Superior Clinical Response and Survival Rates With Initial Bolus

of Cisplatin and 120 Hour Infusion of 5Fluorouracil Before

Definitive Therapy for Locally Advanced Head and Neck Cancer

Arthur Weaver, MD, Allen Park, Michigan

Susan Fleming, PhD, Detroit, Michigan

John Ensley, MD, Allen Park, Michigan

Julie A. Klsh, MD, Detroit, Michigan

John Jacobs, MD, Allen Park, Michigan

Jeamk Klnzle, MD, Detroit, Michigan

John Crlssman, MD, Allen Park, Michigan

Muhyl Al-Sarraf, MD, Detroit, Michigan

Early cancer of the head and neck area generally is successfully managed either by surgery or radio- therapy as a single treatment modality. Results of management of the advanced stages of the disease (stages III and IV), h owever, are still disappointing in a majority of cases. Preoperative or postoperative irradiation is often combined with surgery in an at- tempt to improve the local control rate of these le- sions [l-3]. Since the introduction of cisplatin in the 19708, chemotherapy regimens combining platinum with a large variety of other drugs have resulted in impressive clinical response rates in previously tm- treated patients [4-161. Bleomycin has been most commonly combined with cisplatin for induction chemotherapy in these multidrug protocols [17-201 (Table I).

Although the overall response rates (complete re- sponse plus partial response) have been impressive for these combinations, the complete response rates have been rather modest, varying from 0 to 22 per- cent. The initial pilot study reported by Al-Sarraf et al [5] on 77 patients who received two courses of cis- platin, vincristine (Oncovina), and bleomycin showed an overall response rate of 80 percent with a 22 per- cent complete response rate. Since bleomycin ther-

FromthsDqrrbnerdsdWlW,~.Otderyngdogy.RsdblhereW* fhIldP&Obg#,W8tylll3St8teJtJIIh8ttySChOOlOfMOdiClnO,~~ ~.a!!egt,_dt,atxJthe~VetaaneAdmlnlslratlM1MedlcalCenter,

R~forr~ntsshouklbe adbsseedtOAllhUWeaVer,MD.b z of&py, Veterans Admlnlatratkm Medical Center, Allen Park,

Preaanmd*t~9othAnnualbteaun9ofthesoci*tyofHaadandNedc svgsons. New York. New York, May 1%17.1994.

apy cannot be administered safely to patients with poor pulmonary function, we sought to determine other drug combinations that might prove efficacious for such persons. 5Fluorouracil and cisplatin were initially tested in a two course regimen consisting of 100 mg/ms of cisplatin on day one administered as a rapid infusion followed by 1,000 mg/ms of 5fluo- rouracil administered as a 24 hour infusion for the ensuing 4 days. Twenty-six patients were treated with this protocol. The initial response rates and toxicities were encouraging [21,22]. The 5-fluo- rouracil and cisplatin program was then extended to three courses, and an additional day of Mluorouracil infusion was added to each course. Eighty-eight pa- tients were treated with the three course regimen and were followed for a minimum of 12 months. Herein, we wilI compare results in this three course 5-fluo- rouracil and cisplatin group with those in the group initially treated with cisplatin, vim&tine, and bleomycin, as well as the two course 5-fluorouracil and cisplatin program.

Material and Methods

One hundred ninety-one patienta with stage III and IV squamous cell carcinomas of the head and neck partici- pated in the pilot studies. Those with distarit metastasis were not included, but many patienta had multiple primary lesions of the head and neck area, lung, or esophagus. A history was obtained, and physical examination and triple endoscopy (laryngoecopy, bronchoscopy, and esophagos- copy) with appropriate biopsies were carried out on all patients. Each patient was then evaluated by a surgeon, radiotherapist, and medical oncologist at the time of en-

vohlma 148. octobu 1984 525

Weaver et al

TABLE I Response to Induction Chemotherapy With Clsplatln and Bleomycln In Previously Untreated Cancer Patlents

Author Year Patients Courses Agents CR PR %

Al-Sarraf et al

An!r:i?et al

Brt!Z et al

Et iFet al

En!i!et al

GliFet al

I 101 Hong et al [71,721

Kloss et al

Kt!e?k al

[ 741 Randolph et al

ScL!Zr et al

[ 161 Spaulding et al

Tat!rZk et al

[ 761 Vogl et al

Wi!tZet al

I201

1979, 1981

1983

1980

1979

1981

1980

1979, 1982

1981

1983

1978

1983

1982

1982

1982

1979

77 2

37 2

23 3

22 1

29 2

29 2

41 2

16 3

10 3

21 2

58 l-3

50 2

33 2

22 2

21 1

COB 22

COB 2

CVB 5

CMB 4

CMB 7

CB . . .

CB 7

CB 1

CMB 2

CB 4

CMOB 15

COB 11

CMB 3

CMB 2 f MC

CMVB . . .

39 80

23 67

12 74

12 73

22 100

14 48

22 73

12 81

5 70

11 71

20 66

33 88

17 60

15 77

10 48

B = bleornycin; C = cisplatin; CR = complete response; M = methotrexate; MC = mitornycin-C; 0 = Oncovin (vincristine); PR = partial response; V = vinblastine.

rollment in the study. Treatment modalities, including proposed extent of surgery, were decided before the start of therapy.

Laboratory workup included hematologic studies, multiphasic profile, 24 hour creatinine clearance, bilateral audiogram, chest roentgenogram, and intravenous pyelo- gram. Bone surveys and scanning procedures were utilized only where indicated to rule out metastatic disease. Pa- tients with a blood urea nitrogen level of 20 mg/lOO ml, a creatinine concentration of 1.5 mg/lOO ml, or a creatinine clearance of 60 mmlmin or more, with at least one unob- structed kidney visualized by intravenous pyelography, were considered to have adequate renal function for ther- apy. A white blood cell count of 4,OOO/mms and a platelet count of 100,000/mm3 were considered minimum levels as screening parameters.

All patients were initially hydrated with 2 liters of 5 percent dextrose in 50 percent N saline solution with 50 mEq/liter of postassium chloride before the start of che- motherapy with cisplatin. Therapy began with adminis- tration of 12.5 g of mannitol followed by an intravenous bolus of 100 mg/mz of cisplatin. A 4 hour infusion of 25 g of mannitol in 1 liter of 5 percent dextrose in 50 percent N saline solution with 30 mEq/liter of potassium chloride followed the cisplatin injection. The first 77 patients then received bleomycin at a dose of 30 units/day in 2,006 ml of 5 percent dextrose and 50 percent N saline solution as a continuous 24 hour infusion on the second through the fifth day, beginning 24 hours after the administration of cis-

platin. One milligram of vincristine was administered in- travenously on the second and fifth days. This drug course was repeated at 3 weeks. The next 26 patients had 4 con- secutive days of 5-fluorouracil infusion, consisting of 1,000 mg/mz of 5-fluorouracil in 2 liters of 5 percent dextrose and 50 percent N saline solution, as a 24 hour infusion imme- diately after cisplatin injection. A second course of treat- ment followed 3 weeks thereafter. The remaining 66 pa- tients had 5 days of this infusion. Patients received the second course of therapy at a 3 week interval; a similar interval was used for the third course of treatment. Allo- purinol, 300 mg by mouth daily, was administered. Two weeks after completion of chemotherapy, all patients were again evaluated by the surgeon, radiotherapist, and med- ical oncologist for operability and response to chemo- therapy, and a final decision regarding further treatment was made.

Complete response was defined as complete disappear- ance of all measurable disease, both of the primary lesion and in the neck, and absence of symptoms related to the disease. Partial response was recorded for those patients who demonstrated a greater than 50 percent reduction in the dimensions of the measurable primary lesion or the lymph nodes as initially noted and absence of any new le- sions. A minimal response was recorded for patients with a 25 to 49.9 percent reduction in the size of the initial dis- ease. No response was defined as anything less than partial response, stable disease, or progression of cancer while receiving chemotherapy.

526 The American Journal of Suraery

TABLE II Patient Characteristics

Parameter COB 5-FU & C

(2 courses) 2 courses 3 courses

Sex Male Female

Race White Black

Age Raw Median

Disease stage III IV

Morphologic characteristics Well-differentiated Moderately differentiated Poorly differentiated

Site Oropharynx Oral cavity

Z~~‘” SlJb@%tlc Pharynx HypopharVnx Nasopherynx Paranasal sinus Unknown

Second primary tumor

62 24 70 15 2 18

40 18 45 37 10 43

15-73 22-70 30-84 55 56 56 56 54 57

16 0 17 61 26 71

6 1 9 43 16 54 28 9 25

25 3 21 8 9 1

12 4 . . .

3 2

. . 5

. . . 10

. . . 2 3 1 3 1

13

28 20 13 11 1 4 8 2 2 3

15

COB = cisplatin, Oncovin (vincristine), and bleomycin; ‘5-FU & C = 5-fluorowacil and cisplatln.

Results

This study compares the makeup, response rates, and survival rates for three different inductive che- motherapeutic regimens sequentially piloted on 191 patients at Wayne State University teaching hospi- tals. Cisplatin, vincristine, and bleomycin were given in two courses to 77 patients, 54luorouracil and cis- platin were given in two courses to 26 patients, and 5fluorouracil and cisplatin were given in three courses to 66 patients. The patient characteristics for each of these groups are described in Table II.

Toxicities associated with each of these regimens were quite acceptable and have been published pre- viously [5,21,22]. There was minimal hair loss in the patients receiving cisplatin and 54luorouraci1, and these patients generally appeared to tolerate this regimen better than those given cisplatin, vincristine, and bleomycin. Patients were evaluated by surgical, radiation, and medical oncologists approximately 2 weeks after completion of their final chemotherapy course. Patients who were considered surgically resectable proceeded to the predetermined operative procedure; patients not rendered resectable by in-

vohlma 148, october 1984

Advanced Head and Neck Cancer Treatment

TABLE III Responses to Initial Chemotherapy*

COB 5-FU & C Response (2 courses) 2 courses 3 courses

Complete 22 (28.6) 5 (19.3) 48 (54.5) Partial 39 (50.6) 18 (69.2) 35 (39.8) None 16 (20.8) 3 (11.5) 5 (5.7) Total

CR&PR 61177 23126 83188 (79.2) (88.5) (94.3)

l Values in parentheses are percentages. COB = cispiatin, Oncovin (vincristine) and bleomycin; CR 8 PR

= complete response and partial response; 5-FU 8 C = 5-fluo- rouracil and cisplatin.

duction chemotherapy and those refusing surgery were treated with approximately 5,000 rads to the primary lesion and lymph nodes and were reevalu- ated for possible surgical resection. Those still con- sidered inoperable continued to receive an additional 1,600 rads to the gross residual disease.

All patients continue to be followed until death, and all patients who received at least one course of chemotherapy have been included and evahrated for response, toxicity, and survival in this report. All deaths occurring after enrollment in these studies are considered cancer deaths, as are any patients lost to follow-up, even though they have shown no evidence of disease. The response rates for patients in each of the three induction protocols are described in Table III. So far, the usual criterion of response, that is, the number of complete responses plus the number of partial responses, has been good for each of these regimens and has not been statistically different; however, the complete response rate for the three courses of 54luorouracil and cisplatin has been sig- nificantly better (54.5 percent, p = 0.04) than the rate for the two courses of 54luorouracil and cisplatin (19 percent) or the two courses of cisplatin, vincristine, and bleomycin (29 percent). The three course 5-flu- orouracil and cisplatin protocol is the only induction therapeutic program to have demonstrated that a majority of patients will have an initial complete response to chemotherapy. Response ra’ - catagorized by sex, race, morphologic characteristics: and staging are included in Table IV. Female pati:. s appear to have a slight edge over male patients, I : is partic- ularly evident in the group that had t ! * pee course 5-fluorouracil and cisplatin treatr I. protocol. There is no apparent racial advantag td chemo- therapy, as given in this study, seemu to produce a good response rate for tumors of all differentiation. It is interesting to note that the three course 5-fluo- rouracil and cisplatin protocol may have advantages over the other two regimens for moderately and well-differentiated tumors. In most patients with leas than complete response, response appeared to be better in the primary lesion than in the nodal disease.

527

Weaver et al

TABLE IV Responses Categorized by Sex, Race, Morphologic Characterlstlcs, and Stages of Dlsease

COB 5-FU 8 C 5-FU & C (2 courses) (2 courses) (3 courses)

Parameter CR PR NR CR PR NR CR PR NR

Morphologic characteristics Well-differentiated Moderately differentiated Poorly differentiated

Sex Male Female

Race White Black

Disease stage III IV

2 5 ’ 1 6 2 1 9 24 ‘9 2 12 ‘2’ 28 23 3

11 10 7 3 5 1 14 10 1

20 27 15 5 16 3 33 33 4 2 12 1 . . . 2 . . 15 2 1

9 23 t 3 11 2 23 19 3 13 16 2 7 1 25 16 2

4 9 4 ’ 18 30 13 -5. ‘l-i ‘ii

13 2 2 35 33 3

COB = cisolatin. Dncovln McrMine), and bleomycin; CR = complete response, 5-FU & C = Mluorouracil and cisplatin; NR = no response; PR = partial iesp&se. . ..

Twelve of 16 patients who received the three course protocol classified with TdNo disease had complete clinical remission, whereas only 7 of 23 patients with T4N, disease had complete remission. This rather dramatic response to chemotherapy, particularly with the three course protocol, proved, however, to be a mixed blessing in patient management. For most of these patients, surgery was planned as an integral aspect of tumor therapy. From the total group of 191 patients, 37(19 percent) refused surgery after com- pleting their chemotherapy. This tendency to refuse surgery after good results were achieved was even more evident in patients having complete clinical remission of their disease. In the three course 5-flu- orouracil and cisplatin protocol, where the majority of patients had complete clinical remission, 21 of 38 patients who had previously agreed to surgical re- section refused an operation after complete response to chemotherapy. Many of these patients were con- vinced to have radiotherapy, but seven patients re- fused any further treatment whatsoever. Overall survival curves for each of the three groups are pre- sented in Figure 1.

Comments

In the past few years, there has been considerable interest in the use of chemotherapy for advanced head and neck cancer. The most common combina- tions employed in initial therapy have been cisplatin and bleomycin, often combined with other agents. One such regimen, cisplatin, vincristine, and bleomycin, was used in two course therapy by us beginning in 1977. When, in some of our patients, this protocol was contraindicated because of pulmonary disease, we switched to two courses of 5-fluorouracil and cisplatin, which proved nearly as efficacious as the cisplatin, vincristine, and bleomycin protocol in

response rates. When three courses of 5-fluorouracil and cisplatin were instituted, we discovered that a far greater number of patients demonstrated com- plete remission than we had seen with either of the two previous protocols. This increased complete re- sponse proved to be a mixed blessing as many pa- tients refused other planned therapy. Many who did receive radiotherapy in lieu of surgery were still free of disease at the most recent follow-up. Several pa- tients refused all further therapy, and most of them have returned with recurrent disease 7 to 9 months after chemotherapy. One patient with a carcinoma in the base of the tongue is still without evidence of disease approximately 2$ years after his chemo- therapy. The survival rate of responders to initial chemotherapy was statistically greater than that of nonresponders (p <0.05), regardless of subsequent definitive treatment by surgery, radiotherapy, or both. This may be a result of selection of patients who show by their response to initial chemotherapy that they would have done better regardless of the type of therapy instituted, or it may represent improved survival results due to chemotherapy or a combina- tion of factors. A survival advantage was also seen for patients treated with induction chemotherapy as compared with matched historical control patients treated at our institution.

With a minimum follow-up of 1 year for every patient and a median follow-up of more than 40 months, the survival rate of patients who received three courses of combination 5-fluorouracil and cis- platin was statistically superior to the survival rates of patients in the other two pilot studies. This may be a result of the greater complete clinical response obtained in the three course group. These increased survival figures are despite the fact that many of the patients did not complete their recommended ther- apy. We consider surgery to be the prime therapeutic

528 The American Journal of Surgery

Advanced Head and Neck Cancer Treatment

tine, and bleomvcin (29 percent) and-two course 5-

arm for advanced head and neck cancer after com- plete response to chemotherapy, and the refusal on the part of many patients to have surgery has led us to recommend protocols in which surgery is the initial therapeutic arm, and chemotherapy and radiother- apy are being evaluated as adjuvant modalities of therapy. Randomized clinical trials are now in progress to evaluate Sfluorouracil and cisplatin in this sequence of therapy.

We must warn that these single arm pilot studies have the limiting objectives of determining feasibil- ity, toxicity, and effectiveness of induction chemo- therapy. No certain comparisons can be made be- tween sequential pilot studies, even in the same in- stitution with historical control patients due to the various prognostic factors that may influence results. Only well-designed, randomized, and stratified trials may determine the efficacy of combined modality treatment by comparing the disease-free interval and the overall survival rate.

The feasibility and acceptance of combined che- motherapy as induction therapy has been estab- lished. The efficacy and sequencing of chemotherapy as part of the multimodality approach for patients with advanced head and neck cancer needs continued investigation.

Summary

One hundred ninety-one patients were treated by one of three cisplatm-containing multidrug protocols. The initial 77 natients received two courses of cis- platin and viniristine plus bleomycin. The next 26 patients received two courses of Sfluorouracil and cisplatin, and the final 88 patients were placed on a three course Sfluorouracil and cisplatin protocol. Overall response rates were similar-for each of the three protocols. The complete response rate, how- ever, was much better (54 percent) for three course 5-fluorouracil and cisnlatin versus cisnlatin vincris-

previously untreated head and neck cancer. Final report. In: Jones SE, Salmon SE, eds. Adjuvant therapy of cancer Ill, New York: Grune and Stratton, 1981:145-52.

8. Amrein PC. Fingert H, Waitzman JA. Gis-platinum-vincrls- tine-bleomycin therapy in squamous cell carcinoma of the head and neck. J Clin Oncol 1983;1:421-7.

7. Brown AW, Blom J, Butler WM, et al. Combination chemo- therapy with vinblastine, bleomycin and cisdlamminedi- chloroplatinum (II) in squamous cell carcinoma of the head and neck. Cancer 1980;45:2830-5.

8. Elias EG, Chretien PB, Monnard E, et al. Chemotherapy prior

17.

to local therapy in advanced squamous cell carcinoma of

Spaulding MB, Kahn A. Delos Santos R, Klotch 0. Lore JH, Jr.

the head and neck. Preliminary assessment of an intensive drug regimen. Cancer 1979;43: 1025-31.

9. Ervin TJ, Weichselbaum R, Miller D, et al. Treatment of ad- vanced squamous cell carcinoma of the head and neck with cis-platinum, bleomycin and methotrexate (PBM). Cancer Treat Rep 1981;65:787-91.

10. Glick JH, Marcia1 V, Richter M, et al. The adjuvant treatment of inoperable stage Ill and IV epidermoid carcinoma of the head and neck with platinum and bleomycin infusion prior to definitive radiotherapy. An RTOG pilot study. Cancer 1980;46:1919-24.

11. Hong WK, Shapshay SM, Bhutani R, et al. Induction chemo- therapy in advanced squamous head and neck carcinoma with high dose cis-platinum and bleomycin infusion. Cancer 1979;44:19-25.

12. Pennacchio JL, Hong WK. Shapshay S, et al. Combination of cis-platinum and bleomycin prior to surgery and/or radio- therapy compared with radiotherapy alone for the treatment of advanced squamous cell carcinoma of ths head and neck. Cancer 1982;50:2795-801.

13. Kloss R, Oster M, Blffer A, et al. Cis-platinun (P) and bleomycin (B) for previously untreated locally advanced squamous cell carcinoma of the head and neck (abstr). ASCO 1981;22: 535.

14. Kuten A, Zidan J, Cohen Y, Robinson E. Multi-drug cherno- therapy using bleomycin, methotrexate and cis-platinum alone or combined with radiotherapy in advanced head and neck cancer. (- Cancer Treat Rep 1983;67:573-4.

15. Randolph VL. Va llajo A, Spiro RH, et al. Combination therapy of advancedhc___.._ ..--.. --..--.. . ..___ _ ._.. -. ._....__._.._ sad and neck cancer Inductton of remiariona with diamminodichloroplatinum (II), bleomycin and radiation therapy. Cancer 1978;41:460-7.

16. &huller DE, Wilson HE, Smfth RE, et al. Preoperative reductive chemotherapy for locally advanced carcinoma of the oral cavity, oropharynx. and hypopharynx. Cancer 1983;51: 15-9.

fluorouracil and cisplatin (19 percent). Survival curves were also better for the three course Sfluo- rouracil and cisplatin segment of this nonrandomized pilot study.

References

Adjuvant c hemotherapy in advanced head and neck cancer. An update. Am J Surg 1982; 144:432-6.

18. Tannock I, Cummings B, Sorrenti V. and the ENT Group. Combination chemotherapv used orior to radiation theraov for locally advanced squamous cell carcinoma of the head and neck. Cancer Treat Rep 1982;66:1421-4.

1. Sllverberg E. Cancer statistics 1982. CA 1981;32:15-31. 2. Barkley HT Jr, Fletcher GH, Jesse RH, et al. Management of

cervilymph node me&stases in squamous cell carcinoma of the tonsillar fossa, base of tongue, supraglottic laryns and hypopharynx. Am J Surg 1972;124:462-7.

3. Fletcher GH. Jesse RH. The place of irradiation in the man- agement of the primary lesion in head and neck cancer. Cancer 1977;39:862-7.

4. Al-Sarraf M, Amer MH, Vaishaupayon G, et al. A mufti-modallty therapeutic approach for advanced previously untreated eoidermokf cancer of the head and neck: Preliminaw reocft. Int J Radlat Oncol Blol Phys 1979;5:1421-3. - ’

5. Al-Sarraf M, Drelfchman A, Jacobs J, et al. Adjuvant cherno- therapy wlth cls-platlnum, Oncovin and bleomycin followed by surgery and/or radiotherapy in patlents with advanced

19. Vogl SE, Lerner H, Kaplan BH, Caughlin C, McCormick 8, Ca- macho F, Cinsberg J. Failure of effective initial chemo- therapy to modify the course of stage IV (MO) squamous cancer of the head and neck. Cancer 1982;50:840-7.

20. Wittes R, Heller K, Randolph V, et al. Cisdichlorodiammine platinum (II)-based chemotherapy as initial treatment of advanced head and neck cancer. Cancer Treat Rep 1979; 63: 1522-38.

21. Weaver A. Fleming S, Vandenberg H, et al. Cis-platinum and 5-fluorouracil as initial therapy in advanced epidermoid cancer of the head and neck. Head Neck Surg 1982;4: 370-3.

22. Kish J, Drelichman A, Jacobs J, Hos&ner J, Kinzie J, Loh J J-H, Weaver A, Al-Sarraf M. Clinical trial of cis-pfatinum and 5-FU infusion as initial treatment for advanced squamous carci- noma of the head and neck. Cancer Treat Rep 1982;66: 471-4.

vollHm 110, October 1994 529