CT, chest radiography, and chest CT must all be negativefor metastatic disease before a patient can be labeled as having clini-cal stage A disease. In this clinical setting, approximately 30% ofpatients will suffer a relapse if no other therapy is administered, withthe retroperitoneum remaining as the area at highest risk.

There are now reports of almost 1,000 patients worldwide withclinical stage A disease, who have had no other therapy administeredfollowing orchiectomy, with relapse rates and survival remarkablysimilar between trials, regardless of the size of the study or country oforigin (Table 110.6). These studies have confirmed a relapse rate ofalmost 30% despite optimal clinical staging. Of 236 relapsing patientsin these trials in whom current disease status is available,104 94% werealive and disease free at the time of the reports. This survival figure iscompetitive with that of pathologic stage A disease, confirming thatthis is a reasonable therapeutic alternative in experienced hands.

Optimally, prognostic factors could be identified to select a group ofpatients at higher risk for disease recurrence than the remainder of stageA patients, which would allow the targeting of toxic therapy (surgery orchemotherapy) to those individuals most likely to benefit from it. Alarge number of retrospective and prospective analyses of patients withclinical stage A disease have now been performed, and severalhistopathologic features of the primary tumor have been identified thatare independently predictive of relapse in multivariate analysis. Theseinclude vascular invasion;105113 lymphatic invasion;105,107 pathologic Tstage higher than 1 (see Table 110.6);106108,111,114,115 the presence ofcomponents of embryonal carcinoma;108,112 percent of the primarytumor occupied by teratoma;106 and the presence or absence of yolk sacelements.105 Freedman and colleagues developed a mathematical model

with clinical stage A patients (and nerve-sparing RPLND) has con-firmed the early results with the procedure. Ejaculation is reliablymaintained, retroperitoneal recurrence is rare, and more than 99% ofpatients ultimately are cured.83 Thus, it appears that the majority ofpatients can have their ejaculatory function preserved followingretroperitoneal node dissection for early-stage disease, without a sac-rifice in terms of retroperitoneal relapse or survival.RADIOTHERAPY While RPLND has been a mainstay of therapy forearly-stage nonseminomatous germ cell tumors in the United Statesfor the past 40 years, radiation therapy has been used in similar clini-cal situations in Europe, particularly in the United Kingdom and Den-mark. Data from the Royal Marsden Hospital were reported for bothclinical stage A (with negative lymphangiogram) and clinical stage B(positive lymphangiogram).93

Patients with clinical stage A disease received 4,000 cGy to theretroperitoneum, experienced a 17% relapse rate (including 4.7% inthe retroperitoneum), and a 2-year disease-free survival of 84%. Radi-ation therapy was well tolerated with minimal acute toxicity, althougha later report from the same institution suggested an increased inci-dence of peptic ulcer disease in irradiated patients, a finding now con-firmed by other groups.94 In patients with clinical stage B disease,4,500 cGy was given to the retroperitoneum, as well as 4,000 cGy tothe mediastinum and the supraclavicular regions bilaterally. Radio-therapy was much less effective in this clinical setting, with a relapserate of 52% (42% in the retroperitoneum) and an overall survival ofonly 58% on follow-up of 3 to 12 years.

Extensive experience with radiotherapy has also been reported bythe Danish Testicular Carcinoma Study Group (DATECA). Prior to1980, patients with clinical stage A disease were treated with infradi-aphragmatic radiotherapy, as well as adjuvant chemotherapy withbleomycin and vincristine. The 2-year disease-free survival of 87%was found to be statistically significantly better than that of 74% in agroup of patients treated off-study with radiotherapy alone.95 In a sub-sequent randomized DATECA study on clinical stage A disease,patients received either orchiectomy alone or orchiectomy followed byinfradiaphragmatic radiotherapy.96 The group receiving radiotherapyhad a significantly lower overall relapse rate, with complete elimina-tion of retroperitoneal relapses.

Although data from the United States on radiotherapy in early-stage disease have been sparse97 they have, in general, supported theEuropean trials. Today, the use of radiotherapy in this clinical situationis limited, on the basis of both the success of cisplatin-based combina-tion chemotherapy in distant metastatic disease and the prevalence ofsurveillance as a treatment option in clinical stage A disease.

TREATMENT VERSUS CANCER STAGE

PATHOLOGIC STAGE A Patients with disease clinically limited tothe testicle who undergo staging RPLND and are found to havepathologically negative lymph nodes are classified as pathologicstage A. Relapse rates and 5-year survivals in these surgically stagedpatients have been reported from a number of institutions.81,91,98101

With relatively few changes in the surgical technique of RPLNDfrom 1950 to 1980, relapse rates, and particularly intra-abdominalrecurrences, have remained at a constant level. The overall relapserate for these patients is approximately l0%, with the great majorityof relapses occurring in the lungs, since the surgical procedure haseffectively removed the retroperitoneum as a significant site ofrelapse. However, with a significant improvement in the therapy fordistant metastatic disease and clinical staging techniques over thatsame period, 5-year survival rates improved from 77% in 1969102 toalmost 98% in 1987.103

In the largest prospective study of observation in pathologic stageA nonseminomatous disease, the Testicular Cancer Intergroup Studyenrolled 264 patients after RPLND.103 With a median follow-up of 45months, 28 patients (10.5%) had recurred, 25 of whom developed afirst relapse within 24 months of node dissection. Six patients (2.3%)died, although only 2 of the 6 died of drug-resistant cancer. At the timeof the report, 97.7% of patients were alive and disease free.

Table 110.6. Studies of Surveillance Following Orchiectomy in ClinicalStage A Nonseminomatous Germ Cell Tumors

Series Relapse Alive/NED Follow-up

(reference) Patients (%) post-relapse (median), months

(234) 67 14(21) 13 12-60 (NR)(205) 85 23(27) 22 24-64 (42)(83) 259 70(27) 67 NR (30)(64) 93 28(30) NR 12-61 (34)

(219) 85 23(28) 23 60 (NR)(250) 69 15(22) 13 2-63 (31)(210) 46 13(28) 11 6-88 (40)(196) 109 30(28) 30 6-66 (30)(212) 45 11(24) 11 6-39 (NR)(191) 14 3 (21) 3 NR (16)(258) 20 8(40) 8 NR (14)(269) 36 12(33) 10 14-92 (36)(114) 24 5(21) 3 33-27 (NR)(195) 41 9(22) 9 11-127 (37)

Total 993 264(26.6%)

on the basis of the four identified prognostic factors in the MedicalResearch Council (MRC) study in the United Kingdom and were able toidentify a subset of patients with a 58% relapse rate at 2 years.105

While the excellent results with surveillance in centers with greatexpertise in the treatment of testicular cancer are clear, there are someinherent dangers with this approach, making its applicability on thecommunity level somewhat less clear. Patients selected for thisapproach in reported studies have, in general, been highly motivatedindividuals, able logistically and psychologically to comply with man-dated follow-up procedures. Accuracy of clinical staging is critical andis proportional to the number of cases seen. This staging may be infe-rior at institutions seeing only a handful of cases per year. The optimalfrequency of visualization of the retroperitoneum (the most frequentsite of relapse) has not been determined. The schedule of intensive fol-low-up (normally 2 years) may be insufficient, as relapses have contin-ued (4% a year) in the third and fourth years of follow-up in the MRCtrial. Patients have the potential to relapse with larger-volume diseasethan after RPLND. Such patients may have an inferior response tochemotherapy and reduced survival. The presence of occult teratoma inthe retroperitoneum that is not removed at staging RPLND may predis-pose to late relapse (see Special Considerations below).

Primary Chemotherapy. The efficacy and safety ofchemotherapy for good risk metastatic disease and the near perfectresults of two cycles of chemotherapy in the setting of fully resectedstage II disease has prompted investigators to consider the use of pri-mary chemotherapy in high-risk stage I disease. Several small serieshave been reported.24,116118 Most recently, a report from the MRCreported the use of bleomycin, vincristine, and cisplatin for two cyclesas an adjuvant therapy for those patients with high-risk clinical stage Idisease defined by the presence of vascular invasion.119 In this studyof 115 patients, therapy was well tolerated, but there have been 2relapses and 1 death.

Primary chemotherapy is incompletely investigated and has thepotential for significantly more long-term consequences. While favor-able initial reports have suggested a near universal cure with twocycles of chemotherapy in patients with poor-risk early-stage disease,these studies have reported deaths from treatment and progressive dis-ease. The studies are significantly underpowered to be definitive,especially when one considers that 50% or more of such patients hadbeen cured with orchiectomy alone. In addition, it is a not unusual, atthe time of surgery, to find grossly involved lymph nodes despite anegative abdominal CT scan. It is such patients who are at risk forundertreatment with abbreviated chemotherapy. Such patients mayultimately require significantly more treatment than would have beenrequired with nonchemotherapeutic approaches. As well, patients mayhave an increased risk of developing drug-resistant disease and failure.Until more accurate discriminators of risk are available, we do notfavor exposing patients to chemotherapy with the attendant risk of sec-ond malignancies and endocrinologic consequences whennonchemotherapeutic approaches are readily available and effective.PATHOLOGIC STAGES B1, B2 There is controversy regarding the opti-mal management of patients with clinical stage A disease who arefound at RPLND to have nodal metastases, either microscopically(B1) or grossly (B2) involved. Approximately 50% of patients withnodal involvement at RPLND relapse, if no additional therapy isgiven. Surgical series have shown that pathologic B1 patients recur atthe 10 to 25% level, if managed by observation after RPLND, whereaspathologic stage B2 patients recur 50% of the time, if observed afterRPLND.120,121 In light of the effectiveness of chemotherapy in dis-seminated disease, investigators have logically addressed the possibil-ity of using it as a postoperative adjuvant in resected stage B patientsor even as a substitute for surgery in clinical stage B disease.

A number of nonrandomized studies using single-agent or low-dose chemotherapy have been reported and have had little impact onthe relapse rate in resected patients.80,122

Significant improvements in relapse rates following adjuvantchemotherapy were not seen until cisplatin-based regimens were intro-duced. At the Memoral Sloan-Kettering Cancer Center (VAB-3), useof an early cisplatin-containing regimen in 29 patients with resected Bdisease completely eliminated relapses, with a median follow-up of 24

months.122 Similarly striking results were noted in two nonrandomizedtrials in patients with low-volume retroperitoneal metastases using cis-platin, vinblastine, and bleomycin.123,124

A large, prospective, randomized, multi-national trial in this clini-cal setting was the Testicular Cancer Intergroup Study.125 In this study,195 pathologic stage B patients were randomly assigned to no furthertherapy after RPLND, or to two immediate postoperative courses ofadjuvant chemotherapy, either PVB (cisplatin, vinblastine, bleomycin)or VAB-6 (cisplatin, vinblastine, bleomycin, actinomycin-D,cyclophosphamide). Results were reported in 1987, with a median fol-low-up of 4 years. Predictably, there was a significant difference inrelapse-free survival, with 49% of the observation group relapsing,compared with 6% of patients assigned to receive adjuvant chemother-apy. However, the difference is even more striking, as only 1 of the 6relapsing patients in the adjuvant arm actually received his assignedtherapy, and 1 patient on retrospective analysis had an inadequateRPLND. Thus, two courses of cisplatin-based therapy in completelyresected stage B patients effectively eliminated the possibility ofrelapse. No specific histopathologic features were predictive of relapse,although there was a nonstatistically significant trend toward a higherrelapse rate with increasing nodal stage. This contrasts with previousreports suggesting that relapse was highly correlated with the degree ofnodal involvement. In terms of survival, there was no significant dif-ference between the two groups, indicating that either approach shouldresult in a greater than 95% cure rate, provided that complete surgicalresection is undertaken and meticulous follow-up observed.

More recently, Motzer and colleagues have investigated the use oftwo cycles of etoposide and cisplatin at 3-week intervals in the settingof pathologic stage II nonseminomatous germ cell tumor.126 Fiftypatients were treated. All remain alive and disease free. The smallnumber of patients in the study and the fact that a large number ofpatients were likely cured with surgery alone raises the questionregarding the power of the study to detect a small nagative impact onoutcome of the two-drug combination. Behnia and colleagues at Indi-ana University reviewed 86 patients treated with two cycles ofbleomycin, etoposide, and cisplatin at 4-week intervals.127 Again, allpatients remained cancer free in long-term follow-up. In keeping withthe principles of adjuvant therapy for other diseases in which the besttherapy for metastatic disease makes the best adjuvant therapy, we cur-rently recommend two cycles of BEP in this setting.CLINICAL STAGE B2 In patients undergoing clinical staging andthose found to have nonbulky abdominal disease (nonpalpable, mass 5 cm, more than five nodes involved on CT) should be treatedwith primary chemotherapy. After achievement of a serologic com-plete remission (normalization of serum -hCG and AFP), restagingwith abdominal CT is performed followed by, if necessary, surgicalresection of residual radiographic abnormalities, as discussed below. SEMINOMA EARLY STAGE Orchiectomy and postoperative radiationtherapy have constituted the standard of care for early-stage seminomapatients during most of the 20th century.128131 A properly performedradical orchiectomy by an inguinal approach is highly effective ther-apy for controlling disease at the primary tumor site. Occult or grosspara-aortic lymphatic tumor deposits can be eradicated with highprobability after low doses of radiation therapy, owing to the extremeradiosensitivity of seminoma. More recently, success in surveillancetrials in stage A nonseminomatous testicular cancers has naturally ledto similar investigations for seminoma. These trials, while still ongo-ing, have afforded the opportunity to learn more about the natural his-tory of early-stage seminoma. Regardless of whether surveillancebecomes a standard part of clinical practice for seminoma, these sci-entific trials are providing information that will undoubtedly affectclinical practice. With a large majority of patients experiencing pro-longed disease-free survival in early-stage seminoma, long-term qual-ity-of-life end points will assume increasing significance in evaluatingtreatment strategies.

Stage I Seminoma: Primary and Adjuvant Therapy. Prior tothe advent of lymphangiography and other sensitive staging studies,policies of postorchiectomy adjuvant radiation therapy for seminomawere adopted at major institutions in the United States and overseas.Postoperative radiation therapy was felt to be justified given the sig-nificant fraction of patients who would have recurrences after orchiec-tomy, the extreme radiosensitivity of seminoma, and the lack of ade-quate systemic therapies for disseminated recurrence. Thesetherapeutic recommendations continued even after improvementswere made in the sensitivity and specificity of staging studies and afterthe recognition of highly effective systemic therapies. The reluctanceto modify treatment recommendations stems from the very high curerate and acceptable toxicity profiles with postorchiectomy adjuvantradiation therapy. Stage I patients treated with postorchiectomy radia-tion therapy as described below will experience 15 to 20 year cause-specific survival in excess of 90%.132,133

Standard treatment starts with radical orchiectomy consisting ofearly clamping of the spermatic cord at the external inguinal ring, fol-lowed by en bloc resection of the testis with its surrounding tunics.After appropriate staging evaluations, postoperative radiation therapyis delivered to include the bilateral abdominal para-aortic/paracavaland common iliac lymphatics and the ipsilateral external iliac lym-phatics. The mediastinal and left supraclavicular lymphatics are notincluded in the treatment portals for stage I, as the risk of eventualrelapse in these sites is only around 1 to 2%.73,134 The upper border ofthe field is typically placed at the upper plate of T10, while the lowerborder includes the cut end of the ipsilateral spermatic cord, typicallyat the top of the obturator foramen. The field width should be designedto give margin on the para-aortic/paracaval lymph nodes, the renalhilar lymph nodes (particularly for left-sided primary tumors), andiliac lymph nodes. The remaining testicle should be shielded fromscatter dose using a gonadal shield or clam shell in patients whowish to preserve fertility.135 The treatment is carried out in anteriorand posterior opposed fields, utilizing megavoltage equipment. Thetotal dose should not exceed 30 Gy, and a dose of around 25 Gy in a1.25- to 1.5-Gy daily fraction appears adequate.136,137

Modifications to the standard portals may be appropriate on thebasis of atypical patient characteristics. If the primary tumor is mas-sive or invades the scrotum, or if tumor is present at the cut end of thespermatic cord, the remaining ipsilateral hemiscrotum and inguinallymphatics should be treated, usually with electrons, matching to theinferior border of the primary field. The proper treatment for patientswith scrotal violation or previous groin surgery is controversial. In the

ria for an effective surveillance program in seminoma after orchiec-tomy have been established: (1) the incidence of occult metastatic dis-ease should be low, (2) follow-up should be carried out such thatrelapses are detected early, (3) relapses should be readily curable, and(4) the morbidity of the follow-up policy and salvage therapies shouldbe less than that produced by initial adjuvant therapy of all patients.Although the actual incidence of occult metastatic disease in clinicalstage I seminoma patients was not known prior to the inception ofsurveillance trials, it was felt to be as low as 8% and as high as 20 to30%.144,145 If follow-up policies were properly designed, relapsingpatients could be identified early with low-stage disease, which couldbe treated with radiation therapy appropriate for nonbulky stage II ini-tial presentations. Modern cisplatin-containing multi-agentchemotherapy has been recognized as a highly effective systemic ther-apy for both salvage and initially extensive presentations of seminoma.While these regimens include a significant risk of complications,including early toxic deaths,146 the expected low rate of relapsingpatients ultimately requiring systemic therapy theoretically wouldtranslate into an overall highly acceptable toxicity profile, given thatthe majority of patients would be cured by orchietomy alone andspared adjuvant therapy altogether.

The experiences from three surveillance studies with more than100 patients and long-term follow-up have been reported.139141 Asseen in Table 110.7, 17% of enrolled patients eventually relapsed in thecumulative experience after orchiectomy alone, which is significantlyhigher than the < 5% relapse rate seen in series with similar follow-upemploying postorchiectomy radiation therapy. Despite fairly intensivefollow-up, including frequent abdominal imaging, 22% of relapsingpatients had either bulky abdominal, supradiaphragmatic, or dissemi-nated disease. Additional patients had a second relapse after salvageradiation therapy, such that a higher than expected 36% of relapsingpatients (6% of all patients enrolled) ultimately required systemicchemotherapy for salvage. Unlike nonseminoma surveillance trials,where the median time to relapse is < 6 months,147 seminoma relapsesoccur much later, with a median interval of 15 months, as well as sev-eral late relapses up to 5 years. The vast majority of relapsing patientswere eventually salvaged so that less than 1% of patients died of semi-noma or seminoma therapy.

Each of these large studies used multivariate analysis to identifysubset characteristics associated with higher relapse. The Danish studyexamined several variables but only identified higher relapse withlarger primary testicular tumors and recommended avoiding surveil-

lance when the primary tumor is larger than 6 cm (a small minority ofpatients). Blood vessel and/or lymphatic vessel invasion was associatedwith higher relapse in the Royal Marsden Hospital study, but not in theothers. The investigators from the Princess Margaret Hospital studywere the only group to identify younger patient age as a variable asso-ciated with higher relapse. Since there is no reliable tumor marker forseminoma, there is currently no effective method to identify patientsmore prone to relapsing up front who might best be treated with pos-torchiectomy radiation therapy as opposed to surveillance.

As predicted, ultimate control and survival for patients enrolled insurveillance trials are equivalent to the excellent results obtained withpostorchiectomy radiation therapy. Around 20% of patients willrelapse, and 40% of these patients subsequently will get more cancertherapy than if treated after orchiectomy. Overall, more than twice asmany patients will ultimately require systemic chemotherapy insurveillance trials, compared with those treated with postorchiectomyradiation therapy. This must be balanced by the fact that 80% ofpatients are cured in surveillance programs without any adjuvant ther-apies and their associated toxicities. The merits of surveillance, then,rest on the degree of associated toxicity and the potential ability todecrease that toxicity. To avoid chemotherapy, the relapse must bedetected early. As shown in Table 110.7, follow-up examinations werethe least frequent in the Royal Marsden Hospital trial, and the requireduse of chemotherapy was the most frequent. More frequent follow-up,including abdominal imaging, may allow the earlier detection ofsmall-volume disease but clearly will add to the costs of surveillance.Quality-of-life end points, such as psychologic stress associated withsurveillance and fear of second malignant neoplasms, have not beencarefully examined in either postorchiectomy adjuvant therapy orsurveillance reports. Careful long-term toxicity follow-up in patientstreated with surveillance will be necessary before surveillance gainswidespread acceptance. Currently, it should still be considered aninvestigational approach.

Stage II Seminoma: Nonbulky Disease. The first controversyencountered when setting out to describe how to manage nonbulkystage II seminoma is in defining nonbulky. Numerous staging sys-tems have been proposed, as outlined in Table 110.4. There is generalagreement that nodal disease with a dimension > 10 cm is bulky, andthat disease < 5 cm is nonbulky. The Princess Margaret Hospitals iden-tification of a palpable abdominal mass as bulky may correlate with a

CHAPTER 110 / Neoplasms of the Testis 1605

Table 110.7. Results of Stage I Seminoma Surveillance Trials

Royal Marsden Princess Margaret Danish

Hospital* Hospital Test Totals

Number of patients 113 148 261 522Median follow-up, months 62 47 48 50.8Range of follow-up, months 14-141 7-87 6-67 6-141No. of follow-up examsd in 3 years 10 15 11 12

No. of CT/US examse in 3 years 5 9 8 7.3

No. of relapses (% of all patients) 17 (15%) 23(16%) 49 (19%) 89(17%)Median interval to relapse, months 18 15 14 15.2**Range of interval to relapse, months 8-55 2-61 2-37 2-61No. with non-bulky infradiaphragmatic nodal first relapse# 14 (82%) NR 37 (75%) 51/66(77)

(% of relapsing patients)No. salvaged with radiation therapy alone (% of relapsing patients) 8 (47%) 16 (70%) 33 (67%) 57 (64%)No. with second relapse 4 (24%) 4 (17%) 4 (8%) 12 (13%)No. patients requiring chemotherapy (% of relapsing patients) 9 (53%) 7 (30%) 16 (33%) 32 (36%)No. deaths from seminoma or seminoma therapy (% of all patients) 0 (0%) 1 (0.7%) 3 (1%) 4 (0.8%)

NR = not reported.

* From Horwich et al. From Wood et al.

From von der Masse et al.140

Including history and physical examination, tumor markers, and chest x-ray.|| Refers to computed tomography (CT) and/or ultrasound (US) of the abdomen.# Maximum nodal dimension less than 5 cm (Royal Marsden stage IIA/IIB).

**Weighted mean based on number of patients per study. Simple average.

1606 SECTION 30 / Neoplasms of the Genitourinary TractTHERAPY FOR DISSEMINATED DISEASE

CHEMOTHERAPY: PRECISPLATIN A broad spectrum of chemothera-peutic agents was tested from 1952 to 1972 in disseminated germ celltumors, and virtually all were found to have some degree of activityin chemotherapy-naive patients. In the early 1960s, the Vinca alka-loids were finally tested in testicular cancer after demonstrating activ-ity in nonHodgkins lymphoma and Hodgkins disease. Vinblastine,as a single agent, was able to induce complete remissions in 4 of 30treated patients.87,154 Although these were of short duration, they pro-vided investigators with a rational component of subsequent combi-nation regimens.

Several antitumor antibiotics were also found to have single-agentactivity, including the least (actinomycin-D) and most (mithramycin)extensively studied compounds.155,156 Ultimately, a third antitumorantibiotic, bleomycin, was reported in 1970 to have significant activ-ity, including the ability to induce complete remissions.157

An early combination regimen reported by Li and colleagues in1960, which contained methotrexate, actinomycin-D, and chlorambu-cil, remained popular throughout the rest of the decade.158 Li reportedan objective response rate of 52%, with over half of those being com-plete responses. More importantly, they represented the first durableremissions, with 5 patients alive at 9 to 39 months after treatment atthe time of the report.

A major advance in the development of effective chemotherapy formetastatic disease occurred when vinblastine and bleomycin wereused in combination, as reported by Samuels and colleagues at theM.D. Anderson Cancer Center.154,159,160 These regimens used eitherbiweekly bolus (VB-1) or continuous infusion (VB-3) bleomycin, witha reported response rate for VB-3 of 95%, with 65% of patients achiev-ing a complete remission and most responses being enduring.

The most important event in the development of curative therapyfor disseminated disease was the 1965 report by Rosenberg and col-leagues of the antibacterial effect of platinum coordination com-pounds.161 One of these compounds, cis-diamminedichloroplatinum(II) (cisplatin), was found also to have significant antitumor activity.Preclinical studies revealed testicular atrophy as a side effect in the dogmodel, prompting some investigators to predict activity for this com-pound against human testicular malignancies in the clinical setting.Cisplatin was soon reported to be the single most active agent againsttesticular germ cell tumors, with response rates of 70% and completeremission rates of 50%.162 Twenty years later, it remains the mostactive drug in germ cell tumors. The relatively unique toxicities of cis-platin, including renal dysfunction, made it an excellent candidate forincorporation into combination regimens containing drugs which hadmyelosuppression as their primary side effect. Existing data on the useof intensive combination chemotherapy regimens for lymphomas andleukemia provided the background for similar approaches to the treat-ment of testicular cancer. Such combination regimens were subse-quently developed at both Memorial Sloan-Kettering Cancer Centerand Indiana University.VAB REGIMENS: MEMORIAL SLOAN-KETTERING CANCER CENTERIn the first of a series of combination regimens, investigators atMemorial Hospital added actinomycin-D to the combination of vin-blastine and bleomycin. This regimen, termed VAB-I, was used from1972 to 1974, and had a response rate of 34%, including 15% com-plete responses, results that were no better than those for vinblastineplus bleomycin alone.163 In the first VAB regimen to contain cisplatin,VAB-II, 50 patients were treated from 1974 to 1976, with an 84%response rate and 50% complete remissions. Of the complete remis-sions, 46% were disease free at 16 to 33 months.164 From 1975 to1976, 80 patients were treated on a complicated protocol (VAB-3),which added chlorambucil, doxorubicin, and cyclophosphamide to aVAB regimen that lasted 24 to 30 months. The rate of response to thisprotocol was 81%, with 61% complete remissions, and a relapse fromcomplete remission rate that fell to 31%.89

Several changes in the schedule of administration of drugs wereundertaken with VAB-4 in an attempt to decrease the frequency ofearly relapses. From 1976 to 1978, 41 evaluable patients were treated,with a response rate of 85% and a 61% complete remission rate; with

variety of nodal dimensions, depending on the location of disease andthe particular patients habitus. Historically, in an era when all patientswith stage II disease received mediastinal radiation therapy, patientswith disease between 5 and 10 cm had the same relapse rate as thosewith less than 5 cm.148 However, in newer series where mediastinalradiation therapy was omitted in an attempt to spare toxicity, relapserates for disease dimensions < 5 cm have remained low, whereas relapserates for disease of 5 to 10 cm are rising substantially.132

The treatment for nonbulky stage II seminoma starts with a radicalorchiectomy by an inguinal approach, followed by adjuvant radiationtherapy. Discussions of and recommendations for management previ-ously presented regarding scrotal invasion, positive spermatic cordmargin, previous groin surgery, and scrotal violation also apply topatients with nonbulky stage II seminoma. The standard abdominalfields described for stage I are appropriate as the initial fields for non-bulky stage II carried to a dose of around 25 Gy in 1.25- to 1.5-Gy frac-tions. Areas of gross disease on presentation should be boosted withsmall fields to a dose of around 35 to 40 Gy using the pretherapy lym-phangiogram or CT treatment planning to tightly shape the fields. His-torically, after the abdominal fields were treated, a mediastinal/leftsupraclavicular field was treated for stage II seminoma. The rationalefor such treatment followed from the observation that these areas wereassociated with a high rate of relapse in the untreated patient, and thatthe morbidity of such treatment was low.144 Subsequently, it was rec-ognized that the mediastinal treatment was, in fact, significantly toxic,as it was associated with increased cardiopulmonary morbidity anddeath136 and limited the ability to deliver systemic chemotherapy to sal-vage relapsing patients.67,149 In addition, with modern staging, the rateof subsequent supradiaphragmatic failure in nonbulky stage II semi-noma is reported as only 0 to 5% when the mediastinum is nottreated.73,150,151 These factors, along with the development of effectivesalvage chemotherapy, have led to a general abandonment of prophy-lactic mediastinal radiation therapy for nonbulky stage II seminoma.

Controversy continues regarding the proper management ofpatients with stage II seminoma with disease dimensions between 5and 10 cm. Several European centers have categorized these tumors asbulky and managed them with chemotherapy. When employing para-aortic/ipsilateral pelvic radiation therapy only as management, thesepatients have relapse rates that may be > 50%. The patients continue tobe treated without mediastinal radiation therapy at the M.D. AndersonCancer Center, but left supraclavicular radiation therapy has beenresumed.132 These investigators cite their own data demonstrating thatwhen all supradiaphragmatic fields were omitted, the majority ofrelapses were in the supraclavicular fossa where the thoracic duct emp-ties into the junction of the internal jugular and subclavian veins, andnot in the residual mediastinum. They contend that irradiation of a sin-gle supraclavicular field will avoid the cardiac toxicity and hematopoi-etic suppression associated with mediastinal radiation therapy. Resultsfrom this approach have not been published. Currently, this presenta-tion may be treated with either para-aortic/ipsilateral pelvis radiationtherapy with chemotherapy as salvage or with chemotherapy alone,with equivalent expected overall cure rates.

Stage II Seminoma: Bulky Disease. A treatment rationale forstage II patients with disease dimensions of 5 to 10 cm employingeither initial radiation therapy or chemotherapy was presented in theprevious section. Patients with bulky abdominal disease with dimen-sions > 10 cm are best treated with multi-agent cisplatin-basedchemotherapy. Although there are no particularly large series report-ing this category specifically, the 5-year disease-free survival afterchemotherapy for groups of patients with bulky stage II or moreadvanced disease is in excess of 90%.152 This is better than the 50 to75% cure rates with initial radiation therapy employing abdominal andmediastinal treatment. If a patient is not eligible for chemotherapy,radiation therapy may be offered as primary treatment, and strong con-sideration should be given to including a mediastinum/left supraclav-icular field, as relapse will be reduced from in excess of 50% forabdominal fields alone73 to around 25%153 at the cost of increased car-diopulmonary morbidity.

a median follow-up of 27 months, only 12% of complete respondershad relapsed.165 In 1980, several modifications were made in this pro-tocol to yield VAB-6. These changes increased the emphasis on theintensity of induction therapy (with administration of cycles every 3 to4 weeks) and simultaneously decreased the duration of the mainte-nance phase of therapy to 1 year. At the time of the report, 91% ofpatients had achieved a complete remission, with an 18% relapse ratefrom complete remission with more than 24 months median follow-up.166 There were also significant improvements in terms of toxicity,as this regimen eliminated the mucositis, renal insufficiency, and pul-monary fibrosis that had been seen with prior regimens.INDIANA UNIVERSITY STUDIES In 1974, investigators at Indiana Uni-versity began studies using cisplatin, vinblastine, and bleomycin(PVB) in patients with disseminated testicular cancer. The initial studyof 50 patients remains a landmark study in modern oncology.167 Thisstudy incorporated principles of combination chemotherapy, as well asthe concept of surgically resecting residual disease after the comple-tion of chemotherapy. Induction chemotherapy was brief (three to fourcourses), and maintenance chemotherapy was given for 2 years afterinduction therapy. Three patients died within 2 weeks of the initiationof treatment. Of the remaining group of 47 patients, 33 (70%) obtaineda complete remission with chemotherapy. Of the remaining 14patients, 5 obtained a complete remission with resection of residualdisease after the completion of chemotherapy. Six of the patientsattaining remission have relapsed, but now with follow-up exceeding10 years, it is gratifying to note that there seems to be little evidenceof long-term toxicity from chemotherapy.

The initial study proved that PVB was remarkably effective, andyet there was substantial toxicity. The next study was designed to com-pare the original PVB program with a similar regimen with a lowerdose of vinblastine (0.4 mg/kg versus 0.3 mg/kg). A third arm wasadded to assess the possible therapeutic benefit of adding doxorubicinto the PVB combination.3 Seventy-eight patients were entered into thisthree-arm study. The therapeutic results in all three arms were identi-cal, with 70% of all patients remaining continuously free of disease.As expected, however, the reduction in the vinblastine dose was asso-ciated with fewer episodes of sepsis and granulocytopenic fever. Thus,on the basis of equivalent therapeutic results with lesser toxicity, thelower dose of vinblastine, along with cisplatin and bleomycin, becamethe standard regimen.

A third-generation study was begun at Indiana University in 1978in conjunction with the Southeastern Cancer Study Group(SECSG).168 The previous studies had used maintenance therapy withmonthly vinblastine for 2 years after the completion of induction ther-apy. This trial tested the contribution of maintenance chemotherapy. Inthis study, patients with disseminated testicular cancer were given fourcourses of induction chemotherapy with PVB with or without doxoru-bicin. Patients obtaining a complete remission with chemotherapy, orafter resection of teratoma, were randomized to receive maintenancevinblastine or no further therapy. This study failed to demonstrate anadvantage for those patients randomized to the maintenance therapyarm, with a relapse rate of 12% for those receiving treatment versus7% for patients receiving induction therapy only.

Confirmation of the results of these trials at Indiana University hasbeen obtained in a large EORTC trial of chemotherapy for disseminatedtesticular cancer.169 This trial tested the contribution of high-dose vin-blastine (0.4 mg/kg) versus lower-dose vinblastine (0.3 mg/kg) and thevalue of maintenance vinblastine. The trial of 214 patients failed todemonstrate any advantage for patients assigned to high-dose vinblas-tine therapy or for those assigned to maintenance vinblastine.

Initial studies at Indiana University demonstrated