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COMBINATION CHEMOTHERAPY FOR METASTATIC OR LOCALLY ADVANCED GENITOURINARY SQUAMOUS CELL CARCINOMA: A PHASE II STUDY OF METHOTREXATE, CISPLATIN AND BLEOMYCIN
0022-5347/9811605-1770$03.00/0
vol. 160,1770-1774, November 1998 Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright €3 1998 by Amrum UROLOGICAL. ASS~CUTION,INC
1
COMBINATION CHEMOTHERAPY FOR METASTATIC OR LOCALLY ADVANCED GENITOURINARY SQUAMOUS CELL CARCINOMA: A PHASE I1 STUDY OF METHOTREMTE, CISPLATIN AND BLEOMYCIN DAVID A. CORRAL, AVISHAY SELLA, CURTIS A. PETTAWAY, ROBERT J. U T O , DONNAH M. JONES AND JULIE ELLERHORST From the Departments of Urology and Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas
ABSTRACT
Purpose: The prognosis of patients with advanced squamous cell carcinoma of genitourinary origin is poor. While single agent chemotherapy results mainly in partial responses of short duration, data on the efficacy of combination chemotherapy are extremely limited. We determined the response rate and toxicity of a combination of 3 of the most active agents, methotrexate, cisplatin and bleomycin, in patients with advanced genitourinary squamous cell carcinoma. Materials and Methods: Patients with metastatic or locally advanced genitourinary squamous cell carcinoma were eligible for study. Treatment consisted of 200 mg./m.2 methotrexate on days 1, 15 and 22, and 20 mgJm.2 cisplatin and 10 mg./m.' bleomycin on days 2 through 6 during a 28-day cycle. Results: Of the 30 Datients who enrolled in the trial 29 were evaluable for response. Objective response was achievLd in 16 patients (55%,95%confidence interval 36 to 72), 4 of whom achieved a complete response (14%).Median objective response duration was 4.7 months (range 1.9 to 39.5). Median survival of the entire group was 11.5 months (range 1.5 to 87.0). Of the patients 9 achieved disease-free status, including 6 following consolidation surgery or radiation therapy. Median survival of these 9 patients (34.4months, range 9.6 to 87.0) was significantly greater (p = 0.0003)than that of patients who did not become disease-free (7.0 months, range 1.5 to 38.6). Grade I11 or J Y hematological toxicity in 116 courses included neutropenia (13%) and thrombocytopenia (6%). Among 30 patients evaluable for toxicity serious nonhematological toxic effects included stomatitis (3%) and renal toxicity (7%). There was 1 death from neutropenic sepsis. Conclusions: Methotrexate, cisplatin and bleomycin combination chemotherapy for genitourinary squamous cell carcinoma results in a high but short lived overall response rate, and a low complete response rate with manageable toxicity. A multidisciplinary approach to achieve disease-free status may provide the best opportunity to effect survival and should be the focus of future trials. Kcr WORDS: carcinoma, squamous cell; chemotherapy, adjuvant; methotrexate; cisplatin; bleomycins
An unusual characteristic of genitourinary squamous cell carcinoma is that morbidity and mortality commonly result from a protracted locoregional phase. Standard therapy for patients with locally or regionally advanced penile squamous cell carcinoma consists of penectomy and radical lymph node dissection. However, cure by surgery alone is unlikely with involvement of more than 3 inguinal nodes, perinodal infiltration or pelvic node involvement.' Depending on the extent of disease surgical resection results in 5-year survival rates ranging from 0 to 76%.13 Acquisition of data on the efficacy and toxicity of chemotherapy for penile and urethral cancer has been limited by the rarity of these diseases and concomitant integration of other local treatment modalities. Several chemotherapeutic agents have been investigated for treatment of locally recurrent or metastatic penile carcinoma. Among the more active single agents are methotrexate, bleomycin and cisplatin (MPB), each with individual efficacy of approximately 2O%.4-11 Because each agent produces mainly partial responses of short duration but presumably acts via independent mechanisms, we previously conducted a pilot study of combination MPB for advanced squamous cell carcinoma originating in the male genital tract.12 In that initial study Accepted for publication June 12, 1998.
MPB combination was reasonably well tolerated and objective response was achieved in 10 of 14 patients. We now report the results of a larger phase I1 study of this combination chemotherapeutic regimen in patients with advanced squamous cell carcinoma of the genitourinary system. We define the response rate, duration of response and toxicity of MPB in this group of patients. PATIENTS AND METHODS
The study was conducted by the Department of Genitourinary Oncology, University of Texas M. D. Anderson Cancer Center from March 1988 to January 1994. Eligibility criteria included histological proof of squamous cell carcinoma of the penis, scrotum, bladder, renal pelvis, ureter or urethra, which was regionally advanced or metastatic. Patients also were required to have a Zubrod performance status13 of 3 or less, a n estimated life expectancy of more than 12 weeks, adequate hematological function (granulocyte count 1,500/ mm.3 or greater and platelet count 150,00O/mm. or greater), adequate hepatic function (serum bilirubin 2.0 mg./dl. or less and serum glutamic oxaloacetic transaminase twice the upper limit of normal or less) and adequate renal function (creatinine clearance 40 ml. per minute or greater). Patients were excluded from study if they had received prior chemo-
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CHEMOTHERAPY FOR GENITOURINARY SQUAMOUS CELL CARCINOMA
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therapy and at least 3 weeks were required to elapse after for response rates were determined using a 95% confidence prior radiation therapy. A statement of informed consent was coefficient. signed by each patient before MPB therapy began. Pretreatment evaluation included a medical history, physRESULTS ical examination, complete blood count, serum chemistry Patients. A total of 31 patients signed a consent form to study, chest radiograph, radionuclide bone scan, computed tomography (CT) of the abdomen and pelvis, gallium lung participate in the trial. A patient with an initial diagnosis of squamous cell carcinoma of the renal pelvis was excluded scan and pulmonary function testing. During therapy comfrom study after pathological review of the nephroureterecplete blood counts and kidney function tests were repeated weekly, and pulmonary function tests and gallium lung scans tomy specimen revealed the malignancy to be transitional were performed before each chemotherapy cycle until bleo- cell carcinoma with squamous transformation, and so data on response and toxicity for this patient were excluded from mycin was discontinued. Imaging studies of disease sites analysis. Another patient with penile squamous cell carciwere repeated every 8 weeks to assess tumor status. noma appeared to achieve a partial response but did not meet A cycle of therapy were defined as 28 days. On days 1, 15 the requisite 4-week interval for response duration due to and 22, 200 mg./m.' methotrexate were administered intraintervening surgery, and so toxicity but not response data for venously, and 25 mg. leucovorin were given orally every 6 this patient were tabulated. Therefore, toxicity data are hours for a total of 12 doses beginning 24 hours afterwards. available for 30 patients and response data for 29. On days 2 through 6 patients received 10 mg./m.' bleomycin Characteristics of the treatment group and details of therdaily by continuous intravenous infusion for a total of 50 apy before entry into the study are summarized in table 1. mg./m.' and 20 mg./m.' cisplatin daily as a 3-hour intrave- Site of origin and extent of disease categorized according to nous infusion for a total of 100 mg./m.'.12 Therapy on days 1 the TNM staging system14 are shown in table 2. Of the 30 through 6 was administered at the hospital. On days 15 and treated patients 22 had disease originating in the penis, 5 in 22 methotrexate was given as outpatient therapy. For pa- the urethra, 1 in the scrotum, 1 in the prostate and 1 in the tients with local disease only the protocol contained a provi- bladder. Pretreatment hypercalcemia was noted in 5 patients sion for some therapy to be given intra-arterially. In these (17%),(median level 11.2 mg./dl., range 10.3 t o 13.31, and 6 cases intravenous methotrexate and oral leucovorin were (20%)had evidence of infection at presentation. administered as described on days 1, 15 and 22. On days 2 Response and survival. Of the 29 patients objective reand 3, 20 mg./m.' bleomycin were given intra-arterially as a sponse to MPB combination chemotherapy was achieved in continuous infusion and on day 2,100 mg./m.' cisplatin were 16 (55%, 95% CI 36 to 721, including 4 complete responses infused intra-arterially. Chemotherapy courses were re- (14%, 95% CI 4 to 32). The number and duration of repeated every 28 days provided that adequate hematological sponses are shown in table 3. Of the 21 patients with penile recovery occurred (granulocytes 1,500/mm.3or greater, plate- cancer 12 achieved an objective response (8 partial and 4 lets 150,000/mm.3or greater). The criteria for administering complete) and 3 of 5 patients with urethral cancer had a methotrexate on days 15 and 22 included stable creatinine partial response. The remaining partial response was seen in with less than a 0.4 mg./dl. increase above baseline, absence the patient with disease in the prostate. Objective response of stomatitis, granulocyte count l,000/mm.3 or greater and was not limited to patients with local or regional disease. Of platelet count 75,000/1nm.~or greater. Treatment was with- 5 patients with distant metastasis 1 achieved a complete and held for any grade I11 or N toxic reaction based on the 1 a partial response. National Cancer Institute Common Toxicity Criteria, and In general the responses developed rapidly during treatdoses were subsequently reduced by 25%for grade I11 or 50% ment, often with dramatic improvement after 1 or 2 courses for grade N.Bleomycin was withdrawn from patients whose (fig. 1). However, as shown in table 3 the duration of response forced vital capacity decreased more than 15% compared to was limited in many patients. Median objective response durapretreatment value and those with abnormal lung uptake on tion for the 16 patients was 4.7 months (range 1.9 to 39.51, gallium scan. Cisplatin was reduced by 50% for a creatinine and 10 (63%)maintained a response duration of less than 6 clearance between 40 and 50 ml. per minute at baseline or during treatment, and withheld for creatinine clearance below 40 ml. per minute. Treatment continued for at least 2 TABLE 1. Patient characteristics cycles beyond determination of a complete response, or 2 to 4 No. pts. (%) cycles for patients with stable disease, or a partial or minor Registered 31 response. Evaluable for response 29 Complete response was considered as the disappearance of Evaluable for toxicity 30 all radiographic evidence of disease for at least 4 weeks, 51 (31-78) Median age (range) partial response was a 50% or greater decrease in the sum of 29 (96.7) Men Women 1 (3.3) the products of the perpendicular diameters of all measured Race: lesions, also for at least 4 weeks and minor response a 25 to 12 (40.0) Hispanic less than 50% decrease in the sum of the products of the 12 (40.0) White perpendicular diameters of all measured lesions. Stable dis6 (20.0) Black Zubrod performance status: ease was considered as less than 25%change in measurable 5 (16.7) 0 disease for at least 2 cycles and progressive disease as an 1 21 (70.0) increase of 25% or greater in the sum of the products of the 3 (10.0) 2 perpendicular diameters of all measured lesions, the appear1 (3.3) 3 F'rior therapy:* ance of an unequivocal new lesion, an increase in the inten9 (30.0) Local excision, circumcision or biopsy only sity of abnormal uptake on bone scan or new symptoms 14 (46.7) Partial penedomy attributable to disease progression. 4 (13.3) Total penectomy Duration of response was calculated from the date of doc1 (3.3) Hemiscrotectomy Lymph node biopsy (surgical or CT guided): mentation of response to the date of documentation of dis5 (16.7) Unilat. ease progression. Survival from the date of registration to the 3 (10.0) Bilat. date of death or last followup was plotted according to the 5 (16.7) Bilat. inguinal lymphadenedomy %plan-Meier method. Survival and response duration were 2 (6.7) Pelvic lvmohadenectomy 2 (6.7) Inguinai radiation analyzed by the log rank test using computer software and * Multiple procedures were performed in 14 patients. considered significant at p <0.05. Confidence intervals (CI)
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CHEMOTHERAPY FOR GENITOURINARY SQUAMOUS CELL CARCINOMA
TABLE2. Site of origin and stage of30 cases of squamous cell carcinoma before chemotherapy Penis: TlN2MO T2NlMO T2N2MO "2NOMl Lung T2N3MO T3NlMO T3N2MO T3N3MO T3N2M1 Lung T3N3M1 Skin T4N3M1 Skin T4N3M1 Lung Urethra: T2NOMO T2NlMO T3N3MO T4NOMO Scrotum: TlN2MO Prostate: T4NOMO Bladder: T4N2MO Total
1 2 5 1 3 3 1 2 1 1 1 1
rence of bleomycin induced lung disease. Median cumulative dose of bleomycin was 190 mg. (range 70 to 535). There was evidence of bleomycin pulmonary toxicity in 10 patients (33%),of whom 4 had abnormal pulmonary tracer uptake on
1 1 1 2 1 1 1 30
TABLE 3. Response, response duration and survival of 29 evaluable Datients Response Complete response Partial response Minor response Stable disease Progressive disease
No. pts. (%I 4 (13.8) 12 (41.4) 1 (3.4) 1 (3.4) 11 (37.9)
Median Mos. Response Duration (Range)
Median Mos. Survival (Range)
20.9 (3.2-39.5) 3.8 ( l . S l 9 . 3 ) 18.0 5.1
32.7 (9.W37.1) 15.8 (4.4-38.6) 21.2 10.8 6.7 (1.5-34.5)
months. Notably, 4 of 6 patients who attained an objective response for longer than 1 year underwent consolidation surgery after completing chemotherapy. The Kaplan-Meier curve plotted from survival data for the 29 patients is shown in figure 2. At the time of our analysis 4 patients were alive, 2 of whom had no evidence of disease. Overall median survival was 11.5 months (range 1.5 to 87.0). Median survival was 16.6 months (range 4.4 to 87.0) for 16 patients who had an objective response and 7.3 months (range 1.5 to 34.4). Overall disease-free status was achieved in 4 patients with a complete response, 3 with a partial response and 2 with disease progression. One of the 4 patients with a complete response, who underwent groin dissection after after chemotherapy, had microscopic residual disease. Of the 3 patients with a partial response 2 underwent surgery and 1 received radiotherapy. Surgery was performed in both patients with disease progression. Thus, 6 patients achieved disease-free status by consolidation surgery (5) or radiation therapy (1). Median survival for patients who became disease-free (34.4 months, range 9.6 to 87.0) was significantly greater (p = 0.0003) than that of those who did not (7.0 months, range 1.5 to 38.6). Survival curves for these groups are shown in figure 3. Toxic effects. Ofthe 116 chemotherapy courses (median 3 per patient, range 1 to 9) 99 were delivered intravenously and the remaining 17 intra-arterially. Episodes of grade I11 or N hematological toxicity observed among the 116 treatment cycles included neutropenia in 15 (13%)and thrombocytopenia in 7 (6.0%). Median granulocyte nadir was 1,8401 mm.3 (range 140 to 8,780) and median platelet nadir was 143,000/mm.3(range 12 t o 329,000). Significant nonhematological toxic effects were also observed. The patients were carefully monitored for the occur-
FIG. 1. Pelvic CT of patient with regionally advanced enile s ua mous cell carcinoma. A, tumor in inguinal lymph nodestefore apy (arrow).B , marked reduction in nodal volume following 2 courses of Chemotherapy.
tier:
0
12
24
36
48
60
72
84
6
Months FIG. 2. Kaplan-Meier survival curve for 29 patients with squamous cell carcinoma treated with MPB chemotherapy.
CHEMOTHERAPY FOR GENITOURINARY SQUAMOUS CELL CARCINOMA 100
1threatening side effects. An improved toxicity profile might
I
80 /-
8
60
c (
(d
*I fa
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Disease-free
I
40
20
-
0 12
24
36
48
60
72
84
Months FIG.3. Kaplan-Meier survival curves for 9 patients who achieved
disease-free status with or without consolidation surge or radiotherapy following chemotherapy, and 20 patients whoxd not become disease-free.
gallium scan and 6 had a greater than 15%decrease in forced vital capacity on spirometry. Only 1 patient had cough and dyspnea on exertion concurrent with radiographic evidence of bleomycin toxicity, which resolved after treatment with steroids. Median reduction in forced vital capacity for all patients was -9% (range 22 to -58). In 10 patients (33.3%) there was an increase in serum creatinine of greater than 0.4 mg./dl. over baseline. Significant renal toxicity, defined as an increase in serum creatinine greater than 2.5 times baseline, occurred in 2 patients (6.7%). Infections occurred in 6 patients (20%) and comprised staphylococcus bacteremia (21, aspergillus fungemia (1) and urinary tract infections (3). Grade 3 or 4 stomatitis was observed with 3 chemotherapy courses (2.6%).A patient treated with intra-arterial chemotherapy had symptoms of gluteal ischemia which resolved with conservative management. There was 1 death from toxicity, which occurred in a patient who presented with an infected tumor and had neutropenic sepsis during the first cycle of therapy. Clinical course was complicated by acute renal failure and perforation of the ascending colon, He died of multiple organ failure.
permit the addition of another agent to the MPB regimen. Recent data suggest that a interferon in combination with cisplatin has activity against squamous penile cancer.20 There are also promising data regarding the use of 13-cisretinoic acid in combination regimens for squamous cell carcinomas.21 Considering the low complete response, short duration of response and lack of demonstrable survival benefit for responders over nonresponders, it appears that the MPB regimen is incapable of affecting the natural history of advanced squamous cell carcinoma of genitourinary origin when used as the sole treatment modality. However, previous reports involving small numbers of patients have suggested that select patients with locally advanced genitourinary squamow cell carcinoma may achieve long-term survival following combined chemotherapy and surgery.15-18 Significant therapeutic benefit has also been reported for other solid tumors when chemotherapy has been used in combination with other regional treatment modalities, despite its limited benefit when used alone in advanced disease.22~23 In penile cancer, the most common genitourinary squamous cell carcinoma, prognosis is greatly dependent on stage at presentation and due to a protracted locoregional phase the battle for cure is often won or lost at the level of the regional lymphatics. llioinguinal and pelvic lymphadenectomy is commonly required for control of locoregionally advanced disease, and can be associated with considerable morbidity. In our study 12 of 21 patients with penile squamous cell carcinoma achieved an objective response with MPB Combination chemotherapy and 6 achieved disease-free status, including 3 following adjuvant surgery. Median survival of these 6 patients (27.8 months) was significantly greater (p = 0.004) than that of the penile cancer patients who did not become disease-free (6.7 months). Thus, while combination chemotherapy in this and other studies15-1s is rarely curative as monotherapy for locally advanced disease, its greatest benefit may be to improve surgical resectability. The integration of systemic chemotherapy and aggressive surgical resection with curative intent should be emphasized in future studies. The end points of such trials should focus on potential down staging of the tumor, increase in resectability, decrease in the extent of surgical resection necessary to achieve disease-free status and possible impact on survival. CONCLUSIONS
Our phase I1 study of MPB combination chemotherapy for locally advanced or metastatic squamous cell carcinoma demonstrated a high (55%)objective response with manageable DISCUSSION toxicity but responses tended to be short. Patients who beOverall response rates to single agent or combination che- came disease-free through a combination of chemotherapy motherapy in patients with advanced penile and urethral and consolidation surgery or radiation had an improved outcancer have ranged between 15 and 61%, the majority of come. The MPB regimen or other chemotherapy programs which have been partial responses of short d~ration.~-ll. 15-18 may, therefore, be most useful as part of a multidisciplinary Similarly, for the core of patients with advanced penile can- approach to the care of these patients. cer (21) or urethral cancer (5) in our study we observed a 58% objective response with a 15% complete response rate, and REFERENCES median response duration was 4.4 months. The observed toxicity of MPB chemotherapy in our study was considerable 1. Ravi, R.: Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the but manageable. Similar to the experience with testicular penis. Brit. J. Urol., 7 2 817, 1993. cancer patients, close monitoring enabled individualization 2. Horenblas, S.,van Tinteren, H., Delemane, J. F. M., Moonen, of bleomycin doses and avoidance of irreversible bleomycin L. M. F., Lustig, V. and van Waardenburg, E. W.: Squamous lung toxicity.19 However, the schedule necessitated a weekcell carcinoma of the penis 111. Treatment of regional lymph hospitalization each month. To control better the untoward nodes. J. Urol., 149: 492,1993. effects of this regimen we are now attempting to convert this 3. Srinivas, V., Morse, M. J., Herr, H. W., Sogani, P. C. and program to a weekly schedule, whereby the cumulative doses Whitmore,W. F., Jr.: Penile cancer: Relation of extent of nodal remain approximately the same but the drugs are adminismetastasis to survival. J. Urol., 137: 880, 1987. tered in smaller fractions at shorter intervals. Potential ad4. Ahmed, T., Sklaroff, R. and Yagoda, A.: An appraisal of the efficacy of bleomycin in epidermoid carcinoma of the penis. vantages may include outpatient administration, improved Anticancer Res., 4:289, 1984. tolerance and avoidance of potentially irreversible or life
5. Sklaroff, R. B. and Yagoda, A,: Methotrexate in the treatment of penile carcinoma. Cancer, 4 5 214, 1980. 6. Gagliano, R. G., Blumenstein, B. A,, Crawford, E. D., Stephens, R. L., Coltman, C. A., J r . and Constanzi, J. J.: Cisdiamminedichloroplatinum in the treatment of advanced epidermoid carcinoma of the penis: A Southwest Oncology Groupstudy. J. Urol., 141: 66, 1989. 7. Sklaroff, R. and Yagoda, A.: Cis-diamminedichloride platinum I1 (DDP) in the treatment of penile carcinoma. Cancer, 44:1563, 1979. 8. Ahmed, T., Sklaroff, R. and Yapoda. A.: Seauential trials of methotrexate, cisplatin and bleomycin for penile cancer. J . Urol., 132 465, 1984. 9. Kattan, J., Culine, S., Droz, J . P., Fadel, E., Court, B., P e m n , J. L., Wibault, P. and Haie-Meder, C.: Penile cancer chemotherapy: Twelve years' experience a t Institut Gustave-Roussy. Urology, 42: 559, 1993. 10. Maiche, A. G.: Adjuvant treatment using bleomycin in squamous cell carcinoma of penis: Study of 19 cases. Brit. J. Urol., 5 5 542, 1983. 11. Kyalwazi, S. K., Bhana, D. and Harrison, N. W.: Carcinoma of the penis and Bleomycin chemotherapy in Uganda. Brit. J. Urol., 46:689, 1974. 12. Dexeus, F. H., Logothetis, C. J., Sella, A., Amato, R., Kilbourn, R., Fitz, K. and Striegel, A.: Combination chemotherapy with methotrexate, bleomycin, and cisplatin for advanced squamous cell carcinoma of the male genital tract. J. Urol., 146: 1284,1991. 13. Stanley, K. E.: Prognostic factors for survival in patients with inoperable lung cancer. J. Natl. Cancer Inst., 6 5 25, 1980. 14. h e r . Joint Comm. on Cancer: Penis Manual for Staging of Cancer, 4th edition. Edited by 0. H. Beahrs, D. E., Henson, R. V. P. Hutter and B. J . Kennedy. Philadelphia: J.P. Lippincott Co., chapt. 33, pp. 191-193, 1992. 15. Hussein, A. M., Benedetto, P. and Sridhar, K. S.: Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas. Cancer, 6 5 433, 1990. 16. Shammas, F. V., Ous, S. and Fossa, S. D.: Cisplatin and
5-fluorouracil in advanced cancer of the penis. J. Urol., 147: 630, 1992. 17. Dexeus, F. H., Logothetis, C. J. and Sipahi. H.: Chemotherapy for advanced squamous cell carcinoma of the male external genital tract and urethra. In: Systemic Therapy for Genitourinary Cancer. Edited by D. E. Johnson, C. J. Logothetis and A. C. von Eschenbach. Chicago: Year Book Medical Publishers, pp. 255-259, 1989. 18. Pizzocaro, G. and Piva, L.: Adjuvant and neoadjuvant vincris. tine, bleomycin and methotrexate for inguinal metast;lsrs from squamous cell carcinoma of the penis. Acta Oncol., 27: 823, 1988. 19. Logothetis, C. J., Samuels, M. L., Selig, D. E., %den, S..Dexeus. F.. Swanson. D., Johnson, D. and von Eschenbach, A,: Cyclic chemotherapy with cyclophosphamide, doxorubicin and cisplatin plus vinblastine and bleomycin in advanced germinal tu. mors: results with 100 patients. Amer. J. Med., 81: 219, 1986. 20. Mitropoulos, D., Dimopoulos, M.-A., Iroudi-Voulgari, A,, Zervas, A., Dimopoulos, C. and Logothetis, C. J.: Neoadjuvant cisplatin and interferon a-2b in the treatment and organ preservation of penile carcinoma. J . Urol., 152: 1124, 1994. 21. Lippman, S. M., Kavanagh, J . J., Paredes-Espinoza. M., Delgadillo-Madrueno, F., Paredes-Casillas, P., Hong, W. K., Holdener, E. and Krakoff, I. H.: 13-cis-retinoic acid plus interferon a-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J . Natl. Cancer Inst., 84: 241, 1992. 22. Rosell, R., G6mez-Codina. J., Camps, C., Maestre, J.. Padille, J.. Cant6, A., Mate, J . L., Li, S., Roig, J., Olazabal. A.. Canela, M., Ariza, A,, Skagel, Z., Morera-Prat, J . and Abad, A,: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. New Engl. J . Med., 330 153, 1994. 23. Moertel, C. G., Fleming, T. R., Macdonald, J . S., Haller, D. G., Laurie, J . A., Goodman, P. J., Ungerleider, J. S., Emerson, W. A,, Tormey, D. C., Glick, J. H., Veeder, M. H. and Mailliard, J . A.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl. J. Med., 322: 352, 1990.
vol. 160,1770-1774, November 1998 Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright €3 1998 by Amrum UROLOGICAL. ASS~CUTION,INC
1
COMBINATION CHEMOTHERAPY FOR METASTATIC OR LOCALLY ADVANCED GENITOURINARY SQUAMOUS CELL CARCINOMA: A PHASE I1 STUDY OF METHOTREMTE, CISPLATIN AND BLEOMYCIN DAVID A. CORRAL, AVISHAY SELLA, CURTIS A. PETTAWAY, ROBERT J. U T O , DONNAH M. JONES AND JULIE ELLERHORST From the Departments of Urology and Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas
ABSTRACT
Purpose: The prognosis of patients with advanced squamous cell carcinoma of genitourinary origin is poor. While single agent chemotherapy results mainly in partial responses of short duration, data on the efficacy of combination chemotherapy are extremely limited. We determined the response rate and toxicity of a combination of 3 of the most active agents, methotrexate, cisplatin and bleomycin, in patients with advanced genitourinary squamous cell carcinoma. Materials and Methods: Patients with metastatic or locally advanced genitourinary squamous cell carcinoma were eligible for study. Treatment consisted of 200 mg./m.2 methotrexate on days 1, 15 and 22, and 20 mgJm.2 cisplatin and 10 mg./m.' bleomycin on days 2 through 6 during a 28-day cycle. Results: Of the 30 Datients who enrolled in the trial 29 were evaluable for response. Objective response was achievLd in 16 patients (55%,95%confidence interval 36 to 72), 4 of whom achieved a complete response (14%).Median objective response duration was 4.7 months (range 1.9 to 39.5). Median survival of the entire group was 11.5 months (range 1.5 to 87.0). Of the patients 9 achieved disease-free status, including 6 following consolidation surgery or radiation therapy. Median survival of these 9 patients (34.4months, range 9.6 to 87.0) was significantly greater (p = 0.0003)than that of patients who did not become disease-free (7.0 months, range 1.5 to 38.6). Grade I11 or J Y hematological toxicity in 116 courses included neutropenia (13%) and thrombocytopenia (6%). Among 30 patients evaluable for toxicity serious nonhematological toxic effects included stomatitis (3%) and renal toxicity (7%). There was 1 death from neutropenic sepsis. Conclusions: Methotrexate, cisplatin and bleomycin combination chemotherapy for genitourinary squamous cell carcinoma results in a high but short lived overall response rate, and a low complete response rate with manageable toxicity. A multidisciplinary approach to achieve disease-free status may provide the best opportunity to effect survival and should be the focus of future trials. Kcr WORDS: carcinoma, squamous cell; chemotherapy, adjuvant; methotrexate; cisplatin; bleomycins
An unusual characteristic of genitourinary squamous cell carcinoma is that morbidity and mortality commonly result from a protracted locoregional phase. Standard therapy for patients with locally or regionally advanced penile squamous cell carcinoma consists of penectomy and radical lymph node dissection. However, cure by surgery alone is unlikely with involvement of more than 3 inguinal nodes, perinodal infiltration or pelvic node involvement.' Depending on the extent of disease surgical resection results in 5-year survival rates ranging from 0 to 76%.13 Acquisition of data on the efficacy and toxicity of chemotherapy for penile and urethral cancer has been limited by the rarity of these diseases and concomitant integration of other local treatment modalities. Several chemotherapeutic agents have been investigated for treatment of locally recurrent or metastatic penile carcinoma. Among the more active single agents are methotrexate, bleomycin and cisplatin (MPB), each with individual efficacy of approximately 2O%.4-11 Because each agent produces mainly partial responses of short duration but presumably acts via independent mechanisms, we previously conducted a pilot study of combination MPB for advanced squamous cell carcinoma originating in the male genital tract.12 In that initial study Accepted for publication June 12, 1998.
MPB combination was reasonably well tolerated and objective response was achieved in 10 of 14 patients. We now report the results of a larger phase I1 study of this combination chemotherapeutic regimen in patients with advanced squamous cell carcinoma of the genitourinary system. We define the response rate, duration of response and toxicity of MPB in this group of patients. PATIENTS AND METHODS
The study was conducted by the Department of Genitourinary Oncology, University of Texas M. D. Anderson Cancer Center from March 1988 to January 1994. Eligibility criteria included histological proof of squamous cell carcinoma of the penis, scrotum, bladder, renal pelvis, ureter or urethra, which was regionally advanced or metastatic. Patients also were required to have a Zubrod performance status13 of 3 or less, a n estimated life expectancy of more than 12 weeks, adequate hematological function (granulocyte count 1,500/ mm.3 or greater and platelet count 150,00O/mm. or greater), adequate hepatic function (serum bilirubin 2.0 mg./dl. or less and serum glutamic oxaloacetic transaminase twice the upper limit of normal or less) and adequate renal function (creatinine clearance 40 ml. per minute or greater). Patients were excluded from study if they had received prior chemo-
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therapy and at least 3 weeks were required to elapse after for response rates were determined using a 95% confidence prior radiation therapy. A statement of informed consent was coefficient. signed by each patient before MPB therapy began. Pretreatment evaluation included a medical history, physRESULTS ical examination, complete blood count, serum chemistry Patients. A total of 31 patients signed a consent form to study, chest radiograph, radionuclide bone scan, computed tomography (CT) of the abdomen and pelvis, gallium lung participate in the trial. A patient with an initial diagnosis of squamous cell carcinoma of the renal pelvis was excluded scan and pulmonary function testing. During therapy comfrom study after pathological review of the nephroureterecplete blood counts and kidney function tests were repeated weekly, and pulmonary function tests and gallium lung scans tomy specimen revealed the malignancy to be transitional were performed before each chemotherapy cycle until bleo- cell carcinoma with squamous transformation, and so data on response and toxicity for this patient were excluded from mycin was discontinued. Imaging studies of disease sites analysis. Another patient with penile squamous cell carciwere repeated every 8 weeks to assess tumor status. noma appeared to achieve a partial response but did not meet A cycle of therapy were defined as 28 days. On days 1, 15 the requisite 4-week interval for response duration due to and 22, 200 mg./m.' methotrexate were administered intraintervening surgery, and so toxicity but not response data for venously, and 25 mg. leucovorin were given orally every 6 this patient were tabulated. Therefore, toxicity data are hours for a total of 12 doses beginning 24 hours afterwards. available for 30 patients and response data for 29. On days 2 through 6 patients received 10 mg./m.' bleomycin Characteristics of the treatment group and details of therdaily by continuous intravenous infusion for a total of 50 apy before entry into the study are summarized in table 1. mg./m.' and 20 mg./m.' cisplatin daily as a 3-hour intrave- Site of origin and extent of disease categorized according to nous infusion for a total of 100 mg./m.'.12 Therapy on days 1 the TNM staging system14 are shown in table 2. Of the 30 through 6 was administered at the hospital. On days 15 and treated patients 22 had disease originating in the penis, 5 in 22 methotrexate was given as outpatient therapy. For pa- the urethra, 1 in the scrotum, 1 in the prostate and 1 in the tients with local disease only the protocol contained a provi- bladder. Pretreatment hypercalcemia was noted in 5 patients sion for some therapy to be given intra-arterially. In these (17%),(median level 11.2 mg./dl., range 10.3 t o 13.31, and 6 cases intravenous methotrexate and oral leucovorin were (20%)had evidence of infection at presentation. administered as described on days 1, 15 and 22. On days 2 Response and survival. Of the 29 patients objective reand 3, 20 mg./m.' bleomycin were given intra-arterially as a sponse to MPB combination chemotherapy was achieved in continuous infusion and on day 2,100 mg./m.' cisplatin were 16 (55%, 95% CI 36 to 721, including 4 complete responses infused intra-arterially. Chemotherapy courses were re- (14%, 95% CI 4 to 32). The number and duration of repeated every 28 days provided that adequate hematological sponses are shown in table 3. Of the 21 patients with penile recovery occurred (granulocytes 1,500/mm.3or greater, plate- cancer 12 achieved an objective response (8 partial and 4 lets 150,000/mm.3or greater). The criteria for administering complete) and 3 of 5 patients with urethral cancer had a methotrexate on days 15 and 22 included stable creatinine partial response. The remaining partial response was seen in with less than a 0.4 mg./dl. increase above baseline, absence the patient with disease in the prostate. Objective response of stomatitis, granulocyte count l,000/mm.3 or greater and was not limited to patients with local or regional disease. Of platelet count 75,000/1nm.~or greater. Treatment was with- 5 patients with distant metastasis 1 achieved a complete and held for any grade I11 or N toxic reaction based on the 1 a partial response. National Cancer Institute Common Toxicity Criteria, and In general the responses developed rapidly during treatdoses were subsequently reduced by 25%for grade I11 or 50% ment, often with dramatic improvement after 1 or 2 courses for grade N.Bleomycin was withdrawn from patients whose (fig. 1). However, as shown in table 3 the duration of response forced vital capacity decreased more than 15% compared to was limited in many patients. Median objective response durapretreatment value and those with abnormal lung uptake on tion for the 16 patients was 4.7 months (range 1.9 to 39.51, gallium scan. Cisplatin was reduced by 50% for a creatinine and 10 (63%)maintained a response duration of less than 6 clearance between 40 and 50 ml. per minute at baseline or during treatment, and withheld for creatinine clearance below 40 ml. per minute. Treatment continued for at least 2 TABLE 1. Patient characteristics cycles beyond determination of a complete response, or 2 to 4 No. pts. (%) cycles for patients with stable disease, or a partial or minor Registered 31 response. Evaluable for response 29 Complete response was considered as the disappearance of Evaluable for toxicity 30 all radiographic evidence of disease for at least 4 weeks, 51 (31-78) Median age (range) partial response was a 50% or greater decrease in the sum of 29 (96.7) Men Women 1 (3.3) the products of the perpendicular diameters of all measured Race: lesions, also for at least 4 weeks and minor response a 25 to 12 (40.0) Hispanic less than 50% decrease in the sum of the products of the 12 (40.0) White perpendicular diameters of all measured lesions. Stable dis6 (20.0) Black Zubrod performance status: ease was considered as less than 25%change in measurable 5 (16.7) 0 disease for at least 2 cycles and progressive disease as an 1 21 (70.0) increase of 25% or greater in the sum of the products of the 3 (10.0) 2 perpendicular diameters of all measured lesions, the appear1 (3.3) 3 F'rior therapy:* ance of an unequivocal new lesion, an increase in the inten9 (30.0) Local excision, circumcision or biopsy only sity of abnormal uptake on bone scan or new symptoms 14 (46.7) Partial penedomy attributable to disease progression. 4 (13.3) Total penectomy Duration of response was calculated from the date of doc1 (3.3) Hemiscrotectomy Lymph node biopsy (surgical or CT guided): mentation of response to the date of documentation of dis5 (16.7) Unilat. ease progression. Survival from the date of registration to the 3 (10.0) Bilat. date of death or last followup was plotted according to the 5 (16.7) Bilat. inguinal lymphadenedomy %plan-Meier method. Survival and response duration were 2 (6.7) Pelvic lvmohadenectomy 2 (6.7) Inguinai radiation analyzed by the log rank test using computer software and * Multiple procedures were performed in 14 patients. considered significant at p <0.05. Confidence intervals (CI)
1772
CHEMOTHERAPY FOR GENITOURINARY SQUAMOUS CELL CARCINOMA
TABLE2. Site of origin and stage of30 cases of squamous cell carcinoma before chemotherapy Penis: TlN2MO T2NlMO T2N2MO "2NOMl Lung T2N3MO T3NlMO T3N2MO T3N3MO T3N2M1 Lung T3N3M1 Skin T4N3M1 Skin T4N3M1 Lung Urethra: T2NOMO T2NlMO T3N3MO T4NOMO Scrotum: TlN2MO Prostate: T4NOMO Bladder: T4N2MO Total
1 2 5 1 3 3 1 2 1 1 1 1
rence of bleomycin induced lung disease. Median cumulative dose of bleomycin was 190 mg. (range 70 to 535). There was evidence of bleomycin pulmonary toxicity in 10 patients (33%),of whom 4 had abnormal pulmonary tracer uptake on
1 1 1 2 1 1 1 30
TABLE 3. Response, response duration and survival of 29 evaluable Datients Response Complete response Partial response Minor response Stable disease Progressive disease
No. pts. (%I 4 (13.8) 12 (41.4) 1 (3.4) 1 (3.4) 11 (37.9)
Median Mos. Response Duration (Range)
Median Mos. Survival (Range)
20.9 (3.2-39.5) 3.8 ( l . S l 9 . 3 ) 18.0 5.1
32.7 (9.W37.1) 15.8 (4.4-38.6) 21.2 10.8 6.7 (1.5-34.5)
months. Notably, 4 of 6 patients who attained an objective response for longer than 1 year underwent consolidation surgery after completing chemotherapy. The Kaplan-Meier curve plotted from survival data for the 29 patients is shown in figure 2. At the time of our analysis 4 patients were alive, 2 of whom had no evidence of disease. Overall median survival was 11.5 months (range 1.5 to 87.0). Median survival was 16.6 months (range 4.4 to 87.0) for 16 patients who had an objective response and 7.3 months (range 1.5 to 34.4). Overall disease-free status was achieved in 4 patients with a complete response, 3 with a partial response and 2 with disease progression. One of the 4 patients with a complete response, who underwent groin dissection after after chemotherapy, had microscopic residual disease. Of the 3 patients with a partial response 2 underwent surgery and 1 received radiotherapy. Surgery was performed in both patients with disease progression. Thus, 6 patients achieved disease-free status by consolidation surgery (5) or radiation therapy (1). Median survival for patients who became disease-free (34.4 months, range 9.6 to 87.0) was significantly greater (p = 0.0003) than that of those who did not (7.0 months, range 1.5 to 38.6). Survival curves for these groups are shown in figure 3. Toxic effects. Ofthe 116 chemotherapy courses (median 3 per patient, range 1 to 9) 99 were delivered intravenously and the remaining 17 intra-arterially. Episodes of grade I11 or N hematological toxicity observed among the 116 treatment cycles included neutropenia in 15 (13%)and thrombocytopenia in 7 (6.0%). Median granulocyte nadir was 1,8401 mm.3 (range 140 to 8,780) and median platelet nadir was 143,000/mm.3(range 12 t o 329,000). Significant nonhematological toxic effects were also observed. The patients were carefully monitored for the occur-
FIG. 1. Pelvic CT of patient with regionally advanced enile s ua mous cell carcinoma. A, tumor in inguinal lymph nodestefore apy (arrow).B , marked reduction in nodal volume following 2 courses of Chemotherapy.
tier:
0
12
24
36
48
60
72
84
6
Months FIG. 2. Kaplan-Meier survival curve for 29 patients with squamous cell carcinoma treated with MPB chemotherapy.
CHEMOTHERAPY FOR GENITOURINARY SQUAMOUS CELL CARCINOMA 100
1threatening side effects. An improved toxicity profile might
I
80 /-
8
60
c (
(d
*I fa
1773
Disease-free
I
40
20
-
0 12
24
36
48
60
72
84
Months FIG.3. Kaplan-Meier survival curves for 9 patients who achieved
disease-free status with or without consolidation surge or radiotherapy following chemotherapy, and 20 patients whoxd not become disease-free.
gallium scan and 6 had a greater than 15%decrease in forced vital capacity on spirometry. Only 1 patient had cough and dyspnea on exertion concurrent with radiographic evidence of bleomycin toxicity, which resolved after treatment with steroids. Median reduction in forced vital capacity for all patients was -9% (range 22 to -58). In 10 patients (33.3%) there was an increase in serum creatinine of greater than 0.4 mg./dl. over baseline. Significant renal toxicity, defined as an increase in serum creatinine greater than 2.5 times baseline, occurred in 2 patients (6.7%). Infections occurred in 6 patients (20%) and comprised staphylococcus bacteremia (21, aspergillus fungemia (1) and urinary tract infections (3). Grade 3 or 4 stomatitis was observed with 3 chemotherapy courses (2.6%).A patient treated with intra-arterial chemotherapy had symptoms of gluteal ischemia which resolved with conservative management. There was 1 death from toxicity, which occurred in a patient who presented with an infected tumor and had neutropenic sepsis during the first cycle of therapy. Clinical course was complicated by acute renal failure and perforation of the ascending colon, He died of multiple organ failure.
permit the addition of another agent to the MPB regimen. Recent data suggest that a interferon in combination with cisplatin has activity against squamous penile cancer.20 There are also promising data regarding the use of 13-cisretinoic acid in combination regimens for squamous cell carcinomas.21 Considering the low complete response, short duration of response and lack of demonstrable survival benefit for responders over nonresponders, it appears that the MPB regimen is incapable of affecting the natural history of advanced squamous cell carcinoma of genitourinary origin when used as the sole treatment modality. However, previous reports involving small numbers of patients have suggested that select patients with locally advanced genitourinary squamow cell carcinoma may achieve long-term survival following combined chemotherapy and surgery.15-18 Significant therapeutic benefit has also been reported for other solid tumors when chemotherapy has been used in combination with other regional treatment modalities, despite its limited benefit when used alone in advanced disease.22~23 In penile cancer, the most common genitourinary squamous cell carcinoma, prognosis is greatly dependent on stage at presentation and due to a protracted locoregional phase the battle for cure is often won or lost at the level of the regional lymphatics. llioinguinal and pelvic lymphadenectomy is commonly required for control of locoregionally advanced disease, and can be associated with considerable morbidity. In our study 12 of 21 patients with penile squamous cell carcinoma achieved an objective response with MPB Combination chemotherapy and 6 achieved disease-free status, including 3 following adjuvant surgery. Median survival of these 6 patients (27.8 months) was significantly greater (p = 0.004) than that of the penile cancer patients who did not become disease-free (6.7 months). Thus, while combination chemotherapy in this and other studies15-1s is rarely curative as monotherapy for locally advanced disease, its greatest benefit may be to improve surgical resectability. The integration of systemic chemotherapy and aggressive surgical resection with curative intent should be emphasized in future studies. The end points of such trials should focus on potential down staging of the tumor, increase in resectability, decrease in the extent of surgical resection necessary to achieve disease-free status and possible impact on survival. CONCLUSIONS
Our phase I1 study of MPB combination chemotherapy for locally advanced or metastatic squamous cell carcinoma demonstrated a high (55%)objective response with manageable DISCUSSION toxicity but responses tended to be short. Patients who beOverall response rates to single agent or combination che- came disease-free through a combination of chemotherapy motherapy in patients with advanced penile and urethral and consolidation surgery or radiation had an improved outcancer have ranged between 15 and 61%, the majority of come. The MPB regimen or other chemotherapy programs which have been partial responses of short d~ration.~-ll. 15-18 may, therefore, be most useful as part of a multidisciplinary Similarly, for the core of patients with advanced penile can- approach to the care of these patients. cer (21) or urethral cancer (5) in our study we observed a 58% objective response with a 15% complete response rate, and REFERENCES median response duration was 4.4 months. The observed toxicity of MPB chemotherapy in our study was considerable 1. Ravi, R.: Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the but manageable. Similar to the experience with testicular penis. Brit. J. Urol., 7 2 817, 1993. cancer patients, close monitoring enabled individualization 2. Horenblas, S.,van Tinteren, H., Delemane, J. F. M., Moonen, of bleomycin doses and avoidance of irreversible bleomycin L. M. F., Lustig, V. and van Waardenburg, E. W.: Squamous lung toxicity.19 However, the schedule necessitated a weekcell carcinoma of the penis 111. Treatment of regional lymph hospitalization each month. To control better the untoward nodes. J. Urol., 149: 492,1993. effects of this regimen we are now attempting to convert this 3. Srinivas, V., Morse, M. J., Herr, H. W., Sogani, P. C. and program to a weekly schedule, whereby the cumulative doses Whitmore,W. F., Jr.: Penile cancer: Relation of extent of nodal remain approximately the same but the drugs are adminismetastasis to survival. J. Urol., 137: 880, 1987. tered in smaller fractions at shorter intervals. Potential ad4. Ahmed, T., Sklaroff, R. and Yagoda, A.: An appraisal of the efficacy of bleomycin in epidermoid carcinoma of the penis. vantages may include outpatient administration, improved Anticancer Res., 4:289, 1984. tolerance and avoidance of potentially irreversible or life
5. Sklaroff, R. B. and Yagoda, A,: Methotrexate in the treatment of penile carcinoma. Cancer, 4 5 214, 1980. 6. Gagliano, R. G., Blumenstein, B. A,, Crawford, E. D., Stephens, R. L., Coltman, C. A., J r . and Constanzi, J. J.: Cisdiamminedichloroplatinum in the treatment of advanced epidermoid carcinoma of the penis: A Southwest Oncology Groupstudy. J. Urol., 141: 66, 1989. 7. Sklaroff, R. and Yagoda, A.: Cis-diamminedichloride platinum I1 (DDP) in the treatment of penile carcinoma. Cancer, 44:1563, 1979. 8. Ahmed, T., Sklaroff, R. and Yapoda. A.: Seauential trials of methotrexate, cisplatin and bleomycin for penile cancer. J . Urol., 132 465, 1984. 9. Kattan, J., Culine, S., Droz, J . P., Fadel, E., Court, B., P e m n , J. L., Wibault, P. and Haie-Meder, C.: Penile cancer chemotherapy: Twelve years' experience a t Institut Gustave-Roussy. Urology, 42: 559, 1993. 10. Maiche, A. G.: Adjuvant treatment using bleomycin in squamous cell carcinoma of penis: Study of 19 cases. Brit. J. Urol., 5 5 542, 1983. 11. Kyalwazi, S. K., Bhana, D. and Harrison, N. W.: Carcinoma of the penis and Bleomycin chemotherapy in Uganda. Brit. J. Urol., 46:689, 1974. 12. Dexeus, F. H., Logothetis, C. J., Sella, A., Amato, R., Kilbourn, R., Fitz, K. and Striegel, A.: Combination chemotherapy with methotrexate, bleomycin, and cisplatin for advanced squamous cell carcinoma of the male genital tract. J. Urol., 146: 1284,1991. 13. Stanley, K. E.: Prognostic factors for survival in patients with inoperable lung cancer. J. Natl. Cancer Inst., 6 5 25, 1980. 14. h e r . Joint Comm. on Cancer: Penis Manual for Staging of Cancer, 4th edition. Edited by 0. H. Beahrs, D. E., Henson, R. V. P. Hutter and B. J . Kennedy. Philadelphia: J.P. Lippincott Co., chapt. 33, pp. 191-193, 1992. 15. Hussein, A. M., Benedetto, P. and Sridhar, K. S.: Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas. Cancer, 6 5 433, 1990. 16. Shammas, F. V., Ous, S. and Fossa, S. D.: Cisplatin and
5-fluorouracil in advanced cancer of the penis. J. Urol., 147: 630, 1992. 17. Dexeus, F. H., Logothetis, C. J. and Sipahi. H.: Chemotherapy for advanced squamous cell carcinoma of the male external genital tract and urethra. In: Systemic Therapy for Genitourinary Cancer. Edited by D. E. Johnson, C. J. Logothetis and A. C. von Eschenbach. Chicago: Year Book Medical Publishers, pp. 255-259, 1989. 18. Pizzocaro, G. and Piva, L.: Adjuvant and neoadjuvant vincris. tine, bleomycin and methotrexate for inguinal metast;lsrs from squamous cell carcinoma of the penis. Acta Oncol., 27: 823, 1988. 19. Logothetis, C. J., Samuels, M. L., Selig, D. E., %den, S..Dexeus. F.. Swanson. D., Johnson, D. and von Eschenbach, A,: Cyclic chemotherapy with cyclophosphamide, doxorubicin and cisplatin plus vinblastine and bleomycin in advanced germinal tu. mors: results with 100 patients. Amer. J. Med., 81: 219, 1986. 20. Mitropoulos, D., Dimopoulos, M.-A., Iroudi-Voulgari, A,, Zervas, A., Dimopoulos, C. and Logothetis, C. J.: Neoadjuvant cisplatin and interferon a-2b in the treatment and organ preservation of penile carcinoma. J . Urol., 152: 1124, 1994. 21. Lippman, S. M., Kavanagh, J . J., Paredes-Espinoza. M., Delgadillo-Madrueno, F., Paredes-Casillas, P., Hong, W. K., Holdener, E. and Krakoff, I. H.: 13-cis-retinoic acid plus interferon a-2a: highly active systemic therapy for squamous cell carcinoma of the cervix. J . Natl. Cancer Inst., 84: 241, 1992. 22. Rosell, R., G6mez-Codina. J., Camps, C., Maestre, J.. Padille, J.. Cant6, A., Mate, J . L., Li, S., Roig, J., Olazabal. A.. Canela, M., Ariza, A,, Skagel, Z., Morera-Prat, J . and Abad, A,: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. New Engl. J . Med., 330 153, 1994. 23. Moertel, C. G., Fleming, T. R., Macdonald, J . S., Haller, D. G., Laurie, J . A., Goodman, P. J., Ungerleider, J. S., Emerson, W. A,, Tormey, D. C., Glick, J. H., Veeder, M. H. and Mailliard, J . A.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl. J. Med., 322: 352, 1990.