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Improved Chemotherapy in Disseminated Testicular Cancer
LAWRENCE H. EINHORN*
AND
JOHN P. DONOHUE
From the Departments uf Hematology-Oncology and Urology, Indiana University Medical Center, Indianapolis, Indiana
ABSTRACT
Two combination chemotherapy regimens for disseminated testicular cancer are described. Our present regimen of platinum vinblastine and bleomycin has been highly successful, producing 16 complete (80 per cent) and 4 partial (20 per cent) remissions. Furthermore, 2 patients have been rendered free of disease by the surgical removal of residual disease, making the effective complete remission rate in these 20 patients 90 per cent. Of these patients 16 are alive and 14 are free of disease for more than 8 to more than 20 months. Despite the significant toxicity during the first 12 weeks of this therapeutic regimen it usually was manageable and maintenance therapy produced minimal toxicity. We believe that this regimen is a major advance in the management of patients with disseminated testicular cancer. Although testicular cancer accounts for only 1 per cent of all malignant tumors in male subjects it ranks first in incidence rate of cancer deaths in the 25 to 34-year age group. 1 Therefore, cancer of the testis has a significant on the social, economic and emotional status of this young population, Radiotherapy is the treatment of choice for seminoma since this tumor is radiosensitive, producing a 90 to 95 cure rate, and a retroperitoneal operation rarely is Indeed, radiotherapy for metastatic lesions produces an excellent 55 per cent 5-year survival rate. 3 However, the treatment for non-seminomatous germinal neoplasms has produced much less satisfactory results with considerably more controversy as to the preferred treatment for all stages of disease. In 1960 Li and associates introduced the first major thrust of chemotherapy in advanced testis cancer with the combination of actinomycin D, chlorambucil and methotrexate. 4 Subsequent studies confirmed a 50 to 70 per cent response rate, which included 10 to 20 per cent complete remissions. 5 • 6 Mackenzie concluded that ac.,ca1v11,y D was as effecti.ve alone as the triple therapy.' The last 15 years also have seen the development of many new agents with substantial in this disorder, notably vinblastine, 7 bleomycin, 8 adriamycin 9 and cisdiamminedichloroolatinum. 10 'Ne describe 2 separate combination used on with disseminated
intravenously for 4 consecutive days once a month was used at the completion of adriamycin, although patients 2 and 5 received actinomycin D as a single 4 mg. intravenous injection. Vincristine and bleomycin were used in sequential combination in an attempt to synchronize neoplasm with vincristine for subsequent destruction by bleomycin, with the bleomycin being given 6 hours after vincristine. 12 Bleomycin was shown to be most effective in killing Chinese hamster ovary cells in mitosis 13 and since vinblastine, like vincristine, also produces an arrest in the mitotic phase of the cell cycle, vinblastine and bleomycin also were used in sequential combination for potential maximal tumor destruction bleornycin, The bleomycin was at a total dosage of 360 units because of cumulative pulmonary fibrosis. Platinum was given as a 15-minute intravenous infusion for 5 consecutive days (days 1 to 5) every 3 weeks for 3 courses. Three patients (Nos. 16, 21 and 25) were given a fourth course of platinum because they had no nephrotoxicity and had minimal evidence of residual disease after the first 3 courses, Vinblastine was given on days l and 2 in a total dosage of 0.4 mg. per kg. for a total of 5 courses and then as a single injection in a dosage of 0.3 mg. per kg. every 4 weeks for 2 years. bacillus Calmette-Guerin was given scarificaand 3 weeks after each vinblastine for 4 thereafter, 1 and 3 weeks after each vinblastine This was used in an attempt to the duration of remission and 1m,rn,uP prospects for tot,li cell kill and eventual cure. Bleomycin was 2, 9 and 16 of each course and with the 6 hours after vinblasand then for a total of 12 weeks. The criterion for a partial response was a decrease of 50 per cent or more in the sum of the of diameters of all measurable lesions. A complete response was defined as a complete disappearance of all clinical, radiographic and biochemical evidence of including normal whole lung tomograms, serum and urine human chorionic gonadotropin, and serum alpha-fetoprotein. Blood cell counts, platelet counts and differentials were determined weekly for all patients, and liver and renal function tests were done every 3 weeks. Electrocardiograms were obtained before each dose of adriamycin. Arterial blood gases and pulmonary functions were done every 3 weeks while patients were on bleomycin. Tumor measurements were recorded at least every 3 weeks and appropriate radiologic and biochemical studies were repeated at least every 6 to 8 weeks. HHH>CHW
regimen v,as platinum, vinblastine and apy. MATERIALS AND METHODS
There were 27 patients with germ cell tumors of the testis studied 1 and 2). All patients had metastatic measurable disease and were no longer amenable to attempts at surgical cure. The 2 drug regimens were administered according to the schedules shown in tables 3 and 4. Adriamycin was given to a total dosage of 450 mg. per M. 2 because of its cumulative cardiotoxicity. Maintenance therapy with 1 mg. actinomycin D Accepted for publication May 7, 1976. *Requests for reprints: Indiana University Medical Center, Emerson Hall, Rm. 435, 1100 W. Michigan, Indianapolis, Indiana 46202.
66
EINHORN AND DONOHUE TABLE
Pt.
Diagnosis
1. Characteristics of patients treated with adriamycin, bleomycin and vincristine
Tumor Grade*
Prior Therapy
Chorioca.
V
Orchiectomy
2
Embryonal Ca
II
Orchiectomy
3
Embryonal Ca
II
Orchiectomy and retroperitoneal node dissection
4
Embryonal Ca
II
Orchiectomy
5
Teratoca.
IV
Orchiectomy
6
IV
Orchiectomy
7
Teratoca. and embryonal Ca Seminoma
8
Embryonal Ca
II
Orchiectomy, radiotherapy (multiple areas) and chlorambucil Orchiectomy, retroperitoneal node dissection, radiotherapy and actinomycin D
Disease
Response
Duration (mos.)
Inguinal nodes, large abdominal mass, human chorionic gonadotropin 800,000 units Bilat. pulmonary metastases and pos. lymphangiogram Bilat. pulmonary metastases
Complete
30+
Well 34+ mos.
Complete
25+
Well 26+ mos.
Complete
7
Bilat. pulmonary metastases Bilat. pulmonary metastases Bilat. pulmonary metastases, liver, nodes Multiple bones, liver, bilat. pulmonary metastases
Partial
7
Partial
12
Partial
3
Partial
5
Bilat. pulmonary metastases
None
Present Status
Well 26+ mos. in 2nd complete remission on platinum, vinblastine and bleomycin Alive with progressive disease 24+ mos. Died of brain metastases 14 mos. Died of progressive disease 5 mos. Died of progressive disease 7 mos.
Died of progressive disease 4 mos.
* Dixon-Moore classification.
RESULTS
therapy because of recurrent operative complications. Interestingly, there was no gross or histological evidence of tumor at Adriamycin, bleomycin and vincristine. There were 8 autopsy. Patient 12, the oldest patient in this series (age 63), patients treated with this regimen from June 1973 to June 1974 died 3 months after initiation of chemotherapy azotemia and (table 1). There were 3 complete and 4 partial responses in this granulocytopenic pneumonia secondary to the chemotherapy. group of patients. All 3 patients with complete remissions At autopsy there was no gross evidence of tumor but microremained free of disease for more than 2 years after initiation of scopically a single focus of embryonal carcinoma was noted in this therapy, although 1 patient (No. 3) had a relapse after the right lung. The other 2 deaths (patient Nos. 18 and 20) were being in complete remission for 7 months and has been in a of recurrent disease 6 and 8 months after achieving complete second complete remission now for more than 18 months. It is remission. Patient 18 refused all maintenance chemotherapy interesting that 1 of these patients (No. 1) has pure choriocar- and immunotherapy and, thus, only 1 patient (No. 20) truly has cinoma (Dixon-Moore group V), which has been in a continu- had a relapse. Two of our 4 partial responders to this chemotherapy regious complete remission for more than 30 months, and has been off all therapy for 8 months. Three of the 4 partial responders men are presently free of disease after surgical removal of the have died of progressive disease; only 1 of these 4 patients (No. remaining disease. Patient 14 had a complete disappearance 4) was treated subsequently with platinum, vinblastine and of 6 of the 7 pulmonary metastases and the remaining nodule bleomycin and he achieved a second prolonged partial re- was removed at thoracotomy and found to be a mature terasponse. The patient is alive presently but with progressive toma. This patient remains free of disease 7 months postdisease 2 years after starting adriamycin, bleomycin and thoracotomy. This phenomenon has been described previously vincristine. Toxicity consisted of severe stomatitis, nausea, in other regimens of combination chemotherapy. 14 Patient 23 vomiting, weight loss, myelosuppression, neuromuscular toxic- presented with a large abdominal mass and bilateral pulmonary ity and pulmonary fibrosis. Because of the superior results with metastases. After 3 courses of combination chemotherapy ail our present regimen of platinum, vinblastine and bleomycin we pulmonary metastases completely disappeared and the abdomwill not present the adriamycin regimen in further detail, since inal mass was markedly reduced in size. The remaining tumor we no longer use it. However, we merely presented those 8 was removed at laparotomy and the patient has remained free patients to exhibit the potential durability of complete remis- of disease for 6 months postoperatively. Our other 2 partial sions achieved with potent combination chemotherapy. responders are alive at 16 and 12 months after initiation of Platinum, vinblastine and bleomycin. There were 21 patients platinum, vinblastine and bleomycin chemotherapy, although treated with this regimen (table 2). One of these patients could 1 of these patients (No. 11) presently has progressive disease. not be evaluated since he died of progressive tumor 4 days after Toxicity could be described best by separating this 3-drug initiation of therapy. Two of these patients (Nos. 10 and 11) combination into its individual components. previously had been treated with our earlier regimen of adriaPlatinum caused moderate to severe nausea and vomiting in mycin, bleomycin and vincristine. Of the 20 patients who could all patients during each 5-day course. Hydration with intravebe evaluated there were 16 complete remissions (80 per cent) nous fluids occasionally was required to prevent significant and 4 partial remissions (20 per cent), for an over-all response dehydration and potential platinum nephrotoxicity. Despite rate of 100 per cent. Twelve of the 16 patients with complete these precautions 3 patients had significant azotemia (blood remissions have remained free of disease for 6 to 18 months. urea nitrogen greater than 50 mg. per cent) and 1 patient Four complete responders have died. Patient 9 died of multiple required hemodialysis for acute renal failure. There were no small bowel fistulas and obstruction. This patient had a huge observed audiological abnormalities. Hyperuricemia and hypoinoperable abdominal tumor and a subtotal resection was done kalemia commonly were seen but were not clinical problems. followed by chemotherapy. He died 7 months after initiation No patient has any evidence of residual nephrotoxicity. of chemotherapy and had received only 12 weeks of chemoBleomycin produced fever, chills and cutaneous striae in all
67
CBEi\/10THERAP'l IN TESTICULAR CANCER TABLE
PL
Diagnosis
2, Characteristics of patients treated with platinum, uinblastine and bleomycin
Tun1or
Grade*
Prior Therapy
Disease
Response
Duration (mos,)
Present Status Died of operative complications, no tumor at autopsy Well
9
Embryonal Ca
II
Orchiectomy
Huge abdominal mass
Complete
6
10
Embryonal Ca
II
Bilat, pulmonary metastases
Complete
18+
11
Embryonal Ca
II
Orchiectomy, retroperitoneal node dissection, chemotherapy Orchiectomy, chemotherapy
Partial
13
12
Embryonal Ca
II
Orchiectomy, chemotherapy
Nodes, bilat, pulmonary metastases Bilal, pulmonary metastases
Complete
3
13
Teratoma
Complete
14+
14
Embryonal Ca
II
Partial
12+
15
Embryonal Ca
II
Orchiectomy, retroperitoneal node dissection, radiotherapy, chemotherapy Orchiectomy
Large abdominal mass, cervical nodes, liver, bilat, pulmonary metastases BilaL pulmonary metastases
Complete
12+
Well, free of disease 7 mos. after surgical removal of solitary pulmonary nodule Well
16
Embryonal Ca
II
Orchiectomy
Complete
12+
Well
17
Tetatoca,, embryonal Ca, chorioca.
IV
Orchiectomy
Partial
12+
18
IV
Orchiectomy, chemotherapy
Bilat, pulmonary metastases, nodes, liver
Complete
6
19
Teratoca,, embryonal Ca, chorioca. Embryonal Ca
II
Bilat, pulmonary metastases
Complete
11+
20
Seminoma
Abdominal mass, bilat, pulmonary metastases
Complete
8
21
Embryonal Ca
II
Cervical nodes, bilat pulmonary metastases
Complete
8+
22
Embryonal Ca and seminoma Chorioca, and embryonal Ca
II
Orchiectomy, retroperitoneal node dissection Orchiectomy, retruperitoneal node dissection, radiotherapy Orchiectomy, retroperitoneal node dissection, chemotherapy Orchiectomy
Alive and still in partial remission on vinblastine and bacillus CalmetteGuerin Refused maintenance therapy, died 8 mos, after starting therapy Well
None
V
Orchiectomy
Massive bone, liver, lung and bilat, testicular tumors Abdominal mass, bilat, pulmonary metastases
Teratoca, and embryonal Ca Teratoca. and embryonal Ca
IV
Orchiectomy, chemotherapy
IV
23 24
III
Orchiectomy, radiotherapy
laparotomy,
26
Embryonal Ca
II
27
En:i bryonal Ca
II
28
Embryonal Ca
II
Orchiectomy, retroperitoneal node dissection, radiotherapy, chemotherapy Orchiectomy, retroperitoneal node dissection, chemotherapy Orchiectomy, retroperitoneal node dissection, chemotherapy Orchiectomy
29
Embryonal Ca
II
Orchiectomy
25
Abdominal mass, liver, bilat, pulmonary metastases Nodes, bilat, pulmonary metastases Nodes, liver, bilat, pulmonary metastases
Alive with progressive disease Died of chemotherapy complications Well
Died of progressive disease 10 mos. after starting therapy Well
Partial
8+
BilaL pulmonary metastases
Complete
7+
Died 4 days after starting therapy Well, free of disease 6 mos, after surgical removal of residual abdominal mass Well
Large (6 by 7 cm,) solitary pulmonary metastasis and hilar mass Bilat, pulmonary metastases
Complete
7+
Well
Complete
7+
Well
Bilat, pulmonary metastases
Complete
6+
Well
Nodes and bilat, pulmonary metastases Nodes and bilat, pulmonary metastases
Complete
6+
Well
Complete
6+
Well
* Dixon-l\1oore classification.
TABLE
3, Regimen with adriamycin, bleomycin and uincristine
L Adriamycin, 75 mg. per M,' intravenously, everv :l weeks (total 450 mg per M.') 2, Vincristine, 1 mg, intravenously followed in 6 hours by 30 units bleomycin intravenously weekly for 12 weeks :J, At completion of 450 mg, per M,' adriamycin substitute actinomycin D and continue for 2 years of therapy TABLE 4,
Regimen with platinum, vinblastine and bleomycin
L Platinum 20 mg, per M,' intravenously (during 15 minutes) daily for 5 days, once every :1 weeks for :~ courses 2, Bleomycin, 30 units intravenously weekly for 12 weeks 3, Vinblastine, 0,2 mg, per kg, intravenously daily for 2 days every 3 weeks a, Vinblastine given 6 hours prior to bleomycin b, After 5 courses (12 weeks) of vinblastine, maintenance therapy consisted of vinblastine 0,3 mg, per kg, intravenously every 4 weeks and bacillus Calmette-Guerin by scarification 1, 2 and :3 weeks after each dosage of vinblastine c. Therapy to be continued for 2 years
patients but these were not clinical problems and did not require alteration of the bleomycin dosages, All patients had significant alopecia, There were no cases of clinically significant pulmonary fibrosis, Weight loss (from platinum and bleomycin) was seen in all patients during the 12 weeks of bleomycin and averaged 20 pounds, No patient required hospitalization for intravenous hyperalimentation, Vinblastine produced myalgia in half of the patients, Although this was occasionally severe enough to require narcotic analgesics during the first 12 weeks of therapy it was not a clinical problem during maintenance therapy with the lower dosage (0.3 mg, per kg,) of vinblastine. Anemia and thrombocytopenia were observed in several patients but no patient had thrombocytopenic bleeding or required platelet transfusions, Only 2 patients experienced thrombocytopenia between 50,000 and 100,000 and no patient had a platelet count less than 50,000, Anemia was more of a problem, especially in patients who had had prior radiotherapy. Leukopenia also was
68
EINHORN AND DONOHUE TABLE
Reference
Wyatt and McAninch" Mackenzie 6 Mendelson and Serpick" Jacobs 17 Kennedy" Samuels and Howe 7 Samuels and associates 19
5. Results with chemotherapy in disseminated testicular cancer Treatment
Total Pts.
Methotrexate Actinomycin D (alone or in double or triple therapy) Cyclophosphamide, vincristine, methotrexate and fluorouracil Vincristine, actinomycin D and cyclophosphamide Mithramycin Vinblastine Vinblastine and bleomycin
Complete Remissions No.(%)
10 154 17 58
23 21 23
Prolonged Survivors*
4 (40) 24 (16) 5 (29) 7 (12)
13 1 4
5 (22)
5
4 (19) 9 (39)
2
4
* Refers to patients remaining free of disease at time of publication.
more severe in these patients and they were started on a lowered dosage of vinblastine (0.15 mg. per kg. for 2 consecutive days). Packed red blood cell transfusions were required periodically on 4 patients during the first several months of therapy. The most serious side effect, which was seen in all patients, was severe leukopenia. The nadir of the white blood count usually was 1,000 between days 7 and 14. Seven patients required hospitalization for presumed sepsis with granulocytopenic fever and were cultured and started on antibiotic coverage with broad-spectrum antibiotics. Four of these patients had documented gram-negative sepsis with Escherichia coli and 1 of these patients died of sepsis (patient No. 12). Bacillus Calmette-Guerin immunotherapy caused mild local erythema, pruritus, fever and myalgia but was generally well tolerated by all patients except 1 who had severe local reactivity and an ulcerated regional lymph node requiring cessation of the bacillus Calmette-Guerin. Despite the aforementioned severe toxicity this occurred primarily during the 12 weeks of remission induction therapy. Maintenance therapy with vinblastine and bacillus Calmette-Guerin was well tolerated and all patients regained their hair growth and weight during this period. No patient required hospitalization for complications of therapy during vinblastine and bacillus Calmette-Guerin maintenance and they were all able to continue school or work full time. DISCUSSION
Since the original report by Li and associates, demonstrating activity of chemotherapy in disseminated testicular cancer,• there have been numerous clinical trials evaluating a variety of drugs in these diseases (table 5). 6 • 7 • 15- 19 Generally speaking, the only meaningful response for the patient has been complete remission, since partial remissions usually were of brief duration. Although it is not possible to extract present survival data on all patients reported in table 5 there does appear to be a general trend revealing that approximately 50 per cent of all complete remissions in disseminated testicular cancer have prolonged survival and potential cure. Indeed, in testicular cancer in general most relapses occur within a 2-year period from the date of operation or chemotherapy.2°· 21 Although we do not have long-term followup data on any of our patients treated with platinum, vinblastine and bleomycin it seems quite reasonable to expect that at least 50 per cent of our patients in complete remission will have cures and, hopefully, with the aggressive chemotherapy used in this regimen and the addition of bacillus Calmette-Guerin immunotherapy, considerably less than 50 per cent of our patients with complete remissions will eventually have a relapse. This present regimen has produced the highest complete remission rate reported thus far. Furthermore, we believe that chemotherapy can significantly alter the course of this disease in some patients, even when a complete response is not seen (patient Nos. 14 and 23). Present aggressive chemotherapy regimens appear to be capable of changing the histology to a
more benign form and transforming previously inoperable patients to potentially operable and hopefully curable patients. 1 • Although this report included only our first 20 patients treated with platinum, vinblastine and bleomycin who could be evaluated we have treated an additional 7 patients in the last 6 months and all have achieved complete remission. Thus, our complete remission rate on these 27 patients treated with platinum, vinblastine and bleomycin is 85 per cent (23 of 27 complete remissions) and, including our operation plus chemotherapy complete remission patients, the rate increased to 93 per cent (25 of 27). This is the highest complete remission rate with chemotherapy seen in any adult malignancy. In addition to the regimens described in table 5 we have reviewed all patients with disseminated testicular cancer treated at our hospital from 1965 to 1972. The majority of these patients were treated with actinomycin D regimens. There were 28 patients seen during this period, only 1 of whom achieved a complete remission, which lasted only 9 months. All 28 patients died of their disease within 2 years of initiation of chemotherapy and only 5 patients (18 per cent) survived 1 year. In contrast, of the 27 aforementioned patients only 9 have died (4 on adriamycin, bleomycin and vincristine, and 5 on platinum, vinblastine and bleomycin), with 12 of 20 patients (60 per cent) surviving for 12 months or longer (7 patients on platinum, vinblastine and bleomycin are free of disease but have been in the study for only 7 to 9 months). Only 1 of the 9 deaths occurred after a I-year survival. The results of recent regimens and this regimen clearly indicate that disseminated testicular cancer is a responsive disease to chemotherapy and many patients are probably curable, even with far-advanced disease. There is no longer any role for pessimism in this disease. However, this program is an aggressive, complicated and toxic therapeutic regimen that probably is administered best by personnel trained in medical oncology. Although this is a preliminary report we believe that the majority of these complete remissions will be prolonged survivals and potential cures. REFERENCES
1. MacKay, E. N. and Sellers, A. H.: A statistical review of malignant testicular tumours based on the experience of the Ontario Cancer Foundation Clinics, 1938 to 1961. Canad. Med. Ass. J., 94: 889, 1966. 2. Maier, J. G., Mittemeyer, B. T. and Sulak, M. H.: Treatment and prognosis in seminoma of the testis. J. Urol., 99: 72, 1968. 3. Friedman, M. and Purkayastha, M. C.: Recurrent seminoma: the management of late metastasis, recurrence, or a second primary tumor. Amer. J. Roentgen., 83: 25, 1960. 4. Li, M. C., Whitmore, W. F., Jr., Golbey, R. and Grabstald, H.: Effects of combined drug therapy on metastatic cancer of the testis. J .A.M.A., 17 4: 1291, 1960. 5. Ansfield, F. J., Korbitz, B. C., Davis, H. L., Jr. and Ramirez, G.: Triple drug therapy in testicular tumors. Cancer, 24: 442, 1969. 6. Mackenzie, A. R.: Chemotherapy of metastatic testis cancer: results in 154 patients. Cancer, 19: 1369, 1966. 7. Samuels, M. L. and Howe, C. D.: Vinblastine in the management of testicular cancer. Cancer, 25: 1009, 1970.
CHEJv~ O'T'HERAP"'i
8. Bh2rr1) R. H., Carter, S. K. and Agre, K,: A c;inical rev'ew of bleomycin-a new antir,eool11st1 agent. Cancer, 31: 903, 1973, R and Bonadonna, G,, 9, Monfardini, S,, Bajetta, Clinical use of adriamycin m advanced testicular cancer. J, UroL, 108: 29'.3, 1972, m Higby, D, J,, Wallace, ff J,, Jr., Albert, D, and Holland, '.J, F,: Diamminodichloroplatinum in the chemotherapy of testicular tumors, J, UroL, 112: 100, 1974, lL Burgess, IVL A,, Einhorn, L, R and Gottlieb, J, A,: Treatment of metastatic germ cell tumors with adriamycin, vincristine, and bleomycin, Proc, Amer. Soc, Clin, OncoL, 16: 244, 1975, 12, Livingston, R R, Bodey, G, P,, Gottlieb, J, A, and Frei, K, III: Kinetic scheduling of vincristine (NSC-67574) and bleomycm (NSC-125066) in patients with lung cancer and other malignant tumors, Cancer Chemother. Rep,, part 1, 57: 219, 1973, 13, Barranco, S, C, and Humphrey, RM,: The effects of bleomycin on survival and cell progression in Chinese hamster cells in vitro, Cancer Res,, 31: 1218, 197L 14, Merrin, C,, Takita, R, Weber, R, Wajsman, Z,, Baumgartner, G, and Murphy, G, P,: Combination radical surgery and mult1pl,e sequential chemotherapy for the treatment of advanced carcinoma of the testis (stage III), Cancer, 37: 20, 1976, 15, Wyatt, J, Kand McAninch, L, N,: A chemotherapeutic approach to advanced testicular carcinoma, Canad, J, Surg,, 10: 421, 1967, 16, Mendelson, D, and Serpick, A, A: Combination chemotherapy of testicular tumors, J, UroL, 103: 619, 1970, n Jacobs, K IvL: Combination chemotherapy of metastatic testicular germinal cell tumors and soft part sarcomas, Cancer, 25: 324, 1970, 18, Kennedy, R J,: Mithramycin therapy in advanced testicular neoplasms, Cancer, 26: 755, 1970, , 19, Samuels, M, L,, Johnson, D, K and Holoye, P, Y: Contmuous intravenous bleomycin (NSC-125066) therapy with vinblastine (NSC-49842) in stage III testicular neoplasia, Cancer Chemother, Rep,, 59: 563, 1975, 20, Nefzger, M, D, and Mostofi, F, K: Survival ,after, sur,gery for germinal malignancies of the testis, L Rates of survival m tumor groups, Cancer, 30: 1225, 1972, 2L LeFevre, R K, Levin, H, S,, Banowsky, L ff, Stewart, R R, Straffon, R A, and Hewitt, C, R: Testis tumors: review of 125 cases at the Cleveland Clinic, Urology, 6: 588, 1975,
TESTICULAR CANCE~
COMMENT This is an paper, response rate and, particularly, a complete response rate, responses are seen in patients who have had prim chemotherapy, which is obviously important, This paper is one of the first using immunotherapy in testicular cancer, It confirms the observation that we and others have made that bleomycin, vinblastine and cis-platinum are all active compounds, There have been many studies using various combinations of the same drugs, indicating the marked effectiveness of antineoplastic chemotherapy with response rates as high as 60 to 90 per cent, Therefore, it is no longer a question of whether a remission is possible, The questions now are: 1) How many complete remissions can we get? 2) Is the intensity of the induction phase too much, that is can we back off and perhaps combine the induction phase with immunotherapy? 3) What should be the intensity of the maintenance phase? 4) What should be the duration of the maintenance phase? Perhaps we are treating too long, 5) What is the place ofreductive surgery? We have an article in the May issue of The Journal of Urology concerning the place of second look or re-exploration surgery, 1 We believe that there is definitely a place for re-exploration with good response to improved chemotherapy, 6) With improvement in chemotherapy will the place of radiation therapy be diminished or even eliminated, except for seminomas? Another possibility that should be considered with the use of multiple drugs is that relating to the potential for an increase in second tumors, This was seen by de Vita in Hodgkin's disease, Perhaps there is a need to reduce the dosage of these carcinogenic agents, Perhaps and hopefully an old era is ending, Disseminated testicular cancer is now treatable and probably a curable disease, With response rates more than 75 per cent studies with 20 to 50 patients with median followups of less than 1 year will no longer be acceptable, Prospective randomized trials are now needed, Perhaps another national cooperative study should be undertaken to answer some of the questions,
Harry Grabstald and Alan Yagoda Memorial Hospital New York, New York L Comisarow, R H, and Grabstald, ff: Re-exploration for retroperitoneal lymph node metastases from testis tumors, J, UroL, 115: 569, 1976,
AND
JOHN P. DONOHUE
From the Departments uf Hematology-Oncology and Urology, Indiana University Medical Center, Indianapolis, Indiana
ABSTRACT
Two combination chemotherapy regimens for disseminated testicular cancer are described. Our present regimen of platinum vinblastine and bleomycin has been highly successful, producing 16 complete (80 per cent) and 4 partial (20 per cent) remissions. Furthermore, 2 patients have been rendered free of disease by the surgical removal of residual disease, making the effective complete remission rate in these 20 patients 90 per cent. Of these patients 16 are alive and 14 are free of disease for more than 8 to more than 20 months. Despite the significant toxicity during the first 12 weeks of this therapeutic regimen it usually was manageable and maintenance therapy produced minimal toxicity. We believe that this regimen is a major advance in the management of patients with disseminated testicular cancer. Although testicular cancer accounts for only 1 per cent of all malignant tumors in male subjects it ranks first in incidence rate of cancer deaths in the 25 to 34-year age group. 1 Therefore, cancer of the testis has a significant on the social, economic and emotional status of this young population, Radiotherapy is the treatment of choice for seminoma since this tumor is radiosensitive, producing a 90 to 95 cure rate, and a retroperitoneal operation rarely is Indeed, radiotherapy for metastatic lesions produces an excellent 55 per cent 5-year survival rate. 3 However, the treatment for non-seminomatous germinal neoplasms has produced much less satisfactory results with considerably more controversy as to the preferred treatment for all stages of disease. In 1960 Li and associates introduced the first major thrust of chemotherapy in advanced testis cancer with the combination of actinomycin D, chlorambucil and methotrexate. 4 Subsequent studies confirmed a 50 to 70 per cent response rate, which included 10 to 20 per cent complete remissions. 5 • 6 Mackenzie concluded that ac.,ca1v11,y D was as effecti.ve alone as the triple therapy.' The last 15 years also have seen the development of many new agents with substantial in this disorder, notably vinblastine, 7 bleomycin, 8 adriamycin 9 and cisdiamminedichloroolatinum. 10 'Ne describe 2 separate combination used on with disseminated
intravenously for 4 consecutive days once a month was used at the completion of adriamycin, although patients 2 and 5 received actinomycin D as a single 4 mg. intravenous injection. Vincristine and bleomycin were used in sequential combination in an attempt to synchronize neoplasm with vincristine for subsequent destruction by bleomycin, with the bleomycin being given 6 hours after vincristine. 12 Bleomycin was shown to be most effective in killing Chinese hamster ovary cells in mitosis 13 and since vinblastine, like vincristine, also produces an arrest in the mitotic phase of the cell cycle, vinblastine and bleomycin also were used in sequential combination for potential maximal tumor destruction bleornycin, The bleomycin was at a total dosage of 360 units because of cumulative pulmonary fibrosis. Platinum was given as a 15-minute intravenous infusion for 5 consecutive days (days 1 to 5) every 3 weeks for 3 courses. Three patients (Nos. 16, 21 and 25) were given a fourth course of platinum because they had no nephrotoxicity and had minimal evidence of residual disease after the first 3 courses, Vinblastine was given on days l and 2 in a total dosage of 0.4 mg. per kg. for a total of 5 courses and then as a single injection in a dosage of 0.3 mg. per kg. every 4 weeks for 2 years. bacillus Calmette-Guerin was given scarificaand 3 weeks after each vinblastine for 4 thereafter, 1 and 3 weeks after each vinblastine This was used in an attempt to the duration of remission and 1m,rn,uP prospects for tot,li cell kill and eventual cure. Bleomycin was 2, 9 and 16 of each course and with the 6 hours after vinblasand then for a total of 12 weeks. The criterion for a partial response was a decrease of 50 per cent or more in the sum of the of diameters of all measurable lesions. A complete response was defined as a complete disappearance of all clinical, radiographic and biochemical evidence of including normal whole lung tomograms, serum and urine human chorionic gonadotropin, and serum alpha-fetoprotein. Blood cell counts, platelet counts and differentials were determined weekly for all patients, and liver and renal function tests were done every 3 weeks. Electrocardiograms were obtained before each dose of adriamycin. Arterial blood gases and pulmonary functions were done every 3 weeks while patients were on bleomycin. Tumor measurements were recorded at least every 3 weeks and appropriate radiologic and biochemical studies were repeated at least every 6 to 8 weeks. HHH>CHW
regimen v,as platinum, vinblastine and apy. MATERIALS AND METHODS
There were 27 patients with germ cell tumors of the testis studied 1 and 2). All patients had metastatic measurable disease and were no longer amenable to attempts at surgical cure. The 2 drug regimens were administered according to the schedules shown in tables 3 and 4. Adriamycin was given to a total dosage of 450 mg. per M. 2 because of its cumulative cardiotoxicity. Maintenance therapy with 1 mg. actinomycin D Accepted for publication May 7, 1976. *Requests for reprints: Indiana University Medical Center, Emerson Hall, Rm. 435, 1100 W. Michigan, Indianapolis, Indiana 46202.
66
EINHORN AND DONOHUE TABLE
Pt.
Diagnosis
1. Characteristics of patients treated with adriamycin, bleomycin and vincristine
Tumor Grade*
Prior Therapy
Chorioca.
V
Orchiectomy
2
Embryonal Ca
II
Orchiectomy
3
Embryonal Ca
II
Orchiectomy and retroperitoneal node dissection
4
Embryonal Ca
II
Orchiectomy
5
Teratoca.
IV
Orchiectomy
6
IV
Orchiectomy
7
Teratoca. and embryonal Ca Seminoma
8
Embryonal Ca
II
Orchiectomy, radiotherapy (multiple areas) and chlorambucil Orchiectomy, retroperitoneal node dissection, radiotherapy and actinomycin D
Disease
Response
Duration (mos.)
Inguinal nodes, large abdominal mass, human chorionic gonadotropin 800,000 units Bilat. pulmonary metastases and pos. lymphangiogram Bilat. pulmonary metastases
Complete
30+
Well 34+ mos.
Complete
25+
Well 26+ mos.
Complete
7
Bilat. pulmonary metastases Bilat. pulmonary metastases Bilat. pulmonary metastases, liver, nodes Multiple bones, liver, bilat. pulmonary metastases
Partial
7
Partial
12
Partial
3
Partial
5
Bilat. pulmonary metastases
None
Present Status
Well 26+ mos. in 2nd complete remission on platinum, vinblastine and bleomycin Alive with progressive disease 24+ mos. Died of brain metastases 14 mos. Died of progressive disease 5 mos. Died of progressive disease 7 mos.
Died of progressive disease 4 mos.
* Dixon-Moore classification.
RESULTS
therapy because of recurrent operative complications. Interestingly, there was no gross or histological evidence of tumor at Adriamycin, bleomycin and vincristine. There were 8 autopsy. Patient 12, the oldest patient in this series (age 63), patients treated with this regimen from June 1973 to June 1974 died 3 months after initiation of chemotherapy azotemia and (table 1). There were 3 complete and 4 partial responses in this granulocytopenic pneumonia secondary to the chemotherapy. group of patients. All 3 patients with complete remissions At autopsy there was no gross evidence of tumor but microremained free of disease for more than 2 years after initiation of scopically a single focus of embryonal carcinoma was noted in this therapy, although 1 patient (No. 3) had a relapse after the right lung. The other 2 deaths (patient Nos. 18 and 20) were being in complete remission for 7 months and has been in a of recurrent disease 6 and 8 months after achieving complete second complete remission now for more than 18 months. It is remission. Patient 18 refused all maintenance chemotherapy interesting that 1 of these patients (No. 1) has pure choriocar- and immunotherapy and, thus, only 1 patient (No. 20) truly has cinoma (Dixon-Moore group V), which has been in a continu- had a relapse. Two of our 4 partial responders to this chemotherapy regious complete remission for more than 30 months, and has been off all therapy for 8 months. Three of the 4 partial responders men are presently free of disease after surgical removal of the have died of progressive disease; only 1 of these 4 patients (No. remaining disease. Patient 14 had a complete disappearance 4) was treated subsequently with platinum, vinblastine and of 6 of the 7 pulmonary metastases and the remaining nodule bleomycin and he achieved a second prolonged partial re- was removed at thoracotomy and found to be a mature terasponse. The patient is alive presently but with progressive toma. This patient remains free of disease 7 months postdisease 2 years after starting adriamycin, bleomycin and thoracotomy. This phenomenon has been described previously vincristine. Toxicity consisted of severe stomatitis, nausea, in other regimens of combination chemotherapy. 14 Patient 23 vomiting, weight loss, myelosuppression, neuromuscular toxic- presented with a large abdominal mass and bilateral pulmonary ity and pulmonary fibrosis. Because of the superior results with metastases. After 3 courses of combination chemotherapy ail our present regimen of platinum, vinblastine and bleomycin we pulmonary metastases completely disappeared and the abdomwill not present the adriamycin regimen in further detail, since inal mass was markedly reduced in size. The remaining tumor we no longer use it. However, we merely presented those 8 was removed at laparotomy and the patient has remained free patients to exhibit the potential durability of complete remis- of disease for 6 months postoperatively. Our other 2 partial sions achieved with potent combination chemotherapy. responders are alive at 16 and 12 months after initiation of Platinum, vinblastine and bleomycin. There were 21 patients platinum, vinblastine and bleomycin chemotherapy, although treated with this regimen (table 2). One of these patients could 1 of these patients (No. 11) presently has progressive disease. not be evaluated since he died of progressive tumor 4 days after Toxicity could be described best by separating this 3-drug initiation of therapy. Two of these patients (Nos. 10 and 11) combination into its individual components. previously had been treated with our earlier regimen of adriaPlatinum caused moderate to severe nausea and vomiting in mycin, bleomycin and vincristine. Of the 20 patients who could all patients during each 5-day course. Hydration with intravebe evaluated there were 16 complete remissions (80 per cent) nous fluids occasionally was required to prevent significant and 4 partial remissions (20 per cent), for an over-all response dehydration and potential platinum nephrotoxicity. Despite rate of 100 per cent. Twelve of the 16 patients with complete these precautions 3 patients had significant azotemia (blood remissions have remained free of disease for 6 to 18 months. urea nitrogen greater than 50 mg. per cent) and 1 patient Four complete responders have died. Patient 9 died of multiple required hemodialysis for acute renal failure. There were no small bowel fistulas and obstruction. This patient had a huge observed audiological abnormalities. Hyperuricemia and hypoinoperable abdominal tumor and a subtotal resection was done kalemia commonly were seen but were not clinical problems. followed by chemotherapy. He died 7 months after initiation No patient has any evidence of residual nephrotoxicity. of chemotherapy and had received only 12 weeks of chemoBleomycin produced fever, chills and cutaneous striae in all
67
CBEi\/10THERAP'l IN TESTICULAR CANCER TABLE
PL
Diagnosis
2, Characteristics of patients treated with platinum, uinblastine and bleomycin
Tun1or
Grade*
Prior Therapy
Disease
Response
Duration (mos,)
Present Status Died of operative complications, no tumor at autopsy Well
9
Embryonal Ca
II
Orchiectomy
Huge abdominal mass
Complete
6
10
Embryonal Ca
II
Bilat, pulmonary metastases
Complete
18+
11
Embryonal Ca
II
Orchiectomy, retroperitoneal node dissection, chemotherapy Orchiectomy, chemotherapy
Partial
13
12
Embryonal Ca
II
Orchiectomy, chemotherapy
Nodes, bilat, pulmonary metastases Bilal, pulmonary metastases
Complete
3
13
Teratoma
Complete
14+
14
Embryonal Ca
II
Partial
12+
15
Embryonal Ca
II
Orchiectomy, retroperitoneal node dissection, radiotherapy, chemotherapy Orchiectomy
Large abdominal mass, cervical nodes, liver, bilat, pulmonary metastases BilaL pulmonary metastases
Complete
12+
Well, free of disease 7 mos. after surgical removal of solitary pulmonary nodule Well
16
Embryonal Ca
II
Orchiectomy
Complete
12+
Well
17
Tetatoca,, embryonal Ca, chorioca.
IV
Orchiectomy
Partial
12+
18
IV
Orchiectomy, chemotherapy
Bilat, pulmonary metastases, nodes, liver
Complete
6
19
Teratoca,, embryonal Ca, chorioca. Embryonal Ca
II
Bilat, pulmonary metastases
Complete
11+
20
Seminoma
Abdominal mass, bilat, pulmonary metastases
Complete
8
21
Embryonal Ca
II
Cervical nodes, bilat pulmonary metastases
Complete
8+
22
Embryonal Ca and seminoma Chorioca, and embryonal Ca
II
Orchiectomy, retroperitoneal node dissection Orchiectomy, retruperitoneal node dissection, radiotherapy Orchiectomy, retroperitoneal node dissection, chemotherapy Orchiectomy
Alive and still in partial remission on vinblastine and bacillus CalmetteGuerin Refused maintenance therapy, died 8 mos, after starting therapy Well
None
V
Orchiectomy
Massive bone, liver, lung and bilat, testicular tumors Abdominal mass, bilat, pulmonary metastases
Teratoca, and embryonal Ca Teratoca. and embryonal Ca
IV
Orchiectomy, chemotherapy
IV
23 24
III
Orchiectomy, radiotherapy
laparotomy,
26
Embryonal Ca
II
27
En:i bryonal Ca
II
28
Embryonal Ca
II
Orchiectomy, retroperitoneal node dissection, radiotherapy, chemotherapy Orchiectomy, retroperitoneal node dissection, chemotherapy Orchiectomy, retroperitoneal node dissection, chemotherapy Orchiectomy
29
Embryonal Ca
II
Orchiectomy
25
Abdominal mass, liver, bilat, pulmonary metastases Nodes, bilat, pulmonary metastases Nodes, liver, bilat, pulmonary metastases
Alive with progressive disease Died of chemotherapy complications Well
Died of progressive disease 10 mos. after starting therapy Well
Partial
8+
BilaL pulmonary metastases
Complete
7+
Died 4 days after starting therapy Well, free of disease 6 mos, after surgical removal of residual abdominal mass Well
Large (6 by 7 cm,) solitary pulmonary metastasis and hilar mass Bilat, pulmonary metastases
Complete
7+
Well
Complete
7+
Well
Bilat, pulmonary metastases
Complete
6+
Well
Nodes and bilat, pulmonary metastases Nodes and bilat, pulmonary metastases
Complete
6+
Well
Complete
6+
Well
* Dixon-l\1oore classification.
TABLE
3, Regimen with adriamycin, bleomycin and uincristine
L Adriamycin, 75 mg. per M,' intravenously, everv :l weeks (total 450 mg per M.') 2, Vincristine, 1 mg, intravenously followed in 6 hours by 30 units bleomycin intravenously weekly for 12 weeks :J, At completion of 450 mg, per M,' adriamycin substitute actinomycin D and continue for 2 years of therapy TABLE 4,
Regimen with platinum, vinblastine and bleomycin
L Platinum 20 mg, per M,' intravenously (during 15 minutes) daily for 5 days, once every :1 weeks for :~ courses 2, Bleomycin, 30 units intravenously weekly for 12 weeks 3, Vinblastine, 0,2 mg, per kg, intravenously daily for 2 days every 3 weeks a, Vinblastine given 6 hours prior to bleomycin b, After 5 courses (12 weeks) of vinblastine, maintenance therapy consisted of vinblastine 0,3 mg, per kg, intravenously every 4 weeks and bacillus Calmette-Guerin by scarification 1, 2 and :3 weeks after each dosage of vinblastine c. Therapy to be continued for 2 years
patients but these were not clinical problems and did not require alteration of the bleomycin dosages, All patients had significant alopecia, There were no cases of clinically significant pulmonary fibrosis, Weight loss (from platinum and bleomycin) was seen in all patients during the 12 weeks of bleomycin and averaged 20 pounds, No patient required hospitalization for intravenous hyperalimentation, Vinblastine produced myalgia in half of the patients, Although this was occasionally severe enough to require narcotic analgesics during the first 12 weeks of therapy it was not a clinical problem during maintenance therapy with the lower dosage (0.3 mg, per kg,) of vinblastine. Anemia and thrombocytopenia were observed in several patients but no patient had thrombocytopenic bleeding or required platelet transfusions, Only 2 patients experienced thrombocytopenia between 50,000 and 100,000 and no patient had a platelet count less than 50,000, Anemia was more of a problem, especially in patients who had had prior radiotherapy. Leukopenia also was
68
EINHORN AND DONOHUE TABLE
Reference
Wyatt and McAninch" Mackenzie 6 Mendelson and Serpick" Jacobs 17 Kennedy" Samuels and Howe 7 Samuels and associates 19
5. Results with chemotherapy in disseminated testicular cancer Treatment
Total Pts.
Methotrexate Actinomycin D (alone or in double or triple therapy) Cyclophosphamide, vincristine, methotrexate and fluorouracil Vincristine, actinomycin D and cyclophosphamide Mithramycin Vinblastine Vinblastine and bleomycin
Complete Remissions No.(%)
10 154 17 58
23 21 23
Prolonged Survivors*
4 (40) 24 (16) 5 (29) 7 (12)
13 1 4
5 (22)
5
4 (19) 9 (39)
2
4
* Refers to patients remaining free of disease at time of publication.
more severe in these patients and they were started on a lowered dosage of vinblastine (0.15 mg. per kg. for 2 consecutive days). Packed red blood cell transfusions were required periodically on 4 patients during the first several months of therapy. The most serious side effect, which was seen in all patients, was severe leukopenia. The nadir of the white blood count usually was 1,000 between days 7 and 14. Seven patients required hospitalization for presumed sepsis with granulocytopenic fever and were cultured and started on antibiotic coverage with broad-spectrum antibiotics. Four of these patients had documented gram-negative sepsis with Escherichia coli and 1 of these patients died of sepsis (patient No. 12). Bacillus Calmette-Guerin immunotherapy caused mild local erythema, pruritus, fever and myalgia but was generally well tolerated by all patients except 1 who had severe local reactivity and an ulcerated regional lymph node requiring cessation of the bacillus Calmette-Guerin. Despite the aforementioned severe toxicity this occurred primarily during the 12 weeks of remission induction therapy. Maintenance therapy with vinblastine and bacillus Calmette-Guerin was well tolerated and all patients regained their hair growth and weight during this period. No patient required hospitalization for complications of therapy during vinblastine and bacillus Calmette-Guerin maintenance and they were all able to continue school or work full time. DISCUSSION
Since the original report by Li and associates, demonstrating activity of chemotherapy in disseminated testicular cancer,• there have been numerous clinical trials evaluating a variety of drugs in these diseases (table 5). 6 • 7 • 15- 19 Generally speaking, the only meaningful response for the patient has been complete remission, since partial remissions usually were of brief duration. Although it is not possible to extract present survival data on all patients reported in table 5 there does appear to be a general trend revealing that approximately 50 per cent of all complete remissions in disseminated testicular cancer have prolonged survival and potential cure. Indeed, in testicular cancer in general most relapses occur within a 2-year period from the date of operation or chemotherapy.2°· 21 Although we do not have long-term followup data on any of our patients treated with platinum, vinblastine and bleomycin it seems quite reasonable to expect that at least 50 per cent of our patients in complete remission will have cures and, hopefully, with the aggressive chemotherapy used in this regimen and the addition of bacillus Calmette-Guerin immunotherapy, considerably less than 50 per cent of our patients with complete remissions will eventually have a relapse. This present regimen has produced the highest complete remission rate reported thus far. Furthermore, we believe that chemotherapy can significantly alter the course of this disease in some patients, even when a complete response is not seen (patient Nos. 14 and 23). Present aggressive chemotherapy regimens appear to be capable of changing the histology to a
more benign form and transforming previously inoperable patients to potentially operable and hopefully curable patients. 1 • Although this report included only our first 20 patients treated with platinum, vinblastine and bleomycin who could be evaluated we have treated an additional 7 patients in the last 6 months and all have achieved complete remission. Thus, our complete remission rate on these 27 patients treated with platinum, vinblastine and bleomycin is 85 per cent (23 of 27 complete remissions) and, including our operation plus chemotherapy complete remission patients, the rate increased to 93 per cent (25 of 27). This is the highest complete remission rate with chemotherapy seen in any adult malignancy. In addition to the regimens described in table 5 we have reviewed all patients with disseminated testicular cancer treated at our hospital from 1965 to 1972. The majority of these patients were treated with actinomycin D regimens. There were 28 patients seen during this period, only 1 of whom achieved a complete remission, which lasted only 9 months. All 28 patients died of their disease within 2 years of initiation of chemotherapy and only 5 patients (18 per cent) survived 1 year. In contrast, of the 27 aforementioned patients only 9 have died (4 on adriamycin, bleomycin and vincristine, and 5 on platinum, vinblastine and bleomycin), with 12 of 20 patients (60 per cent) surviving for 12 months or longer (7 patients on platinum, vinblastine and bleomycin are free of disease but have been in the study for only 7 to 9 months). Only 1 of the 9 deaths occurred after a I-year survival. The results of recent regimens and this regimen clearly indicate that disseminated testicular cancer is a responsive disease to chemotherapy and many patients are probably curable, even with far-advanced disease. There is no longer any role for pessimism in this disease. However, this program is an aggressive, complicated and toxic therapeutic regimen that probably is administered best by personnel trained in medical oncology. Although this is a preliminary report we believe that the majority of these complete remissions will be prolonged survivals and potential cures. REFERENCES
1. MacKay, E. N. and Sellers, A. H.: A statistical review of malignant testicular tumours based on the experience of the Ontario Cancer Foundation Clinics, 1938 to 1961. Canad. Med. Ass. J., 94: 889, 1966. 2. Maier, J. G., Mittemeyer, B. T. and Sulak, M. H.: Treatment and prognosis in seminoma of the testis. J. Urol., 99: 72, 1968. 3. Friedman, M. and Purkayastha, M. C.: Recurrent seminoma: the management of late metastasis, recurrence, or a second primary tumor. Amer. J. Roentgen., 83: 25, 1960. 4. Li, M. C., Whitmore, W. F., Jr., Golbey, R. and Grabstald, H.: Effects of combined drug therapy on metastatic cancer of the testis. J .A.M.A., 17 4: 1291, 1960. 5. Ansfield, F. J., Korbitz, B. C., Davis, H. L., Jr. and Ramirez, G.: Triple drug therapy in testicular tumors. Cancer, 24: 442, 1969. 6. Mackenzie, A. R.: Chemotherapy of metastatic testis cancer: results in 154 patients. Cancer, 19: 1369, 1966. 7. Samuels, M. L. and Howe, C. D.: Vinblastine in the management of testicular cancer. Cancer, 25: 1009, 1970.
CHEJv~ O'T'HERAP"'i
8. Bh2rr1) R. H., Carter, S. K. and Agre, K,: A c;inical rev'ew of bleomycin-a new antir,eool11st1 agent. Cancer, 31: 903, 1973, R and Bonadonna, G,, 9, Monfardini, S,, Bajetta, Clinical use of adriamycin m advanced testicular cancer. J, UroL, 108: 29'.3, 1972, m Higby, D, J,, Wallace, ff J,, Jr., Albert, D, and Holland, '.J, F,: Diamminodichloroplatinum in the chemotherapy of testicular tumors, J, UroL, 112: 100, 1974, lL Burgess, IVL A,, Einhorn, L, R and Gottlieb, J, A,: Treatment of metastatic germ cell tumors with adriamycin, vincristine, and bleomycin, Proc, Amer. Soc, Clin, OncoL, 16: 244, 1975, 12, Livingston, R R, Bodey, G, P,, Gottlieb, J, A, and Frei, K, III: Kinetic scheduling of vincristine (NSC-67574) and bleomycm (NSC-125066) in patients with lung cancer and other malignant tumors, Cancer Chemother. Rep,, part 1, 57: 219, 1973, 13, Barranco, S, C, and Humphrey, RM,: The effects of bleomycin on survival and cell progression in Chinese hamster cells in vitro, Cancer Res,, 31: 1218, 197L 14, Merrin, C,, Takita, R, Weber, R, Wajsman, Z,, Baumgartner, G, and Murphy, G, P,: Combination radical surgery and mult1pl,e sequential chemotherapy for the treatment of advanced carcinoma of the testis (stage III), Cancer, 37: 20, 1976, 15, Wyatt, J, Kand McAninch, L, N,: A chemotherapeutic approach to advanced testicular carcinoma, Canad, J, Surg,, 10: 421, 1967, 16, Mendelson, D, and Serpick, A, A: Combination chemotherapy of testicular tumors, J, UroL, 103: 619, 1970, n Jacobs, K IvL: Combination chemotherapy of metastatic testicular germinal cell tumors and soft part sarcomas, Cancer, 25: 324, 1970, 18, Kennedy, R J,: Mithramycin therapy in advanced testicular neoplasms, Cancer, 26: 755, 1970, , 19, Samuels, M, L,, Johnson, D, K and Holoye, P, Y: Contmuous intravenous bleomycin (NSC-125066) therapy with vinblastine (NSC-49842) in stage III testicular neoplasia, Cancer Chemother, Rep,, 59: 563, 1975, 20, Nefzger, M, D, and Mostofi, F, K: Survival ,after, sur,gery for germinal malignancies of the testis, L Rates of survival m tumor groups, Cancer, 30: 1225, 1972, 2L LeFevre, R K, Levin, H, S,, Banowsky, L ff, Stewart, R R, Straffon, R A, and Hewitt, C, R: Testis tumors: review of 125 cases at the Cleveland Clinic, Urology, 6: 588, 1975,
TESTICULAR CANCE~
COMMENT This is an paper, response rate and, particularly, a complete response rate, responses are seen in patients who have had prim chemotherapy, which is obviously important, This paper is one of the first using immunotherapy in testicular cancer, It confirms the observation that we and others have made that bleomycin, vinblastine and cis-platinum are all active compounds, There have been many studies using various combinations of the same drugs, indicating the marked effectiveness of antineoplastic chemotherapy with response rates as high as 60 to 90 per cent, Therefore, it is no longer a question of whether a remission is possible, The questions now are: 1) How many complete remissions can we get? 2) Is the intensity of the induction phase too much, that is can we back off and perhaps combine the induction phase with immunotherapy? 3) What should be the intensity of the maintenance phase? 4) What should be the duration of the maintenance phase? Perhaps we are treating too long, 5) What is the place ofreductive surgery? We have an article in the May issue of The Journal of Urology concerning the place of second look or re-exploration surgery, 1 We believe that there is definitely a place for re-exploration with good response to improved chemotherapy, 6) With improvement in chemotherapy will the place of radiation therapy be diminished or even eliminated, except for seminomas? Another possibility that should be considered with the use of multiple drugs is that relating to the potential for an increase in second tumors, This was seen by de Vita in Hodgkin's disease, Perhaps there is a need to reduce the dosage of these carcinogenic agents, Perhaps and hopefully an old era is ending, Disseminated testicular cancer is now treatable and probably a curable disease, With response rates more than 75 per cent studies with 20 to 50 patients with median followups of less than 1 year will no longer be acceptable, Prospective randomized trials are now needed, Perhaps another national cooperative study should be undertaken to answer some of the questions,
Harry Grabstald and Alan Yagoda Memorial Hospital New York, New York L Comisarow, R H, and Grabstald, ff: Re-exploration for retroperitoneal lymph node metastases from testis tumors, J, UroL, 115: 569, 1976,