This prospective Phase II study assesses the clinical efficacy and complications of a treatment regimen of combination chemotherapy with cyclophosphamide and carboplatin and selective consolidation in advanced seminoma. Of 46 patients who entered the study between December 1992 and October 1998,46 were evaluable. Thirty-two achieved a complete remission (70%; 95%confidence interval, 56–83%) after chemotherapy alone. Fourteen achieved a complete remission (30%; 95% confidence interval,18–46%) after chemotherapy plus consolidation. Forty-three of the 46 patients (93%; 95% confidence interval, 82–97%) remained in remission after a median follow-up period of 27.4 months. No patient experienced nephrotoxic, neurotoxic, or ototoxic effects or hemorrhagic cystitis. No patient had neutropenic fever requiring hospitalization. Thirteen % required platelet transfusions, and 9% required transfusions of packed RBCs. For patients with advanced seminoma,treatment with cyclophosphamide and carboplatin and selective consolidation is safe and effective.

At the University of Texas M. D. Anderson Cancer Center, the treatment protocol for patients with advanced seminoma is different from that for patients with nonseminomatous germ cell tumor. The difference in strategy is based on the apparent greater sensitivity of the seminoma to both chemotherapy and radiation therapy, the relative difficulty of surgical resection, and unique clinical features.

The different sensitivities to chemotherapy of seminoma and nonseminomatous germ cell tumors were most apparent during the initial development of chemotherapy for germ cell tumors, before the availability of cisplatin. The combination chemotherapy regimen of vinblastine and bleomycin was effective in a significant proportion of patients with nonseminomatous tumors but ineffective in patients with seminoma (1). The major advance in chemotherapy of seminoma came with the incorporation of cisplatin. In the initial reports of the use of cisplatin as a single agent in patients with germ cell tumors, 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 and relative resistance to the vinblastine/bleomycin regimen led us to study cisplatin-based chemotherapy regimens in patients with advanced seminoma. The addition of an alkylating agent to cisplatin for these patients was prompted by the significant antitumor activity of these agents and their reported synergy with cisplatin (3, 4, 5, 6).

Besides being more sensitive to cytotoxic chemotherapy than nonseminomatous germ cell tumors, seminoma is known to be more radiation sensitive (7). Furthermore, comparison of the two tumor types by surgical resectability of residual masses after chemotherapy highlights an important difference between the two. Whereas the standard practice in nonseminomatous germ cell tumors is elective surgery for residual disease, in seminomas the situation is quite different. Pronounced fibrotic changes make surgery for seminomas much more difficult and complications more frequent. Finally, the metastatic spread of seminomas appears to be more indolent and predictable than that of other germ cell tumors. The therapy of seminoma at the M. D. Anderson Cancer Center has focused on exploiting these differences.

In our initial experience of treating seminoma patients with a regimen combining cisplatin and cyclophosphamide and selective consolidation,we concluded that the combination was effective. Ninety-two % of the patients had survived, free of disease, for long periods (8). The major side effects were those attributed to repeated doses of cisplatin, i.e., nephrotoxicity, neurotoxicity, and ototoxicity. Encouraged by the therapeutic success of that initial trial, we expanded our study to evaluate combinations of cisplatin analogues and alkylating agents in an attempt to find a treatment with a similar high cure rate without the relatively high complication rate. The first alternative we evaluated was the combination of carboplatin and ifosfamide. These two agents were selected because of their individual 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 treatment-related deaths. Ten % of the patients had neutropenic fever requiring hospitalization. Twenty-six % required transfusion of packed RBCs for a hemoglobin level of <8 g/dl or symptomatic anemia. Twenty-four % required platelet transfusions for a platelet count <20 cells/mm3 or for symptoms of bleeding. Ninety-eight % are alive and disease free with a median follow-up of 84 months.

Further modification of our chemotherapy program to reduce the number of days of administration of chemotherapy, to switch from an inpatient to an outpatient regimen, to reduce hematological toxicity, and to further define the role of consolidation is our present goal.

Study Population.

To make this regimen less complicated, we combined cyclophosphamide and carboplatin. To reduce hematological toxicity, we used granulocyte-colony stimulating factor beginning on day 2 of each chemotherapy cycle. To further modify hematological toxicity, those patients with a predicted creatinine clearance of ≤80 ml/min(calculated by Crockcroft and Gault formulation for estimated creatinine clearance) not related to tumor volume received a modified dose of carboplatin. This is based on our retrospective analysis of our previous program, ifosfamide and carboplatin. Those patients with ≥3 cm residual mass after chemotherapy had a delay in deciding whether to have consolidation radiation therapy for 3 months. Patients who continue to have regression of their residual mass will continue to be observed, whereas those patients who remain stable will receive consolidation radiation therapy.

Patients were enrolled in the study between December 1992 and October 1998. Fifty patients with a diagnosis of advanced seminoma were assessed by: a review of the histological type; serum tumor marker assays for β-HCG,2 AFP, and total LDH and LDH isoenzyme-1; and computed tomographic scans of the thorax, abdomen, and pelvis. Patients with visceral metastases were further staged by isotope bone scan. In addition, a complete blood count with platelet count, electrolytes, and assessment of renal and liver function was performed.

Forty-six of the patients met the following criteria and were evaluated in our study. Patients had histological confirmation of a pure seminoma; advanced disease was defined as any tumor characterized by any of the following: extragonadal origin, supradiaphragmatic involvement, a retroperitoneal mass >10 cm in maximum transverse diameter, visceral disease, or radiation therapy failures. Patients were ineligible if they had an abnormal level of serum AFP (>5 ng/ml)in two measurements 1 week apart. Four patients were excluded from this study for the following reasons: two patients had a histological diagnosis of nonseminomatous germ cell tumor; one patient did not receive chemotherapy; and one patient, who after two courses with a residual mass, died at his house of a drug overdose. The 46 patients signed the informed consent approved by the internal review board of the M. D. Anderson Cancer Center.

Treatment.

The induction chemotherapy consisted of i.v. cyclophosphamide at a dose of 800 mg/m2 of body surface area given over a period of 2 h on day 1, immediately followed by i.v. carboplatin at a dose of 400 mg/m2 of body surface area given over a period of 2 h on day 1. Dose levels are shown in Table 1. Therapy was administered as an outpatient in the Genitourinary Ambulatory Care Center. All patients were scheduled to receive a minimum of four courses of induction chemotherapy at 28-day intervals. Granulocyte-colony stimulating factor at 5 μg/kg/day s.c. was initiated on days 2–11. Doses of cyclophosphamide and carboplatin were modified if indicated by granulocyte counts, platelet counts, or nonhematological toxicity(Table 2). Planned radiation therapy for those patients with a residual mass consisted of a dose of 25 Gy.

Statistical Analysis.

All evaluable patients are included in this analysis. Response duration and survival were measured from the date of initiation of therapy. Survival curves were generated by using the Kaplan-Meier method (8, 9, 10).

Response Criteria.

The treatment of advanced seminoma with chemotherapy classically results in a persistent residual mass (8, 9, 11). Our own experience prompted us to adopt the following criteria. Patients were classified as either having a complete remission in response to chemotherapy or response to chemotherapy that required consolidation. A complete remission to chemotherapy was defined as disappearance of all clinical and biochemical evidence of disease with either complete resolution on radiographic examination or a stable residual mass <3 cm in maximum transverse diameter. A response to chemotherapy requiring consolidation was defined as disappearance of all clinical and biochemical evidence of disease with a persistent stable mass 3 cm or more in maximum transverse diameter. Patients received a minimum of four courses of induction chemotherapy, with an additional requirement of two courses beyond complete remission or prior to consolidation. Patients achieving a complete remission were simply observed. Patients with a persistent stable mass of 3 cm or more in maximum transverse diameter were evaluated for consolidation consisting of definitive radiation therapy. Reevaluation in 3 months occurred. If regression in size of the residual mass occurred, those patients were observed,whereas those patients with stability in the size of the residual mass received radiation therapy. We planned surgical resection of the residual mass only for those patients with clinical features that led us to suspect the existence of nonseminomatous tumor. Patients were defined in our protocol to be at risk if they had a poor response to chemotherapy or a biomarker response that is not characteristic of a pure seminoma, i.e., a late rise in the serum AFP level.

Patient Characteristics.

Clinical features were recorded for the evaluable 46 patients (Table 3). Seventeen % of the patients were radiation therapy failures. Eighty-five % of the patients presented with a primary testicular tumor, whereas 15% 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 β-HCG level, with a median value of 5.7 mIU/ml (normal, <1;range, 1.2–313.3). Sixty-five % of the patients presented with an elevated LDH with a median value of 1028 IU/l (normal, 313–618; range,629–7501). Serum AFP was not elevated in any patient, as defined by the eligibility criteria.

Seminoma is commonly characterized by its advanced local complications,as was the case with our patients (Table 4).

Response and Survival.

The responses to therapy are outlined in Table 5. Between four and six (median, four)courses of cyclophosphamide and carboplatin were delivered to each patient. Of the 46 patients evaluable for response, 32 (70%) achieved a complete remission in response to chemotherapy alone, whereas another 14 (30%) achieved a complete remission in response to chemotherapy plus consolidation, for an overall 100% complete remission rate. Postchemotherapy consolidation consisted of radiation therapy or surgery. Thirteen patients, each with a persistent residual mass of 3 or more cm in maximum transverse diameter, were followed 3 months after the completion of chemotherapy to decide whether the need of definitive radiation therapy was necessary (12 retroperitoneal and 1 in the mediastinum). All patients received definitive radiation therapy. One patient with pineal primary tumor received involved field radiation therapy, despite achieving a complete remission with chemotherapy. Two patients, who underwent planned postchemotherapy surgery for removal of undescended testes in the pelvis, were found to have no evidence of viable seminoma or nonseminomatous elements. These patients were evaluated in the complete remission in response to chemotherapy alone group.

All patients responded to the combination of cyclophosphamide and carboplatin. Three patients who completed four courses of chemotherapy had early relapses at <6 months (two patients had consolidation radiation therapy). One patient, who 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 remaining two patients recurred with elevated AFP with visceral disease. One patient died on salvage chemotherapy with progressive tumor. The other patient was salvaged with cisplatin-based therapy and remains free of disease for 7 months.

The complete remission rate was durable (Fig. 1). Forty-three of the 46 patients (93%)remained free of disease with a median follow-up period of 27.4 months. Three patients relapsed. One with seminoma achieved a second complete remission with cisplatin-based salvage chemotherapy. Of the two patients who relapsed with an elevated AFP and visceral disease, one died of progressive tumor and one achieved a second complete remission with cisplatin-based chemotherapy. The overall survival is shown in Fig. 2. Forty-five patients (98%) are alive and disease-free with a median follow up period of 27.8 months.

Toxic Effects.

Toxic effects are summarized in Table 6. There were no treatment-related deaths. Nadir blood counts are summarized in Table 7. No patient experienced deterioration of renal function, symptomatic peripheral neuropathy, ototoxic effects, or hemorrhagic cystitis. No patient had neutropenic fever. No hospital time was required. Nine % required transfusions of packed RBCs because of a hemoglobin level <8 g/dl or symptomatic anemia. Thirteen % required platelet transfusion for a platelet count <20 cells/mm3 or symptoms of bleeding. Four of the patients (9%) had their chemotherapy dose reduced to dose level minus 1 because of hematological effects. No patient required an additional dose reduction.

Chemotherapy with the combination of cyclophophamide and carboplatin and consolidated therapy as needed is a highly effective approach for patients with advanced pure seminoma. Ninety-three % of the patients treated with this strategy remained in complete remission after a median follow-up period of 27.4 months. This follow-up is beyond the risk of failure for the majority of patients with seminoma. Because none of the patients with a residual mass had further regression at 3 months, radiation therapy consolidation was necessary. The response rate we report compares favorably with that of our previous trial with cyclophosphamide and cisplatin, ifosfamide and carboplatin, and also with those reported by other investigators,despite the advanced stage of disease in patients we treated (8, 7, 11, 12, 13, 14, 15, 16, 17, 18). Our ability to assure that this modification is indeed superior to the regimen used previously is limited, however, by the number of patients that we treated.

The overall rate of long-term, tumor-free survival of the patients treated in this study was 98%, with a median follow up of 27.8 months. Of the three patients who relapsed and were treated with cisplatin-based salvage therapy, the patient with a seminoma remains free of disease after 9 months, and of the other two patients who relapsed with elevated AFP associated with visceral disease, one died of tumor progression and one remains free of disease after 7 months.

These results mirror those achieved in our other patients with advanced pure seminoma who have been treated under this strategy (8, 9). Although recent reports document that carboplatin is inferior to cisplatin in germ cell tumors (12),carboplatin does not appear to adversely effect the outcome of patients we treated. This could be attributed to either the unique sensitivity of seminoma to platinum analogues or to the strategy in which we used the drugs.

In contrast to other chemotherapy regimens reported (12, 13, 14, 15, 16, 17), this combination caused no deaths in the series. The most severe complications of the cyclophosphamide and carboplatin combination were hematological effects. Some patients required transfusions (Table 6). No hospitalization time was required. No neutropenic fever was observed. There were no infectious complications,perhaps because there was no mucositis and because of the use of granulocyte-colony stimulating factor. There were no significant acute nonhematological toxic effects, and no long-term complications have yet been observed. This is in contrast to the moderate toxic effects suffered by patients treated with our initial regimen that incorporated the sequential delivery of cisplatin (8). Total avoidance of the neurotoxic, ototoxic, and nephrotoxic effects that accompany cisplatin is a major advantage of the combination of cyclophosphamide and carboplatin. Moreover, the frequency of nonhematological and hematological toxic effects was lower than that reported with other regimens (11, 12, 13, 14, 15, 16, 17, 18).

Bleomycin-induced pulmonary toxic effects are reported at a higher rate in patients with seminoma than in those with nonseminomatous tumors. The difference in frequency of the occasionally fatal bleomycin effects may be a function of the older age of the patients with seminoma compared with those with nonseminomatous tumors. We believe the data we have reported here confirm the published suggestion that bleomycin is not required for therapy of seminoma (19). In nonseminomatous tumors, bleomycin appears to be essential, even in the patients with a favorable prognosis (19).

The contribution of each of the therapy components to the result we achieved cannot be determined. Two factors that may have contributed to the results were the selection of patients for consolidation and the selection of patients for entry into the trial. The selection of patients for consolidation was based on the radiographic appearance of the residual mass after chemotherapy. Radiographic reevaluation was performed after completion of every two courses of cyclophosphamide and carboplatin. When patients achieved maximum improvement, complete remission to chemotherapy, 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 (<3 cm; Refs. 8, 9, and 11). Because patients in our earlier study who had this characteristic response to chemotherapy have not experienced relapse, we have since considered this response a complete remission requiring no further therapy (8, 9). The data of this trial confirmed the validity of that conclusion. Patients with a residual discreet mass (≥3 cm) in contrast were considered at risk of relapse (8, 9, 11). Such patients had fine-needle aspiration biopsy of the residual mass, followed by radiation therapy to the involved field (8, 9). No biopsy revealed viable disease, indicating either that the majority have no remaining disease or that the fine-needle aspiration has limited ability to detect residual viable cancer in seminoma patients after chemotherapy (8, 9). In our study, the 13 patients who had a residual mass ≥3 cm in maximum transverse diameter were delayed in receiving definitive radiation therapy. Although we realize that regression continues after the completion of chemotherapy, this is a delayed event, and as per our design, by obtaining radiographic evaluation after every two courses, we were able to determine a stable maximum improvement and thus complete chemotherapy without recognizing further regression during that short time frame. In our previous protocols, consolidative radiation therapy was planned immediately after the completion and recovery from chemotherapy (8, 9). To reduce the number of patients receiving radiation therapy, a delay of 3 months was planned. No patient had further regression; thus, all 13 received radiation therapy. A delay in 3 months from the completion and recovery of chemotherapy did not affect the number of patients receiving radiation therapy. A minority of patients (30%) received radiotherapy for consolidation. The dose of radiation therapy was a median of 25 Gy, ranging from 25 to 30 Gy. Twelve of the 14 patients remain free of disease with no additional complications; two of the patients relapsed, and both are in complete remission for 7 and 9 months, respectively.

Patients selected for consolidation therapy at other institutions were similar, but the method of consolidation differed. Surgical excision is used with postoperative radiation therapy or additional chemotherapy if viable seminoma was encountered, whereas we used primary radiation therapy to the involved field. We planned resection only for those patients with clinical features that lead us to suspect the existence of nonseminomatous tumor. Two patients in this clinical trial did undergo surgical exploration to remove undescended testes in the pelvis to exclude the possibility of viable tumor. Neither patient had a viable carcinoma or teratomatous elements.

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 treatment by histological type requires that precautions be taken to assure the correct histological classification of germ cell tumors. Of the patients we treated, 80% had their tumor classified by histopathological study of the primary testicular cancer. An additional 9% were diagnosed by a biopsy of the metastatic site, and 11% were diagnosed by a fine-needle aspiration. The study protocol required that all patients have two measurements of serum levels of AFP assayed 1 week apart and that both levels be within normal range. In two of the 46 patients we treated, the tumor converted to a mixed histological type. Because of our ability to correctly classify the germ cell cancer, we believe review of the tumor specimen by an experienced pathologist and normal serum AFP concentrations together give a safe distinction between seminoma and nonseminomatous tumors for treatment purposes.

The strict pathological entry criteria did not adversely affect our ability to accrue representative patients with truly advanced seminoma. The clinical criteria excluded all patients except those with a retroperitoneal mass of >10 cm in maximum transverse diameter,metastatic sites above the diaphram, primary extragonadal origin, or radiation therapy failures (Table 3). Our patients were characteristic of those with advanced seminoma. A total of seven patients (15%)presented with an extragonadal tumor; three of those were mediastinal,three were retroperitoneal masses >10 cm, and one was pineal. The 39 patients (85%) whose tumors were of testicular origin included 31 retroperitoneal masses >10 cm, 8 with supradiaphramatic involvement,and 8 radiation therapy failures. The advanced stage of the disease in these patients was further reflected by their local complications(Table 4), by the performance status of some of the patients with neglected cancers, and by the frequency of evaluation of both theβ-HCG and LDH levels (Table 3).

Some investigators have reported an adverse treatment outcome in patients whose seminomas are of extragonadal origin have visceral disease, express serum tumor makers, who have poor initial performance status, or who have already been treated by radiation therapy. Because of the high overall complete remission rates in this and our other report (8, 9), we conclude that no single clinical feature of seminoma predicts an adverse outcome, and that patients with seminomas should be considered to have a favorable prognosis. Patients in this study with visceral or bone involvement remain in complete response to induction therapy.

A total of 124 patients with seminoma have now been treated at the M. D. Anderson Cancer Center with the combination of an alkylating agent and a cisplatin analogue and selective consolidation therapy(Table 8). There were no late relapses or second primary malignancies. These results support the concept of seminoma as a unique clinical entity and justify treating seminomas differently from nonseminomatous tumors. They also indicate that seminoma has an excellent prognosis with carboplatin-based therapy. If future studies should confirm these findings, the therapeutic strategy we used should become the treatment of choice for advanced seminoma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

                
2

The abbreviations used are: β-HCG, β-human chorionic gonadotropin; AFP, α-fetoprotein; LDH, lactate dehydrogenase.

Fig. 1.

Disease-free survival.

Fig. 1.

Disease-free survival.

Close modal
Fig. 2.

Overall survival.

Fig. 2.

Overall survival.

Close modal
Table 1

Dose levels

LevelCarboplatinCyclophosphamide
0 (starting dose) 400 mg/m2 800 mg/m2 
−1 360 mg/m2 800 mg/m2 
LevelCarboplatinCyclophosphamide
0 (starting dose) 400 mg/m2 800 mg/m2 
−1 360 mg/m2 800 mg/m2 
Table 2

Dose modification criteria

Reduction by one level (−1)Reduction by two levels (−2)
Grade III nonhematological toxicity Grade IV nonhematological toxicity 
Granulocyte nadir <100 for 72 h Organ infection 
Platelet nadir <25,000 Severe bleeding 
Reduction by one level (−1)Reduction by two levels (−2)
Grade III nonhematological toxicity Grade IV nonhematological toxicity 
Granulocyte nadir <100 for 72 h Organ infection 
Platelet nadir <25,000 Severe bleeding 
Table 3

Characteristics of the 46 patients with advanced seminoma entered in this study

No. of patients (%)
Median age in years (range) 36 (16–61) 
Performance Status, Zubrod  
22 
Previous radiation therapy  
Primary site  
Testis 39a (85) 
Extragonadal site 7 (15) 
Mediastinum 
Retroperitoneum 
Pineal Body 
Elevated serum makers  
β-HCG 39 (85) median/range 5.7 (1.2–313.3) 
LDH 30 (65) median/range 1028 (629–7501) 
No. of patients (%)
Median age in years (range) 36 (16–61) 
Performance Status, Zubrod  
22 
Previous radiation therapy  
Primary site  
Testis 39a (85) 
Extragonadal site 7 (15) 
Mediastinum 
Retroperitoneum 
Pineal Body 
Elevated serum makers  
β-HCG 39 (85) median/range 5.7 (1.2–313.3) 
LDH 30 (65) median/range 1028 (629–7501) 
a

Two undescended testes.

Table 4

Disease complications at presentation

ComplicationNo. of patients (%)
Retroperitoneal pain 15 (33) 
Obstructive uropathy 11 (24) 
Superior vena cava syndrome 1 (2) 
Inferior vena cava syndrome 4 (9) 
Visceral involvement 5 (11) 
Lung 
Adrenal 
Bone involvement 3 (7) 
ComplicationNo. of patients (%)
Retroperitoneal pain 15 (33) 
Obstructive uropathy 11 (24) 
Superior vena cava syndrome 1 (2) 
Inferior vena cava syndrome 4 (9) 
Visceral involvement 5 (11) 
Lung 
Adrenal 
Bone involvement 3 (7) 
Table 5

Responses to therapy of 46 patients with advanced seminoma

ResponseNo. of patients(%)
Complete remission, chemotherapy alone 32 (70) 
Complete remission, chemotherapy plus consolidation 14 (30) 
Treatment failure (0) 
Overall 46 (100) 
ResponseNo. of patients(%)
Complete remission, chemotherapy alone 32 (70) 
Complete remission, chemotherapy plus consolidation 14 (30) 
Treatment failure (0) 
Overall 46 (100) 
Table 6

Complications of chemotherapy

ComplicationsNo. of patients(%)
Nephrotoxicity (0) 
Neurotoxity (0) 
Ototoxicity (0) 
Hemorrhagic cystitis (0) 
Leukopenic fever (0) 
Platelet Transfusions (13) 
Packed RBC transfusion (9) 
ComplicationsNo. of patients(%)
Nephrotoxicity (0) 
Neurotoxity (0) 
Ototoxicity (0) 
Hemorrhagic cystitis (0) 
Leukopenic fever (0) 
Platelet Transfusions (13) 
Packed RBC transfusion (9) 
Table 7

Nadir blood counts

CourseLeucocyesPlateletsHemoglobin
Median (Range)DayMedian (Range)DayMedian (Range)Day
1.3 (0.3–3.7) 11 100 (7–255) 15 11.6 (7.4–15) 16 
2.4 (0.4–3.6) 12 92 (20–187) 15 11.0 (7.3–13.6) 15 
1.5 (0.5–3.8) 12 72 (19–208) 17 10.1 (7.4–13.0) 17 
1.5 (0.2–3.9) 12 82 (9–236) 18 10.3 (7.2–13.7) 14 
CourseLeucocyesPlateletsHemoglobin
Median (Range)DayMedian (Range)DayMedian (Range)Day
1.3 (0.3–3.7) 11 100 (7–255) 15 11.6 (7.4–15) 16 
2.4 (0.4–3.6) 12 92 (20–187) 15 11.0 (7.3–13.6) 15 
1.5 (0.5–3.8) 12 72 (19–208) 17 10.1 (7.4–13.0) 17 
1.5 (0.2–3.9) 12 82 (9–236) 18 10.3 (7.2–13.7) 14 
Table 8

Alkylators and cisplatin/carboplatin

No.NEDa
Cyclophosphamide and cisplatin 33 /36 92% 
Ifosfamide and carboplatin 38 /42 91% 
Cyclophosphamide and carboplatin 43 /46 93% 
No.NEDa
Cyclophosphamide and cisplatin 33 /36 92% 
Ifosfamide and carboplatin 38 /42 91% 
Cyclophosphamide and carboplatin 43 /46 93% 
a

NED, no evidence of disease.

1
Samuels M. L., Johnson D. E., Brown B., et al Velban Plus Continuous Infusion Bleomycin (VB-3) in Stage III Advanced Testicular Cancer: Results in 99 Patients with a Note on High-Dose Velban and Sequential Cisplatin in Cancer of the Genitourinary Tract
159
-172, Raven Press New York  
1979
.
2
Higby D. J., Wallace D. J., Jr., Albert D., et al Diaminodichloroplatin in the chemotherapy of testicular tumors.
J. Urol.
,
112
:
100
-104,  
1974
.
3
Calman F. M. B., Peckham M. J., Hendry W. F. The pattern of spread and treatment of metastases in testicular seminoma.
Br. J. Urol.
,
51
:
154
-160,  
1979
.
4
Frei E., III, Teicher B. A., Holden S. A., et al Preclinical studies and clinical correlation of correlation of the effect of alkylating dose.
Cancer Res.
,
48
:
6417
-6422,  
1977
.
5
Chebotareva, L. I. Late results of sarcolysin therapy in tumors of the testis. Acta U. N. Int. Congress on Cancer, pp. 380–384. 1964.
6
Whitmore, W. F., Smith, W. F., and Yagooda, A. Chemotherapy of seminoma. In: E. Grundmann (ed.), Recent Results in Cancer Research, pp. 224–249. Berlin: Springer-Verlag, 1977.
7
Anscher M. S., Marks L. B., Shipley W. U. The role of radiotherapy in patients with advanced seminomatous germ cell tumors.
Oncology
,
6
:
97
-110,  
1992
.
8
Logothetis C. J., Samuels M. L., Ogden S. L., et al Cyclophosphamide and sequential cisplatin for advanced seminoma: long term follow up in 52 patients.
J. Urol.
,
138
:
789
-794,  
1987
.
9
Amato R. J., Ellerhorst M., Banks M., Logothetis C. J. Carboplatin and ifosfamide and selective consolidation in advanced seminoma.
Eur. J. Cancer.
,
31A
:
2223
-2228,  
1995
.
10
Kaplan E. L., Meier P. Nonparametric estimation from incomplete observations.
J. Am. Stat. Assoc.
,
53
:
457
-481,  
1958
.
11
Motzer R., Bosl G., Heelan R., et al Residual mass: an indication for further therapy in patients with advanced seminoma following systemic chemotherapy.
J. Clin. Oncol.
,
5
:
1064
-1070,  
1987
.
12
Bajorin D. F., Sarosdy M. F., Pfister D. G., et al Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multi-institutional study.
J. Clin. Oncol.
,
11
:
598
-606,  
1993
.
13
Williams S. D., Birch R., Einhorn L. H., et al Treatment of disseminated germ cell tumors.
N. Engl. J. Med.
,
316
:
1435
-1440,  
1987
.
14
Tjulandin S. A., Khlebnov A. V., Nasirova R. J., et al VAB-6 and cisplatin-cyclophosphamide combinations in the treatment of metastatic seminoma patients: the U.S.S.R. experience.
Ann. Oncol.
,
2
:
667
-672,  
1991
.
15
Wilkinson P. M., Read G., Magee G. The treatment of advanced seminoma with chemotherapy and radiotherapy.
Br. J. Cancer
,
57
:
100
-104,  
1988
.
16
Fossa S. D., Borge L., Aass N., Johannessen N. B., Stenwig A. E., Kaalhus O. The treatment of advanced metastatic seminoma: experience in 55 cases.
J. Clin. Oncol.
,
5
:
1071
-1077,  
1987
.
17
Mencel P. J., Motzer R. J., Mazumdar M., et al Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients.
J. Clin. Oncol.
,
12
:
120
-126,  
1994
.
18
Bosl G., Geller N. K., Bajorin D., et al A randomized trial of etoposide + cisplatin actinomycin D (VAB-6) in patients with good prognosis germ cell tumors.
J. Clin. Oncol.
,
6
:
1231
-1238,  
1988
.
19
Levi J. A., Raghavan D., Harvey V., et al The importance of bleomycin in combination chemotherapy for good prognosis germ cell carcinoma.
J. Clin. Oncol.
,
11
:
1300
-1305,  
1993
.