Cyclophosphamide and Carboplatin and Selective Consolidation in Advanced Seminoma

72 Vol. 6, 72–77, January 2000 Clinical Cancer Research

Robert J. Amato,1 Randall Millikan, tive in a significant proportion of patients with nonseminoma- Dania Daliani, Lori Wood, tous tumors but ineffective in patients with seminoma (1). The Christopher Logothetis, and Alan Pollack major advance in chemotherapy of seminoma came with the incorporation of cisplatin. In the initial reports of the use of Departments of Genitourinary Medical Oncology [R. J. A., R. M., cisplatin as a single agent in patients with germ cell tumors, D. D., L. W., C. L.] and Radiation Oncology [A. P.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 long-term, disease-free survival was reported in patients with seminoma but not in patients with nonseminomatous tumor (2). The apparent increased sensitivity of the seminomas to cisplatin ABSTRACT and relative resistance to the vinblastine/bleomycin regimen led This prospective Phase II study assesses the clinical us to study cisplatin-based chemotherapy regimens in patients efficacy and complications of a treatment regimen of com- with advanced seminoma. The addition of an alkylating agent to bination chemotherapy with cyclophosphamide and carbo- cisplatin for these patients was prompted by the significant platin and selective consolidation in advanced seminoma. Of antitumor activity of these agents and their reported synergy 46 patients who entered the study between December 1992 with cisplatin (3–6). and October 1998, 46 were evaluable. Thirty-two achieved a Besides being more sensitive to cytotoxic chemotherapy complete remission (70%; 95% confidence interval, 56– than nonseminomatous germ cell tumors, seminoma is known to 83%) after chemotherapy alone. Fourteen achieved a com- be more radiation sensitive (7). Furthermore, comparison of the plete remission (30%; 95% confidence interval, 18–46%) two tumor types by surgical resectability of residual masses after chemotherapy plus consolidation. Forty-three of the 46 after chemotherapy highlights an important difference between patients (93%; 95% confidence interval, 82–97%) remained the two. Whereas the standard practice in nonseminomatous in remission after a median follow-up period of 27.4 months. germ cell tumors is elective surgery for residual disease, in No patient experienced nephrotoxic, neurotoxic, or ototoxic seminomas the situation is quite different. Pronounced fibrotic effects or hemorrhagic cystitis. No patient had neutropenic changes make surgery for seminomas much more difficult and fever requiring hospitalization. Thirteen % required plate- complications more frequent. Finally, the metastatic spread of let transfusions, and 9% required transfusions of packed seminomas appears to be more indolent and predictable than RBCs. For patients with advanced seminoma, treatment that of other germ cell tumors. The therapy of seminoma at the with cyclophosphamide and carboplatin and selective con- M. D. Anderson Cancer Center has focused on exploiting these solidation is safe and effective. differences. In our initial experience of treating seminoma patients with INTRODUCTION a regimen combining cisplatin and cyclophosphamide and se- At the University of Texas M. D. Anderson Cancer Center, lective consolidation, we concluded that the combination was the treatment protocol for patients with advanced seminoma is effective. Ninety-two % of the patients had survived, free of different from that for patients with nonseminomatous germ cell disease, for long periods (8). The major side effects were those tumor. The difference in strategy is based on the apparent attributed to repeated doses of cisplatin, i.e., nephrotoxicity, greater sensitivity of the seminoma to both chemotherapy and neurotoxicity, and ototoxicity. Encouraged by the therapeutic radiation therapy, the relative difficulty of surgical resection, success of that initial trial, we expanded our study to evaluate and unique clinical features. combinations of cisplatin analogues and alkylating agents in an The different sensitivities to chemotherapy of seminoma attempt to find a treatment with a similar high cure rate without and nonseminomatous germ cell tumors were most apparent the relatively high complication rate. The first alternative we during the initial development of chemotherapy for germ cell evaluated was the combination of carboplatin and ifosfamide. tumors, before the availability of cisplatin. The combination These two agents were selected because of their individual chemotherapy regimen of vinblastine and bleomycin was effec- antitumor activities and their relatively mild toxicity profiles. Ninety-one % of the patients remain free of disease with a median follow-up of 78 months (9). No patients experienced deterioration of renal function, symptomatic peripheral neuropathy, ototoxic effects, or hemorrhagic cystitis. There were no Received 6/9/99; revised 9/15/99; accepted 9/16/99. The costs of publication of this article were defrayed in part by the treatment-related deaths. Ten % of the patients had neutropenic payment of page charges. This article must therefore be hereby marked fever requiring hospitalization. Twenty-six % required transfu- advertisement in accordance with 18 U.S.C. Section 1734 solely to sion of packed RBCs for a hemoglobin level of Ͻ8 g/dl or indicate this fact. 1 symptomatic anemia. Twenty-four % required platelet transfu- To whom requests for reprints should be addressed, at Department of Ͻ 3 Genitourinary Medical Oncology, The University of Texas, M. D. sions for a platelet count 20 cells/mm or for symptoms of Anderson Cancer Center, 1515 Holcombe Boulevard, Box 013, Hous- bleeding. Ninety-eight % are alive and disease free with a ton, TX 77030. Phone: (713) 792-2830; Fax: (713) 745-0827. median follow-up of 84 months.

Further modification of our chemotherapy program to re- Table 1 Dose levels duce the number of days of administration of chemotherapy, to Level Carboplatin Cyclophosphamide switch from an inpatient to an outpatient regimen, to reduce 0 (starting dose) 400 mg/m2 800 mg/m2 hematological toxicity, and to further define the role of consol- Ϫ1 360 mg/m2 800 mg/m2 idation is our present goal.

PATIENTS AND METHODS Study Population. To make this regimen less compli- chemotherapy at 28-day intervals. Granulocyte-colony stimulat- cated, we combined cyclophosphamide and carboplatin. To re- ing factor at 5 ␮g/kg/day s.c. was initiated on days 2–11. Doses duce hematological toxicity, we used granulocyte-colony stim- of cyclophosphamide and carboplatin were modified if indicated ulating factor beginning on day 2 of each chemotherapy cycle. by granulocyte counts, platelet counts, or nonhematological To further modify hematological toxicity, those patients with a toxicity (Table 2). Planned radiation therapy for those patients predicted creatinine clearance of Յ80 ml/min (calculated by with a residual mass consisted of a dose of 25 Gy. Crockcroft and Gault formulation for estimated creatinine clear- Statistical Analysis. All evaluable patients are included ance) not related to tumor volume received a modified dose of in this analysis. Response duration and survival were measured carboplatin. This is based on our retrospective analysis of our from the date of initiation of therapy. Survival curves were previous program, ifosfamide and carboplatin. Those patients generated by using the Kaplan-Meier method (8–10). with Ն3 cm residual mass after chemotherapy had a delay in Response Criteria. The treatment of advanced semi- deciding whether to have consolidation radiation therapy for 3 noma with chemotherapy classically results in a persistent re- months. Patients who continue to have regression of their residual mass (8, 9, 11). Our own experience prompted us to adopt sidual mass will continue to be observed, whereas those patients the following criteria. Patients were classified as either having a who remain stable will receive consolidation radiation therapy. complete remission in response to chemotherapy or response to Patients were enrolled in the study between December chemotherapy that required consolidation. A complete remis- 1992 and October 1998. Fifty patients with a diagnosis of sion to chemotherapy was defined as disappearance of all clin- advanced seminoma were assessed by: a review of the histological and biochemical evidence of disease with either complete ical type; serum tumor marker assays for ␤-HCG,2 AFP, and resolution on radiographic examination or a stable residual mass total LDH and LDH isoenzyme-1; and computed tomographic Ͻ3 cm in maximum transverse diameter. A response to chem- scans of the thorax, abdomen, and pelvis. Patients with visceral otherapy requiring consolidation was defined as disappearance metastases were further staged by isotope bone scan. In addi- of all clinical and biochemical evidence of disease with a tion, a complete blood count with platelet count, electrolytes, persistent stable mass 3 cm or more in maximum transverse and assessment of renal and liver function was performed. diameter. Patients received a minimum of four courses of in- Forty-six of the patients met the following criteria and were duction chemotherapy, with an additional requirement of two evaluated in our study. Patients had histological confirmation of courses beyond complete remission or prior to consolidation. a pure seminoma; advanced disease was defined as any tumor Patients achieving a complete remission were simply observed. characterized by any of the following: extragonadal origin, Patients with a persistent stable mass of 3 cm or more in supradiaphragmatic involvement, a retroperitoneal mass Ͼ10 maximum transverse diameter were evaluated for consolidation cm in maximum transverse diameter, visceral disease, or radi- consisting of definitive radiation therapy. Reevaluation in 3 ation therapy failures. Patients were ineligible if they had an months occurred. If regression in size of the residual mass abnormal level of serum AFP (Ͼ5 ng/ml) in two measurements occurred, those patients were observed, whereas those patients 1 week apart. Four patients were excluded from this study for with stability in the size of the residual mass received radiation the following reasons: two patients had a histological diagnosis therapy. We planned surgical resection of the residual mass only of nonseminomatous germ cell tumor; one patient did not re- for those patients with clinical features that led us to suspect the ceive chemotherapy; and one patient, who after two courses existence of nonseminomatous tumor. Patients were defined in with a residual mass, died at his house of a drug overdose. The our protocol to be at risk if they had a poor response to 46 patients signed the informed consent approved by the internal chemotherapy or a biomarker response that is not characteristic review board of the M. D. Anderson Cancer Center. of a pure seminoma, i.e., a late rise in the serum AFP level. Treatment. The induction chemotherapy consisted of i.v. cyclophosphamide at a dose of 800 mg/m2 of body surface area given over a period of2honday1,immediately followed RESULTS by i.v. carboplatin at a dose of 400 mg/m2 of body surface area Patient Characteristics. Clinical features were recorded given over a period of2honday1.Dose levels are shown in for the evaluable 46 patients (Table 3). Seventeen % of the Table 1. Therapy was administered as an outpatient in the patients were radiation therapy failures. Eighty-five % of the Genitourinary Ambulatory Care Center. All patients were patients presented with a primary testicular tumor, whereas 15% scheduled to receive a minimum of four courses of induction presented with a tumor of extragonadal origin. The extragonadal primary site was the mediastinum for three patients, retroperitoneum for three patients, and pineal body for one patient. Eighty-five % of the patients presented with an elevated ␤-HCG 2 The abbreviations used are: ␤-HCG, ␤-human chorionic gonadotropin; level, with a median value of 5.7 mIU/ml (normal, Ͻ1; range, AFP, ␣-fetoprotein; LDH, lactate dehydrogenase. 1.2–313.3). Sixty-five % of the patients presented with an ele-

Table 2 Dose modification criteria Table 4 Disease complications at presentation Reduction by two levels Complication No. of patients (%) Ϫ Ϫ Reduction by one level ( 1) ( 2) Retroperitoneal pain 15 (33) Grade III nonhematological toxicity Grade IV nonhematological Obstructive uropathy 11 (24) toxicity Superior vena cava syndrome 1 (2) Granulocyte nadir Ͻ100 for 72 h Organ infection Inferior vena cava syndrome 4 (9) Platelet nadir Ͻ25,000 Severe bleeding Visceral involvement 5 (11) Lung 4 Adrenal 1 Bone involvement 3 (7)

Table 3 Characteristics of the 46 patients with advanced seminoma entered in this study No. of patients (%) Table 5 Responses to therapy of 46 patients with advanced Median age in years (range) 36 (16–61) seminoma Performance Status, Zubrod 022 No. of 17 Response patients (%) 25Complete remission, chemotherapy alone 32 (70) 32Complete remission, chemotherapy plus 14 (30) 40consolidation Previous radiation therapy Treatment failure 0 (0) Primary site Overall 46 (100) Testis 39a (85) Extragonadal site 7 (15) Mediastinum 3 Retroperitoneum 3 Pineal Body 1 Elevated serum makers amide and carboplatin. Three patients who completed four ␤ -HCG 39 (85) median/range 5.7 (1.2–313.3) courses of chemotherapy had early relapses at Ͻ6 months (two LDH 30 (65) median/range 1028 (629–7501) patients had consolidation radiation therapy). One patient, who a Two undescended testes. presented with a new supraclavicular node, biopsy-proven seminoma without secreting AFP, was salvaged with cisplatin-based therapy and remained free of disease for 9 months. The remain- vated LDH with a median value of 1028 IU/l (normal, 313–618; ing two patients recurred with elevated AFP with visceral dis- range, 629–7501). Serum AFP was not elevated in any patient, ease. One patient died on salvage chemotherapy with progres- as defined by the eligibility criteria. sive tumor. The other patient was salvaged with cisplatin-based Seminoma is commonly characterized by its advanced lo- therapy and remains free of disease for 7 months. cal complications, as was the case with our patients (Table 4). The complete remission rate was durable (Fig. 1). Forty- Response and Survival. The responses to therapy are three of the 46 patients (93%) remained free of disease with a outlined in Table 5. Between four and six (median, four) courses median follow-up period of 27.4 months. Three patients re- of cyclophosphamide and carboplatin were delivered to each lapsed. One with seminoma achieved a second complete remis- patient. Of the 46 patients evaluable for response, 32 (70%) sion with cisplatin-based salvage chemotherapy. Of the two achieved a complete remission in response to chemotherapy patients who relapsed with an elevated AFP and visceral dis- alone, whereas another 14 (30%) achieved a complete remission ease, one died of progressive tumor and one achieved a second in response to chemotherapy plus consolidation, for an overall complete remission with cisplatin-based chemotherapy. The 100% complete remission rate. Postchemotherapy consolidation overall survival is shown in Fig. 2. Forty-five patients (98%) are consisted of radiation therapy or surgery. Thirteen patients, each alive and disease-free with a median follow up period of 27.8 with a persistent residual mass of 3 or more cm in maximum transverse diameter, were followed 3 months after the comple- months. tion of chemotherapy to decide whether the need of definitive Toxic Effects. Toxic effects are summarized in Table 6. radiation therapy was necessary (12 retroperitoneal and 1 in the There were no treatment-related deaths. Nadir blood counts are mediastinum). All patients received definitive radiation therapy. summarized in Table 7. No patient experienced deterioration of One patient with pineal primary tumor received involved field renal function, symptomatic peripheral neuropathy, ototoxic ef- radiation therapy, despite achieving a complete remission with fects, or hemorrhagic cystitis. No patient had neutropenic fever. chemotherapy. Two patients, who underwent planned postche- No hospital time was required. Nine % required transfusions of motherapy surgery for removal of undescended testes in the packed RBCs because of a hemoglobin level Ͻ8 g/dl or symp- pelvis, were found to have no evidence of viable seminoma or tomatic anemia. Thirteen % required platelet transfusion for a nonseminomatous elements. These patients were evaluated in platelet count Ͻ20 cells/mm3 or symptoms of bleeding. Four of the complete remission in response to chemotherapy alone the patients (9%) had their chemotherapy dose reduced to dose group. level minus 1 because of hematological effects. No patient All patients responded to the combination of cyclophosph- required an additional dose reduction.

Fig. 1 Disease-free survival.

Fig. 2 Overall survival.

DISCUSSION cisplatin, ifosfamide and carboplatin, and also with those Chemotherapy with the combination of cyclophopha- reported by other investigators, despite the advanced stage of mide and carboplatin and consolidated therapy as needed is a disease in patients we treated (8, 7, 11–18). Our ability to highly effective approach for patients with advanced pure assure that this modification is indeed superior to the regimen seminoma. Ninety-three % of the patients treated with this used previously is limited, however, by the number of pa- strategy remained in complete remission after a median fol- tients that we treated. low-up period of 27.4 months. This follow-up is beyond the The overall rate of long-term, tumor-free survival of the risk of failure for the majority of patients with seminoma. patients treated in this study was 98%, with a median follow up Because none of the patients with a residual mass had further of 27.8 months. Of the three patients who relapsed and were regression at 3 months, radiation therapy consolidation was treated with cisplatin-based salvage therapy, the patient with a necessary. The response rate we report compares favorably seminoma remains free of disease after 9 months, and of the with that of our previous trial with cyclophosphamide and other two patients who relapsed with elevated AFP associated

Table 6 Complications of chemotherapy Table 8 Alkylators and cisplatin/carboplatin Complications No. of patients (%) No. NEDa Nephrotoxicity 0 (0) Cyclophosphamide and cisplatin 33/36 92% Neurotoxity 0 (0) Ifosfamide and carboplatin 38/42 91% Ototoxicity 0 (0) Cyclophosphamide and carboplatin 43/46 93% Hemorrhagic cystitis 0 (0) a NED, no evidence of disease. Leukopenic fever 0 (0) Platelet Transfusions 6 (13) Packed RBC transfusion 4 (9) result we achieved cannot be determined. Two factors that may have contributed to the results were the selection of patients for Table 7 Nadir blood counts consolidation and the selection of patients for entry into the trial. Leucocyes Platelets Hemoglobin The selection of patients for consolidation was based on the radi- Course Median (Range) Day Median (Range) Day Median (Range) Day ographic appearance of the residual mass after chemotherapy. Ra- diographic reevaluation was performed after completion of every 1 1.3 (0.3–3.7) 11 100 (7–255) 15 11.6 (7.4–15) 16 2 2.4 (0.4–3.6) 12 92 (20–187) 15 11.0 (7.3–13.6) 15 two courses of cyclophosphamide and carboplatin. When patients 3 1.5 (0.5–3.8) 12 72 (19–208) 17 10.1 (7.4–13.0) 17 achieved maximum improvement, complete remission to chemo- 4 1.5 (0.2–3.9) 12 82 (9–236) 18 10.3 (7.2–13.7) 14 therapy, or response to chemotherapy requiring consolidation, an additional requirement of two courses were administered. The residual mass appeared frequently as a poorly defined desmoplastic response (Ͻ3 cm; Refs. 8, 9, and 11). Because patients in our with visceral disease, one died of tumor progression and one earlier study who had this characteristic response to chemotherapy remains free of disease after 7 months. have not experienced relapse, we have since considered this re- These results mirror those achieved in our other patients sponse a complete remission requiring no further therapy (8, 9). with advanced pure seminoma who have been treated under this The data of this trial confirmed the validity of that conclusion. strategy (8, 9). Although recent reports document that carbopla- Patients with a residual discreet mass (Ն3 cm) in contrast were tin is inferior to cisplatin in germ cell tumors (12), carboplatin considered at risk of relapse (8, 9, 11). Such patients had fine- does not appear to adversely effect the outcome of patients we needle aspiration biopsy of the residual mass, followed by radiation treated. This could be attributed to either the unique sensitivity therapy to the involved field (8, 9). No biopsy revealed viable of seminoma to platinum analogues or to the strategy in which disease, indicating either that the majority have no remaining we used the drugs. disease or that the fine-needle aspiration has limited ability to detect In contrast to other chemotherapy regimens reported (12–17), residual viable cancer in seminoma patients after chemotherapy (8, this combination caused no deaths in the series. The most severe 9). In our study, the 13 patients who had a residual mass Ն3cmin complications of the cyclophosphamide and carboplatin combina- maximum transverse diameter were delayed in receiving definitive tion were hematological effects. Some patients required transfu- radiation therapy. Although we realize that regression continues sions (Table 6). No hospitalization time was required. No neutro- after the completion of chemotherapy, this is a delayed event, and penic fever was observed. There were no infectious complications, as per our design, by obtaining radiographic evaluation after every perhaps because there was no mucositis and because of the use of two courses, we were able to determine a stable maximum im- granulocyte-colony stimulating factor. There were no significant provement and thus complete chemotherapy without recognizing acute nonhematological toxic effects, and no long-term complica- further regression during that short time frame. In our previous tions have yet been observed. This is in contrast to the moderate protocols, consolidative radiation therapy was planned immediately toxic effects suffered by patients treated with our initial regimen after the completion and recovery from chemotherapy (8, 9). To that incorporated the sequential delivery of cisplatin (8). Total reduce the number of patients receiving radiation therapy, a delay avoidance of the neurotoxic, ototoxic, and nephrotoxic effects that of 3 months was planned. No patient had further regression; thus, accompany cisplatin is a major advantage of the combination of all 13 received radiation therapy. A delay in 3 months from the cyclophosphamide and carboplatin. Moreover, the frequency of completion and recovery of chemotherapy did not affect the num- nonhematological and hematological toxic effects was lower than ber of patients receiving radiation therapy. A minority of patients that reported with other regimens (11–18). (30%) received radiotherapy for consolidation. The dose of radia- Bleomycin-induced pulmonary toxic effects are reported at tion therapy was a median of 25 Gy, ranging from 25 to 30 Gy. a higher rate in patients with seminoma than in those with Twelve of the 14 patients remain free of disease with no additional nonseminomatous tumors. The difference in frequency of the complications; two of the patients relapsed, and both are in com- occasionally fatal bleomycin effects may be a function of the plete remission for 7 and 9 months, respectively. older age of the patients with seminoma compared with those Patients selected for consolidation therapy at other institu- with nonseminomatous tumors. We believe the data we have tions were similar, but the method of consolidation differed. reported here confirm the published suggestion that bleomycin Surgical excision is used with postoperative radiation therapy or is not required for therapy of seminoma (19). In nonseminoma- additional chemotherapy if viable seminoma was encountered, tous tumors, bleomycin appears to be essential, even in the whereas we used primary radiation therapy to the involved field. patients with a favorable prognosis (19). We planned resection only for those patients with clinical fea- The contribution of each of the therapy components to the tures that lead us to suspect the existence of nonseminomatous

tumor. Two patients in this clinical trial did undergo surgical They also indicate that seminoma has an excellent prognosis exploration to remove undescended testes in the pelvis to ex- with carboplatin-based therapy. If future studies should confirm clude the possibility of viable tumor. Neither patient had a these findings, the therapeutic strategy we used should become viable carcinoma or teratomatous elements. the treatment of choice for advanced seminoma. The combination of cyclophosphamide and carboplatin is probably inferior to existing regimens for the treatment of patients with nonseminomatous germ cell tumors. This specificity of treat- REFERENCES ment by histological type requires that precautions be taken to 1. Samuels, M. L., Johnson, D. E., Brown, B., et al. Velban Plus Continuous Infusion Bleomycin (VB-3) in Stage III Advanced Testic- assure the correct histological classification of germ cell tumors. Of ular Cancer: Results in 99 Patients with a Note on High-Dose Velban the patients we treated, 80% had their tumor classified by his- and Sequential Cisplatin in Cancer of the Genitourinary Tract, pp. topathological study of the primary testicular cancer. An additional 159–172. New York: Raven Press, 1979. 9% were diagnosed by a biopsy of the metastatic site, and 11% 2. Higby, D. J., Wallace, D. J., Jr., Albert, D., et al. Diaminodichloroplatin were diagnosed by a fine-needle aspiration. The study protocol in the chemotherapy of testicular tumors. J. Urol., 112: 100–104, 1974. required that all patients have two measurements of serum levels of 3. Calman, F. M. B., Peckham, M. J., and Hendry, W. F. The pattern of spread and treatment of metastases in testicular seminoma. Br. J. Urol., AFP assayed 1 week apart and that both levels be within normal 51: 154–160, 1979. range. In two of the 46 patients we treated, the tumor converted to 4. Frei, E., III, Teicher, B. A., Holden, S. A., et al. Preclinical studies a mixed histological type. Because of our ability to correctly and clinical correlation of correlation of the effect of alkylating dose. classify the germ cell cancer, we believe review of the tumor Cancer Res., 48: 6417–6422, 1977. specimen by an experienced pathologist and normal serum AFP 5. Chebotareva, L. I. Late results of sarcolysin therapy in tumors of the concentrations together give a safe distinction between seminoma testis. Acta U. N. Int. Congress on Cancer, pp. 380–384. 1964. and nonseminomatous tumors for treatment purposes. 6. Whitmore, W. F., Smith, W. F., and Yagooda, A. Chemotherapy of seminoma. In: E. Grundmann (ed.), Recent Results in Cancer Research, The strict pathological entry criteria did not adversely pp. 224–249. Berlin: Springer-Verlag, 1977. affect our ability to accrue representative patients with truly 7. Anscher, M. S., Marks, L. B., and Shipley, W. U. The role of advanced seminoma. The clinical criteria excluded all pa- radiotherapy in patients with advanced seminomatous germ cell tumors. tients except those with a retroperitoneal mass of Ͼ10 cm in Oncology, 6: 97–110, 1992. maximum transverse diameter, metastatic sites above the 8. Logothetis, C. J., Samuels, M. L., Ogden, S. L., et al. Cyclophosph- diaphram, primary extragonadal origin, or radiation therapy amide and sequential cisplatin for advanced seminoma: long term follow up in 52 patients. J. Urol., 138: 789–794, 1987. failures (Table 3). Our patients were characteristic of those 9. Amato, R. J., Ellerhorst, M., Banks, M., and Logothetis, C. J. with advanced seminoma. A total of seven patients (15%) Carboplatin and ifosfamide and selective consolidation in advanced presented with an extragonadal tumor; three of those were seminoma. Eur. J. Cancer. 31A: 2223–2228, 1995. mediastinal, three were retroperitoneal masses Ͼ10 cm, and 10. Kaplan, E. L., and Meier, P. Nonparametric estimation from incom- one was pineal. The 39 patients (85%) whose tumors were of plete observations. J. Am. Stat. Assoc., 53: 457–481, 1958. testicular origin included 31 retroperitoneal masses Ͼ10 cm, 11. Motzer, R., Bosl, G., Heelan, R., et al. Residual mass: an indication 8 with supradiaphramatic involvement, and 8 radiation ther- for further therapy in patients with advanced seminoma following sys- temic chemotherapy. J. Clin. Oncol., 5: 1064–1070, 1987. apy failures. The advanced stage of the disease in these 12. Bajorin, D. F., Sarosdy, M. F., Pfister, D. G. et al. Randomized trial patients was further reflected by their local complications of etoposide and cisplatin versus etoposide and carboplatin in patients (Table 4), by the performance status of some of the patients with good-risk germ cell tumors: a multi-institutional study. J. Clin. with neglected cancers, and by the frequency of evaluation of Oncol., 11: 598–606, 1993. both the ␤-HCG and LDH levels (Table 3). 13. Williams, S. D., Birch, R., Einhorn, L. H., et al. Treatment of Some investigators have reported an adverse treatment out- disseminated germ cell tumors. N. Engl. J. Med., 316: 1435–1440, 1987. come in patients whose seminomas are of extragonadal origin have 14. Tjulandin, S. A., Khlebnov, A. V., Nasirova, R. J., et al. VAB-6 and cisplatin-cyclophosphamide combinations in the treatment of metastatic visceral disease, express serum tumor makers, who have poor seminoma patients: the U.S.S.R. experience. Ann. Oncol., 2: 667–672, initial performance status, or who have already been treated by 1991. radiation therapy. Because of the high overall complete remission 15. Wilkinson, P. M., Read, G., and Magee, G. The treatment of rates in this and our other report (8, 9), we conclude that no single advanced seminoma with chemotherapy and radiotherapy. Br. J. Cancer, clinical feature of seminoma predicts an adverse outcome, and that 57: 100–104, 1988. patients with seminomas should be considered to have a favorable 16. Fossa, S. D., Borge, L., Aass, N., Johannessen, N. B., Stenwig, A. E., and Kaalhus, O. The treatment of advanced metastatic seminoma: prognosis. Patients in this study with visceral or bone involvement experience in 55 cases. J. Clin. Oncol., 5: 1071–1077, 1987. remain in complete response to induction therapy. 17. Mencel, P. J., Motzer, R. J., Mazumdar, M., et al. Advanced A total of 124 patients with seminoma have now been seminoma: treatment results, survival, and prognostic factors in 142 treated at the M. D. Anderson Cancer Center with the combi- patients. J. Clin. Oncol., 12: 120–126, 1994. nation of an alkylating agent and a cisplatin analogue and 18. Bosl, G., Geller, N. K., Bajorin, D., et al. A randomized trial of ϩ selective consolidation therapy (Table 8). There were no late etoposide cisplatin actinomycin D (VAB-6) in patients with good prognosis germ cell tumors. J. Clin. Oncol., 6: 1231–1238, 1988. relapses or second primary malignancies. These results support 19. Levi, J. A., Raghavan, D., Harvey, V., et al. The importance of the concept of seminoma as a unique clinical entity and justify bleomycin in combination chemotherapy for good prognosis germ cell treating seminomas differently from nonseminomatous tumors. carcinoma. J. Clin. Oncol., 11: 1300–1305, 1993.

Robert J. Amato, Randall Millikan, Dania Daliani, et al.

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