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Role of etoposide-based chemotherapy in the treatment of patients with refractory or relapsing germ cell tumors
Role of Etoposide-Based Chemotherapy in the Treatment of Patients with Refractory or Relapsing Germ Cell Tumors
GEORGE J. BOSL, M.D. ALAN YAGODA, M.D. ROBERT
B.
GOLBEY,
WILLET
WHITMORE,
HARRY
HERR,
M.D. Jr.,
PRAMOD
SOGANI,
M.D.
MICHAEL
MORSE,
M.D.
New
New
York,
NICHOLAS Chicago, G.
York
VOGELZANG,
M.D.
Illinois
MacDONALD,
Portsmouth,
M.D.
M.D.
M.D.
Virginia
From the Solid Tumor Service, Department of Medicine, and the Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, and the Department of Medicine, Cornell University Medical College, New York, New York; Hematoiogy-Cncoiogy, Department of Medicine, University of Chicago, Chicago, Illinois; and the Department of Urology, Naval Hospital, Portsmouth, Virginia. This work was supported in part by National Cancar instttute Grant CA-95929 and Contract NOlCM-07337. Dr. Vogeizang is an American Cancer Society Junior Faculty Fellow and Gould Foundation Scholar. Requests for reprints should be addressed to Dr. George J. Bosi, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. Manuscript accepted August 23, 1984.
Forty-nine patients with metastatfc germ cell tumors were treated with etoposide 100 mg/m* and cisplatin 20 mg/m* intravenously each day for five days as “salvage” chemotherapy. Forty-seven patients had received standard induction regimens for metastatic germ cell tumors before receiving etopostde and clsplatin. Four patients were treated after surgical resection of a single site of relapse (Group I). Forty-five patients had measurable or evaluable disease at the time of treatment. In 17 patients with evaluable disease who had either achieved a prior complete remfssion or received no prior cisplatin (Group II), eight (47 percent) complete and four (24 percent) partlal remissions were observed. In 28 patients who had never achieved a prior complete remission (Group Ill), no complete and five (18 percent) partial responses were observed. Seven of 21 patients in Groups I and II and none of 28 patients In Group III remain alive and free of disease. Assuming prior treatment with cisplatin-based chemotherapy, these data and a review of the published experience with sfmilar salvage regfmens for patients with relapsing or refractory germ cell tumors suggest that combination chemoWerapy based on etoposide and clsplatln fs effective primarily in those patients who achieved a prior complete remission. Such therapy is ineffective in the absence of a prior complete remission probably because the patients have tumors that are largefy resistant to cisplatin. Observed responses are probably due to etoposide alone. Investigational therapies should be pursued in those patients whose disease is refractory to current induction reglmens. During the past decade, dramatic improvement has occurred in the prognosis in patients with disseminated germ cell tumors. Nearly all patients demonstrate a response to therapy, and approximately 80 percent of patients today are expected to achieve complete remission. Once a complete remission has been achieved following chemotherapy alone or chemotherapy plus surgical excision of residual disease, relapses are rare and the majority of patients are cured [l-4]. However, these dramatic results obscure the poor prognosis in patients in whom a complete remission is not achieved or in whom relapse follows a complete remission. Etoposide (VP 16-213) is an active single agent in the treatment of patients with germ cell tumors after failure of standard therapy [5-71. In vivo synergism in animal models is known to exist between etoposide and cisplatin [8], and evidence supporting synergism between these two drugs in patients with small cell carcinoma of the lung has been reported [9]. In 1980, Williams et al [lo] reported a regimen including etoposide plus cisplatin with or without doxorubicin and
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ETOPOSIDE IN GERM CELL TUMORS-BOSL ET AL
TABLE I
Characteristics
of Patients
Treated
with Etoposide
Number of patients Sex Male Female Primary site Testis ovary Retroperitoneum Mediastinum Unknown Histology Seminoma Embryonal carcinoma f seminoma f yolk sac Teratoma f seminoma f embryonal carcinoma f yolk sac Choriocarcinoma f others “Poorly differentiated carcinoma” Sites of metastasis Lung Pleura Medtastinum Retroperitoneum Supraclavicular lymph nodes Liver Brain Other Number of sites None One Two More than two Markers (number elevated/number tested) Alpha-fetoprotein Human chorionic gonadotropin Lactate dehydrogenase Prior treatment Previously untreated Previously treated VAB VBP MOPP Radiation therapy Other Prior cycles of cisplatin None Two to three Four to six Beven or more
plus Cisplatin Grow I
Grout II
Grow III
4
17
28
4 0
17 0
27 1
14 0 3 0 0
22 1 1 3 1 3 8 10 6 1
-
10 0 1 11 3 0 1 0
-
0 0 0 0
20 2 3 15 7 5 1 3 0 8 12 8
9117 (53%) 6/17 (35%) 9116 (56%)
8126 (31%) 18127 (74%) 23126 (88 % )
1
0
13 3 0 1 5
17 11 1 1 4
2 11 4 0
0 13 13 2
VAB = cyclophosphamide, actlnomycin D, bleomycin + vinblastine, and cisplatin; VBP = vinblastine, bleomycin, and cisplatin; MOPP = nitrogen mustard, vincristine, prednisone, and procarbazine.
bleomycin in the treatment of patients with refractory germ cell tumors. A 47 percent complete remission rate was observed in 30 previously treated patients. The benefit of doxorubicin or bleomycin added to the combination of etoposide and cisplatln is arguable, given the invariable prior therapy with bleomycin and prior randomized and nonrandomized studies indicating no added efficacy for doxorubicin [ 2,11,12]. These observations led us to examine etoposide plus cisplatin in patients 424
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with refractory or relapsing germ cell tumors. Results of therapy with etoposide plus cisplatin in our first 23 patients were recently reported [ 131. Herein we review our expanded experience with etoposide plus cisplatin as “salvage” therapy for patients with refractory and relapsing germ cell tumors, review the published experience of others, and offer recommendations for the use of etoposide plus cisplatin-based therapy in the treatment of this group of patients.
ETOPOSIDE
TABLE ii
Response
and Current
Status of Patients
Treated
Group I Response Complete response Partial response No response or progression Total Current Status No evidence of disease Alive with disease Dead of disease Total
PATIENTS
with Etoposide
TUMORS-BOSL
5 17
10
4
17
Total
0
8
5 23 28
28 45
9
0
4 3
1 0
ET AL
plus Cispiatin
8 4
3
Between February 1981 and March 1984, 49 patients with germ cell tumors were treated with etoposide plus highdose cisplatin-based chemotherapy. Forty-seven patients had received prior chemotherapy including hi doses of cisplatin (100 mg/m2 or more), one received multiple agents but no cispiatin, and one was previously untreated. All patients had pathologic documentation of disease. Prior to therapy, evaluation included a complete blood cell count, determination of creatinine clearance to assure a value greater than 50 ml per minute, SMA-12 analysis, measurement of all sites of disease by physical examination, radiographic studies, or both, and assays for lactate dehydrogenase, alpha-fetoprotein, and human chorionic gonadotropin. Serum levels of alpha-fetoprotein and human chorionic gonadotropin were measured by standard radioimmunoassay techniques as previously described [ 141. These patients were dlltded into three groups. Patients in Group I had relapse after a prior complete remission with a solitary site of disease (three pulmonary and one inguinai) and had undergone complete resection of these solitary sites of disease. These patients were then treated wtth etoposide plus cisplatin following the surgical procedure. Patients in Group II either had received no prior chemotherapy (one patient), had relapse after complete remission with one or more sites of disease, or had undergone incomplete resection of mature teratoma; all were treated with etoposide plus cispiatin prior to any surgical procedure. Patients in Group Ill had never achieved a complete remission, although most patients had had a partial remission before etoposide plus cisplatin was begun. No patient in Group Ill had evidence of stable disease at the time of treatment with etoposide plus cisplatin; all had progressive disease or rising serum values of either alphafetoprotein or human chorionic gonadotropin or both. All patients in Groups Ii and Ill had measurable sites of disease except for two patients in Group II who were treated only for a rising value of alpha-fetoprotein. The disease and prior treatment characteristics are summarized in Table I. Patients were treated with etoposide 100 mg/m2 intravenously daily for five days and cisplatin 20 mg/m2 daily intravenously for five days, repeated at four-week intervals. In one patient in Group I, cisplatin was inadvertently administered as 100 mg/m2 in a single dose. All 49 patients had an adequate trial; no patient was excluded from evaluation. If the
CELL
PatientsEvaluable for Response Group Ill Group II
-
AND METHODS
IN GERM
7 6 36
2 26 28
49
treating physician believed the patient to have a very high risk of severe myelosuppression, then the first course of therapy could consist of etoposide 100 mg/n? intravenously on Days 1,3, and 5. This option was exercised in only three patients, and in one of those three patients, five days of therapy were given during the second cycle. Responses were classified as either complete remission, partiil response, or no response. A complete remission was defined as the complete disappearance of all clinical, radiographic, and biochemical evidence of disease for at least four weeks. A partial remission was defined as a 50 percent decrease in the sum of the products of the longest diameter and its perpendicular for all measurable sites, lasting for at least four weeks wtthout the development of new lesions. All other patients were classified as having had no response. The duration of response and survival were measured from the date of initiation of treatment. RESULTS
Group I. All four patients in this group were treated with etoposide plus cisplatin following surgical excision of all residual disease. Three patients had relapse with solitary pulmonary nodules, and one with inguinai adenopathy. One of these patients had relapse at 15 months. The other three patients are alive at more than 24, 28, and 38 months. Group II. In this group of 17 patients, eight complete and four partial responses were observed for a total major response (complete and partial remissions) rate of 7 1 percent (Table II). Four patients had relapse after complete remission at six, seven, 10, and 12 months. Three of these patients have died from disease. Four patients remain free of disease at more than three, eight, 14, and 34 months. Nine patients in this group had achieved unequivocal prior complete
remission,
but the remaining
eight de-
serve special comment. One patient had achieved a “complete remission” of only three weeks’ duration prior to the initiation of etoposide plus cisplatin. He achieved a complete remission of six months’ duration. The second patient had undergone exploratory iaparotomy for excision of a pelvic mass detected on March 1955
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TABLE III
ET AL
Renal and Bone Marrow Etoposide and Clsplatin
White blood cell nadir (X 103/mm3) Platelet nadir (X 103/mm3) Hemoglobin nadir (gldl) Creatinine peak (mg/dl)
Toxlclty
after
Median
Range
1.5 103.5 a.75 1.4
0.0-7.1 6-310 6.3-12.4 1.0-5.4
patient, who was the only patient with pure seminoma in Group II and had achieved a complete clinical remission of a large palpable abdominal mass on both physical examination and computed tomographic scanning, small residual nodules were found on the left subdiaphragmatic surface. His response was classified as partial. In the fourth patient, residual viable disease was totally resected. No other patient had disease sufficiently localized after chemotherapy to warrant a surgical procedure. Group Ill. No complete remissions and five partial remissions were observed in the 28 patients with failure to achieve a prior complete remission. All remissions were of very short duration; none exceeded four months. This extremely poor prognosis should be expected in patients whose disease is primarily resistant to conventional cisplatin-based induction therapy. Two patients with immature teratoma that was progressing and two patients with malignant differentiation within a teratoma [ 151 were treated, and none achieved a remission. Only three patients had disease sufficiently well localized after chemotherapy to warrant surgical intervention. In one patient, in whom primary progression of disease occurred during VAB6 therapy and in whom a partial response to etoposide plus cisplatin was observed, an unresectable retroperitoneal mass was found. In the second patient, unresectable retroperitoneal disease was encountered; biopsy revealed malignant differentiation within a teratoma. In one patient, a retroperitoneal mass regressed, but a supraclavicular lymph node persisted; biopsy revealed a malignant differentiation within a teratoma. Comparison of Groups II and III. The disease and marker status of patient in Groups II and Ill appeared to differ (Table I). All three patients with mediastinal primary tumors were in Group Ill. The percent of patients with elevated serum values of lactate dehydrogenase and human chorionic gonadotropin was greater in Group Ill than in Group II (88 and 74 percent versus 56 and 35 percent, respectively). Forty-seven percent of Group II patients had two or more sites of metastases, as compared with 71 percent of Group Ill patients. All patients with liver metastases were in Group Ill. Lastly, only four of 17 patients in Group II had received more than three prior cycles of high doses of cisplatin, as compared with 15 of 28 in patients in Group Ill. Survival. The current disease status of all 49 patients is summarized in Table II. As can be seen, seven of 21 patients in Groups I and II remain alive and free of disease. Only two patients in Group Ill have survived more than one year from the start of therapy. Toxicity. The toxicity of this regimen was predictable. Nausea and vomiting were mild, and most patients were discharged the day after the last dose of cisplatin.
computed tomography; however, no mass was found despite a slightly elevated value of alpha-fetoprotein. This patient received three cycles of VA56 [3] and was followed without evidence of disease for 12 months when brain and lung metastases were noted. The pelvic mass had not changed in size on computed tomographic scanning, and the alpha-fetoprotein value had not changed in one year, but the serum values of lactate dehydrogenase and human chorionic gonadotropin became markedly abnormal. This patient had a partial remission lasting three months. The third patient had a primary retroperitoneal choriocarcinoma with markedly elevated values of lactate dehydrogenase and human chorionic gonadotropin and pulmonary metastases and was treated with etoposide plus cisplatin as first therapy. A partial remission of four months’ duration was observed. Two patients had undergone one or more exploratory laparotomies after chemotherapy (one of these had received prior chemotherapy with cisplatin) with incomplete excision of all mature teratoma. Both had relapse with rising values of alpha-fetoprotein and increasing retroperitoneal lymphadenopathy 10 months and 15 years after initial diagnosis. The patient previously treated with cisplatin had no response, the patient not previously treated with cisplatin was lost to follow-up after the first cycle of therapy and is assumed to have no response. In the seventh patient, a mass ruptured during retroperitoneal lymph node dissection. Although the serum value of alpha-fetoprotein returned to normal, it was assumed that the patient had disseminated intra-abdominal disease and he received three cycles of VA56. A relapse occurred three months later, with disease in the left renal hilum and a rising value of alpha-fetoprotein. No response to salvage chemotherapy was noted. In the eighth patient, pulmonary and supraclavicular lymph node metastases completely resolved and serum marker values normalized after cisplatin, vinblastine, and bleomycin (PVB) [2], but a small retroperitoneal mass persisted. The patient was referred at the time of relapse eight months later, and has achieved a complete clinical remission. Five surgical procedures have been performed in four patients for resection of apparent residual disease. In two patients, no viable disease was found. In the third
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ET AL
However, this should not be taken in a completely negative sense. The fact that a patient with relapse after complete remission can be rendered free of disease and possibly cured is very important and unique outside the hematologic malignancies. Two incidental observations can be made from this review. Four patients were considered to have achieved a complete remission but had persistent retroperitoneal disease, either unresected and incompletely resected mature teratoma. All were referred after relapse. This underscores the need for excision of all apparent residual disease. Four patients were found to have malignant differentiation within a teratoma, defined as malignant change within mature or immature teratoma elements (e.g., epidermoid carcinoma, sarcoma). This unusual entity may become a more common finding at relapse and should be considered a cause of resistant disease. It should be emphasized that the patients treated at Memorial Hospital with etoposide plus cisplatin had an extremely poor prognosis. A multivariate analysis of prognostic variables in previously untreated patients revealed that the serum values of lactate dehydrogenase and human chorionic gonadotropin and the total number of sites of metastases were the most important predictive variables [ 141. The patients in Group III had values for lactate dehydrogenase and human chorionic gonadotropin that were generally greater than those of patients in Group II, and the median number of sites of metastasis in Group Ill patients was greater as well. Since Group Ill patients had already exhibited resistance to a cisplatin-based chemotherapy regimen, it is not surprising that responses are unusual with a subsequent cisplatin-based regimen. Certainly, the five partial responses experienced in Group Ill patients could be due solely to etoposide. This experience in germ cell tumors parallels that of “salvage” chemotherapy for patients with Hodgkin’s disease. Bonadonna and Santoro [20] have reviewed the experience of several institutions using doxorubicin plus vinblastine plus bleomycin plus dacarbazine in the treatment of patients with Hodgkin’s disease after failure of therapy with nitrogen mustard plus vincristine plus procarbazine plus prednisone. The complete response rate varied from 4 to 59 percent, and the number of extranodal sites of disease and the disease-free interval seemed to correlate with the likelihood of achieving a complete response to the salvage regimen. From our experience and the experience of others, the following recommendations can be made. (1) Patients who achieve a complete remission with failure at a single site should undergo surgical excision of the mass. In these patients, growth may be due solely to a mature teratoma [21], and chemotherapy would prove
Myelosuppression was frequent (Table Ill). Two patients died during periods of granulocytopenia and fever. Both were patients from Group Ill with recent failure of intensive induction chemotherapy. Neither showed response at the time of death. Renal insufficiency was generally very mild, despite heavy prior exposure to cisplatin. COMMENTS
Etoposide plus cisplatin, with or without other drugs, is recognized as effective therapy for some patients with recurrent or refractory germ cell tumors. Since the report of Williams et al, in which a 47 percent complete remission rate was observed, reports of activity have varied considerably. Whereas the series from the University of Minnesota [ 161 reported that five of seven patients achieved major responses, the Cleveland Clinic [ 171 reported only four durable complete responses in 11 patients, and the Sidney Farber Cancer Institute [ 181 noted only three complete responses in 15 patients. The extent of disease and prior remission status were not clarified in these reports. The data presented in this series suggest that these patients should be divided into at least two major groups, assuming that they have been previously treated with high-dose cisplatin-based regimens: (1) patients who have achieved a previous complete remission; and (2) patients who have failed to achieve a prior complete remission. The overall response rates were 7 1 and 18 percent, respectively, and all complete remissions were in the first group. Etoposide plus cisplatin should be expected to be cross-resistant with standard chemotherapy regimens since it is cisplatin-based. A review of the reports by Williams and co-workers seems to support this hypothesis. Of the 30 patients described in 1980 [lo], five patients had received no prior cisplatin and at least five patients had achieved a prior complete remission. This experience was recently updated [ 191, a low complete response rate was observed in patients who either had failed to achieve a complete remission or had had complete remissions of less than two months’ duration. It is well known that patients who achieve only a partial remission after chemotherapy and attempted surgical excision of any residual disease nearly always die. Thus, the complete response rate is the only meaningful response in relation to long-term survival and should be the most important criterion upon which the activity of a regimen in the treatment of patients with germ cell tumors is judged. The durable complete response rate was low in most of the reported series. Etoposide plus cisplatin may, therefore, not be as effective as “salvage” therapy as was originally thought.
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ETOPOSIDE
IN GERM
CELL TUMORS-BOSL
ET AL
to be ineffective. If the lesion is malignant, etoposide plus cisplatin should be given in an adjuvant fashion. (2) Patients with relapse after a complete remission, with one or more sites of disease and elevated marker values should receive etoposide plus cisplatin. (3) Patients without complete response to standard chemotherapy regimens, but who still have disease localized to a single site, should receive etoposide plus cisplatin until further experience can be gathered in this subgroup.
Subsequent surgical excision may be feasible in the occasional patient. (4) In patients with multiple sites of disease, rising marker values, and apparently refractory disease as evidenced by an incomplete response to standard chemotherapy, innovative therapy needs to be tested. Etoposide plus cisplatin seems to be ineffective in this group of patients. Trials of new drugs (phase II trials) or other investigational therapies seem indicated in this group of patients.
REFERENCES
5.
6.
7.
8.
9.
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Bosl 61, Lange PH. Fraley EE, et al: Vinblastine, bleomycin, and cisdiamminedichloroplatinum in the treatment of advanced testicular carcinoma. Possible importance of longer induction and shorter maintenance schedules. Am J Med 1982; 68: 492-496. Einhorn LH: Testicular cancer as a model for a curable neoplasm. Cancer Res 1981; 41: 32753280. Vugrin D, Herr HH, Whitmore WF Jr, Sogani PC, Golbey RB: VAB-6 combination chemotherapy in disseminated cancer of the testis. Ann Intern Med 1981; 95: 59-81. Scher H, Bosl G, Geller N. Cirrincione C, Whitmore WF Jr, Golbey R: Long term follow up of patients with testicular germ cell tumors achieving complete remission after chemotherapy alone or chemotherapy plus surgery (abstr 621). Proc Am Assoc Cancer Res 1983; 24: 157. Vogelzang NJ, Raghaven D, Kennedy BJ: VP-16-213 (etop oslde): the mandrake root from Issyk-Kul. Am J Med 1982; 72: 136-144. Cavalli F, Klept 0, Revard J, Hansen HH, Albert0 P: A phase II study of oral VP-16213 in patients with nonseminomatous testicular cancer (abstr 547). Proc Am Assoc Cancer Res Am Sot Clin Oncol 1980; 21: 137. Fitzharrls EM, Kaye SB, Saverymuttu S, et al: VP-16213 as a single agent in advanced testicular tumors. Eur J Cancer 1980; 16: 1193-1197. Schabel M Jr, Trader MW, Laster WR, Corbett TH, Griswald DP: Cisdichlorodlammineplatinum (II): combination chemotherapy and cross resistance studies with tumors of mice. Cancer Treat Rep 1979; 63: 1459-1473. Sierocki JS, Hilaris BS, Hopfan S, et al: Cisdichlorodiammineplatinum (II) and VP-16-213: an active induction regimen for small cell carcinoma of the lung. Cancer Treat Rep 1979; 83: 1593-1597. Williams SD, Einhorn LH, Greco FA, Oldham R, Fletcher RF: VP-16213 salvage chemotherapy for refractory germinal neoplasms. Cancer 1980; 48: 2154-2158.
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1985
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Einhom LH, Williams SD: Combination chemotherapy with cisdichlorodiammineplatinum (II) and Adriamycin for testicular cancer refractory to vinblastine plus bleomycin. Cancer Treat Rep 1978; 82: 1351-1353. Vugrin D, Cvltkovic E. Whitrnore WF, Cheng E, Golbey RB: VAB-4 combination chemotherapy in the treatment of metastatic testis tumors. Cancer 1981; 47: 833-839. Bosl 61, Yagoda A, Whitmore WF Jr, et al: VP-16213 and cisplatin in the treatment of patients with refractory germ cell tumors. Am J Clin Dncol 1984; 7: 327-330. Bosl 61, Geller NL, Cirrincione C, et al: A multivariate analysis of prognostic variables in patients with m&static testicular cancer. Cancer Res 1983; 43: 3403-3407. Ahmed T, Bosl 61, Hajdu SI, et al: Malignant teratoma of the testis (abstr). Proc Am Sot Clin Oncol 1982; 1: 114. Vogelzang NJ, Kennedy BJ: Salvage chemotherapy for refractory germ cell tumors (abstr C-540). Proc Am Assoc Cancer Res Am Sot Clin Oncoll981; 22: 471. Mortimer J, Bukowski RM, Montie J, Hewlett JS, Livingston RB: VP-16-213. cisplatinum, and Adriamycin salvage therapy of refractory and/or recurrent nonseminomatous Pharmacoll982; gsrm cell neoplasms. Cancer chemother 61: 99-108. Lederman GS, Gamick MB, Richii JP, Canellos Gp: VP-16213 cis-platinum as secondary therapy in patients with refractory testicular and extragonadal germ cell cancer (abstr 576). hoc Am Assoc Cancer Res 1983; 24: 146. Williams SD, Turner S, Loehrer PJ, Einhorn LH: Testicular cancer: results of m-induction therapy (abstr C-536). F’roc Am Sot Clin Oncol 1983; 2: 137. Bonadonna G, Santoro A: ABVD chemotherapy in the treatment of Hodgkin’s disease. Cancer Treat Rev 1982; 9: 21-35. Logothetls CJ, Samuels ML, Trinidade A, Johnson DE: The growing teratoma syndrome. Cancer 1982; 50: 16291635.
GEORGE J. BOSL, M.D. ALAN YAGODA, M.D. ROBERT
B.
GOLBEY,
WILLET
WHITMORE,
HARRY
HERR,
M.D. Jr.,
PRAMOD
SOGANI,
M.D.
MICHAEL
MORSE,
M.D.
New
New
York,
NICHOLAS Chicago, G.
York
VOGELZANG,
M.D.
Illinois
MacDONALD,
Portsmouth,
M.D.
M.D.
M.D.
Virginia
From the Solid Tumor Service, Department of Medicine, and the Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, and the Department of Medicine, Cornell University Medical College, New York, New York; Hematoiogy-Cncoiogy, Department of Medicine, University of Chicago, Chicago, Illinois; and the Department of Urology, Naval Hospital, Portsmouth, Virginia. This work was supported in part by National Cancar instttute Grant CA-95929 and Contract NOlCM-07337. Dr. Vogeizang is an American Cancer Society Junior Faculty Fellow and Gould Foundation Scholar. Requests for reprints should be addressed to Dr. George J. Bosi, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. Manuscript accepted August 23, 1984.
Forty-nine patients with metastatfc germ cell tumors were treated with etoposide 100 mg/m* and cisplatin 20 mg/m* intravenously each day for five days as “salvage” chemotherapy. Forty-seven patients had received standard induction regimens for metastatic germ cell tumors before receiving etopostde and clsplatin. Four patients were treated after surgical resection of a single site of relapse (Group I). Forty-five patients had measurable or evaluable disease at the time of treatment. In 17 patients with evaluable disease who had either achieved a prior complete remfssion or received no prior cisplatin (Group II), eight (47 percent) complete and four (24 percent) partlal remissions were observed. In 28 patients who had never achieved a prior complete remission (Group Ill), no complete and five (18 percent) partial responses were observed. Seven of 21 patients in Groups I and II and none of 28 patients In Group III remain alive and free of disease. Assuming prior treatment with cisplatin-based chemotherapy, these data and a review of the published experience with sfmilar salvage regfmens for patients with relapsing or refractory germ cell tumors suggest that combination chemoWerapy based on etoposide and clsplatln fs effective primarily in those patients who achieved a prior complete remission. Such therapy is ineffective in the absence of a prior complete remission probably because the patients have tumors that are largefy resistant to cisplatin. Observed responses are probably due to etoposide alone. Investigational therapies should be pursued in those patients whose disease is refractory to current induction reglmens. During the past decade, dramatic improvement has occurred in the prognosis in patients with disseminated germ cell tumors. Nearly all patients demonstrate a response to therapy, and approximately 80 percent of patients today are expected to achieve complete remission. Once a complete remission has been achieved following chemotherapy alone or chemotherapy plus surgical excision of residual disease, relapses are rare and the majority of patients are cured [l-4]. However, these dramatic results obscure the poor prognosis in patients in whom a complete remission is not achieved or in whom relapse follows a complete remission. Etoposide (VP 16-213) is an active single agent in the treatment of patients with germ cell tumors after failure of standard therapy [5-71. In vivo synergism in animal models is known to exist between etoposide and cisplatin [8], and evidence supporting synergism between these two drugs in patients with small cell carcinoma of the lung has been reported [9]. In 1980, Williams et al [lo] reported a regimen including etoposide plus cisplatin with or without doxorubicin and
March
1985
The American
Journal
of Medicine
Volume
78
423
ETOPOSIDE IN GERM CELL TUMORS-BOSL ET AL
TABLE I
Characteristics
of Patients
Treated
with Etoposide
Number of patients Sex Male Female Primary site Testis ovary Retroperitoneum Mediastinum Unknown Histology Seminoma Embryonal carcinoma f seminoma f yolk sac Teratoma f seminoma f embryonal carcinoma f yolk sac Choriocarcinoma f others “Poorly differentiated carcinoma” Sites of metastasis Lung Pleura Medtastinum Retroperitoneum Supraclavicular lymph nodes Liver Brain Other Number of sites None One Two More than two Markers (number elevated/number tested) Alpha-fetoprotein Human chorionic gonadotropin Lactate dehydrogenase Prior treatment Previously untreated Previously treated VAB VBP MOPP Radiation therapy Other Prior cycles of cisplatin None Two to three Four to six Beven or more
plus Cisplatin Grow I
Grout II
Grow III
4
17
28
4 0
17 0
27 1
14 0 3 0 0
22 1 1 3 1 3 8 10 6 1
-
10 0 1 11 3 0 1 0
-
0 0 0 0
20 2 3 15 7 5 1 3 0 8 12 8
9117 (53%) 6/17 (35%) 9116 (56%)
8126 (31%) 18127 (74%) 23126 (88 % )
1
0
13 3 0 1 5
17 11 1 1 4
2 11 4 0
0 13 13 2
VAB = cyclophosphamide, actlnomycin D, bleomycin + vinblastine, and cisplatin; VBP = vinblastine, bleomycin, and cisplatin; MOPP = nitrogen mustard, vincristine, prednisone, and procarbazine.
bleomycin in the treatment of patients with refractory germ cell tumors. A 47 percent complete remission rate was observed in 30 previously treated patients. The benefit of doxorubicin or bleomycin added to the combination of etoposide and cisplatln is arguable, given the invariable prior therapy with bleomycin and prior randomized and nonrandomized studies indicating no added efficacy for doxorubicin [ 2,11,12]. These observations led us to examine etoposide plus cisplatin in patients 424
March lS85
The Amerfcan Journal of Medlcins
Volume 78
with refractory or relapsing germ cell tumors. Results of therapy with etoposide plus cisplatin in our first 23 patients were recently reported [ 131. Herein we review our expanded experience with etoposide plus cisplatin as “salvage” therapy for patients with refractory and relapsing germ cell tumors, review the published experience of others, and offer recommendations for the use of etoposide plus cisplatin-based therapy in the treatment of this group of patients.
ETOPOSIDE
TABLE ii
Response
and Current
Status of Patients
Treated
Group I Response Complete response Partial response No response or progression Total Current Status No evidence of disease Alive with disease Dead of disease Total
PATIENTS
with Etoposide
TUMORS-BOSL
5 17
10
4
17
Total
0
8
5 23 28
28 45
9
0
4 3
1 0
ET AL
plus Cispiatin
8 4
3
Between February 1981 and March 1984, 49 patients with germ cell tumors were treated with etoposide plus highdose cisplatin-based chemotherapy. Forty-seven patients had received prior chemotherapy including hi doses of cisplatin (100 mg/m2 or more), one received multiple agents but no cispiatin, and one was previously untreated. All patients had pathologic documentation of disease. Prior to therapy, evaluation included a complete blood cell count, determination of creatinine clearance to assure a value greater than 50 ml per minute, SMA-12 analysis, measurement of all sites of disease by physical examination, radiographic studies, or both, and assays for lactate dehydrogenase, alpha-fetoprotein, and human chorionic gonadotropin. Serum levels of alpha-fetoprotein and human chorionic gonadotropin were measured by standard radioimmunoassay techniques as previously described [ 141. These patients were dlltded into three groups. Patients in Group I had relapse after a prior complete remission with a solitary site of disease (three pulmonary and one inguinai) and had undergone complete resection of these solitary sites of disease. These patients were then treated wtth etoposide plus cisplatin following the surgical procedure. Patients in Group II either had received no prior chemotherapy (one patient), had relapse after complete remission with one or more sites of disease, or had undergone incomplete resection of mature teratoma; all were treated with etoposide plus cispiatin prior to any surgical procedure. Patients in Group Ill had never achieved a complete remission, although most patients had had a partial remission before etoposide plus cisplatin was begun. No patient in Group Ill had evidence of stable disease at the time of treatment with etoposide plus cisplatin; all had progressive disease or rising serum values of either alphafetoprotein or human chorionic gonadotropin or both. All patients in Groups Ii and Ill had measurable sites of disease except for two patients in Group II who were treated only for a rising value of alpha-fetoprotein. The disease and prior treatment characteristics are summarized in Table I. Patients were treated with etoposide 100 mg/m2 intravenously daily for five days and cisplatin 20 mg/m2 daily intravenously for five days, repeated at four-week intervals. In one patient in Group I, cisplatin was inadvertently administered as 100 mg/m2 in a single dose. All 49 patients had an adequate trial; no patient was excluded from evaluation. If the
CELL
PatientsEvaluable for Response Group Ill Group II
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2 26 28
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treating physician believed the patient to have a very high risk of severe myelosuppression, then the first course of therapy could consist of etoposide 100 mg/n? intravenously on Days 1,3, and 5. This option was exercised in only three patients, and in one of those three patients, five days of therapy were given during the second cycle. Responses were classified as either complete remission, partiil response, or no response. A complete remission was defined as the complete disappearance of all clinical, radiographic, and biochemical evidence of disease for at least four weeks. A partial remission was defined as a 50 percent decrease in the sum of the products of the longest diameter and its perpendicular for all measurable sites, lasting for at least four weeks wtthout the development of new lesions. All other patients were classified as having had no response. The duration of response and survival were measured from the date of initiation of treatment. RESULTS
Group I. All four patients in this group were treated with etoposide plus cisplatin following surgical excision of all residual disease. Three patients had relapse with solitary pulmonary nodules, and one with inguinai adenopathy. One of these patients had relapse at 15 months. The other three patients are alive at more than 24, 28, and 38 months. Group II. In this group of 17 patients, eight complete and four partial responses were observed for a total major response (complete and partial remissions) rate of 7 1 percent (Table II). Four patients had relapse after complete remission at six, seven, 10, and 12 months. Three of these patients have died from disease. Four patients remain free of disease at more than three, eight, 14, and 34 months. Nine patients in this group had achieved unequivocal prior complete
remission,
but the remaining
eight de-
serve special comment. One patient had achieved a “complete remission” of only three weeks’ duration prior to the initiation of etoposide plus cisplatin. He achieved a complete remission of six months’ duration. The second patient had undergone exploratory iaparotomy for excision of a pelvic mass detected on March 1955
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Renal and Bone Marrow Etoposide and Clsplatin
White blood cell nadir (X 103/mm3) Platelet nadir (X 103/mm3) Hemoglobin nadir (gldl) Creatinine peak (mg/dl)
Toxlclty
after
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1.5 103.5 a.75 1.4
0.0-7.1 6-310 6.3-12.4 1.0-5.4
patient, who was the only patient with pure seminoma in Group II and had achieved a complete clinical remission of a large palpable abdominal mass on both physical examination and computed tomographic scanning, small residual nodules were found on the left subdiaphragmatic surface. His response was classified as partial. In the fourth patient, residual viable disease was totally resected. No other patient had disease sufficiently localized after chemotherapy to warrant a surgical procedure. Group Ill. No complete remissions and five partial remissions were observed in the 28 patients with failure to achieve a prior complete remission. All remissions were of very short duration; none exceeded four months. This extremely poor prognosis should be expected in patients whose disease is primarily resistant to conventional cisplatin-based induction therapy. Two patients with immature teratoma that was progressing and two patients with malignant differentiation within a teratoma [ 151 were treated, and none achieved a remission. Only three patients had disease sufficiently well localized after chemotherapy to warrant surgical intervention. In one patient, in whom primary progression of disease occurred during VAB6 therapy and in whom a partial response to etoposide plus cisplatin was observed, an unresectable retroperitoneal mass was found. In the second patient, unresectable retroperitoneal disease was encountered; biopsy revealed malignant differentiation within a teratoma. In one patient, a retroperitoneal mass regressed, but a supraclavicular lymph node persisted; biopsy revealed a malignant differentiation within a teratoma. Comparison of Groups II and III. The disease and marker status of patient in Groups II and Ill appeared to differ (Table I). All three patients with mediastinal primary tumors were in Group Ill. The percent of patients with elevated serum values of lactate dehydrogenase and human chorionic gonadotropin was greater in Group Ill than in Group II (88 and 74 percent versus 56 and 35 percent, respectively). Forty-seven percent of Group II patients had two or more sites of metastases, as compared with 71 percent of Group Ill patients. All patients with liver metastases were in Group Ill. Lastly, only four of 17 patients in Group II had received more than three prior cycles of high doses of cisplatin, as compared with 15 of 28 in patients in Group Ill. Survival. The current disease status of all 49 patients is summarized in Table II. As can be seen, seven of 21 patients in Groups I and II remain alive and free of disease. Only two patients in Group Ill have survived more than one year from the start of therapy. Toxicity. The toxicity of this regimen was predictable. Nausea and vomiting were mild, and most patients were discharged the day after the last dose of cisplatin.
computed tomography; however, no mass was found despite a slightly elevated value of alpha-fetoprotein. This patient received three cycles of VA56 [3] and was followed without evidence of disease for 12 months when brain and lung metastases were noted. The pelvic mass had not changed in size on computed tomographic scanning, and the alpha-fetoprotein value had not changed in one year, but the serum values of lactate dehydrogenase and human chorionic gonadotropin became markedly abnormal. This patient had a partial remission lasting three months. The third patient had a primary retroperitoneal choriocarcinoma with markedly elevated values of lactate dehydrogenase and human chorionic gonadotropin and pulmonary metastases and was treated with etoposide plus cisplatin as first therapy. A partial remission of four months’ duration was observed. Two patients had undergone one or more exploratory laparotomies after chemotherapy (one of these had received prior chemotherapy with cisplatin) with incomplete excision of all mature teratoma. Both had relapse with rising values of alpha-fetoprotein and increasing retroperitoneal lymphadenopathy 10 months and 15 years after initial diagnosis. The patient previously treated with cisplatin had no response, the patient not previously treated with cisplatin was lost to follow-up after the first cycle of therapy and is assumed to have no response. In the seventh patient, a mass ruptured during retroperitoneal lymph node dissection. Although the serum value of alpha-fetoprotein returned to normal, it was assumed that the patient had disseminated intra-abdominal disease and he received three cycles of VA56. A relapse occurred three months later, with disease in the left renal hilum and a rising value of alpha-fetoprotein. No response to salvage chemotherapy was noted. In the eighth patient, pulmonary and supraclavicular lymph node metastases completely resolved and serum marker values normalized after cisplatin, vinblastine, and bleomycin (PVB) [2], but a small retroperitoneal mass persisted. The patient was referred at the time of relapse eight months later, and has achieved a complete clinical remission. Five surgical procedures have been performed in four patients for resection of apparent residual disease. In two patients, no viable disease was found. In the third
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However, this should not be taken in a completely negative sense. The fact that a patient with relapse after complete remission can be rendered free of disease and possibly cured is very important and unique outside the hematologic malignancies. Two incidental observations can be made from this review. Four patients were considered to have achieved a complete remission but had persistent retroperitoneal disease, either unresected and incompletely resected mature teratoma. All were referred after relapse. This underscores the need for excision of all apparent residual disease. Four patients were found to have malignant differentiation within a teratoma, defined as malignant change within mature or immature teratoma elements (e.g., epidermoid carcinoma, sarcoma). This unusual entity may become a more common finding at relapse and should be considered a cause of resistant disease. It should be emphasized that the patients treated at Memorial Hospital with etoposide plus cisplatin had an extremely poor prognosis. A multivariate analysis of prognostic variables in previously untreated patients revealed that the serum values of lactate dehydrogenase and human chorionic gonadotropin and the total number of sites of metastases were the most important predictive variables [ 141. The patients in Group III had values for lactate dehydrogenase and human chorionic gonadotropin that were generally greater than those of patients in Group II, and the median number of sites of metastasis in Group Ill patients was greater as well. Since Group Ill patients had already exhibited resistance to a cisplatin-based chemotherapy regimen, it is not surprising that responses are unusual with a subsequent cisplatin-based regimen. Certainly, the five partial responses experienced in Group Ill patients could be due solely to etoposide. This experience in germ cell tumors parallels that of “salvage” chemotherapy for patients with Hodgkin’s disease. Bonadonna and Santoro [20] have reviewed the experience of several institutions using doxorubicin plus vinblastine plus bleomycin plus dacarbazine in the treatment of patients with Hodgkin’s disease after failure of therapy with nitrogen mustard plus vincristine plus procarbazine plus prednisone. The complete response rate varied from 4 to 59 percent, and the number of extranodal sites of disease and the disease-free interval seemed to correlate with the likelihood of achieving a complete response to the salvage regimen. From our experience and the experience of others, the following recommendations can be made. (1) Patients who achieve a complete remission with failure at a single site should undergo surgical excision of the mass. In these patients, growth may be due solely to a mature teratoma [21], and chemotherapy would prove
Myelosuppression was frequent (Table Ill). Two patients died during periods of granulocytopenia and fever. Both were patients from Group Ill with recent failure of intensive induction chemotherapy. Neither showed response at the time of death. Renal insufficiency was generally very mild, despite heavy prior exposure to cisplatin. COMMENTS
Etoposide plus cisplatin, with or without other drugs, is recognized as effective therapy for some patients with recurrent or refractory germ cell tumors. Since the report of Williams et al, in which a 47 percent complete remission rate was observed, reports of activity have varied considerably. Whereas the series from the University of Minnesota [ 161 reported that five of seven patients achieved major responses, the Cleveland Clinic [ 171 reported only four durable complete responses in 11 patients, and the Sidney Farber Cancer Institute [ 181 noted only three complete responses in 15 patients. The extent of disease and prior remission status were not clarified in these reports. The data presented in this series suggest that these patients should be divided into at least two major groups, assuming that they have been previously treated with high-dose cisplatin-based regimens: (1) patients who have achieved a previous complete remission; and (2) patients who have failed to achieve a prior complete remission. The overall response rates were 7 1 and 18 percent, respectively, and all complete remissions were in the first group. Etoposide plus cisplatin should be expected to be cross-resistant with standard chemotherapy regimens since it is cisplatin-based. A review of the reports by Williams and co-workers seems to support this hypothesis. Of the 30 patients described in 1980 [lo], five patients had received no prior cisplatin and at least five patients had achieved a prior complete remission. This experience was recently updated [ 191, a low complete response rate was observed in patients who either had failed to achieve a complete remission or had had complete remissions of less than two months’ duration. It is well known that patients who achieve only a partial remission after chemotherapy and attempted surgical excision of any residual disease nearly always die. Thus, the complete response rate is the only meaningful response in relation to long-term survival and should be the most important criterion upon which the activity of a regimen in the treatment of patients with germ cell tumors is judged. The durable complete response rate was low in most of the reported series. Etoposide plus cisplatin may, therefore, not be as effective as “salvage” therapy as was originally thought.
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to be ineffective. If the lesion is malignant, etoposide plus cisplatin should be given in an adjuvant fashion. (2) Patients with relapse after a complete remission, with one or more sites of disease and elevated marker values should receive etoposide plus cisplatin. (3) Patients without complete response to standard chemotherapy regimens, but who still have disease localized to a single site, should receive etoposide plus cisplatin until further experience can be gathered in this subgroup.
Subsequent surgical excision may be feasible in the occasional patient. (4) In patients with multiple sites of disease, rising marker values, and apparently refractory disease as evidenced by an incomplete response to standard chemotherapy, innovative therapy needs to be tested. Etoposide plus cisplatin seems to be ineffective in this group of patients. Trials of new drugs (phase II trials) or other investigational therapies seem indicated in this group of patients.
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