Southeastern Cancer Study Group Research Articles

Chapter 4: Chemotherapy and radiotherapy

Chapter 4: Chemotherapy and radiotherapy

Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience.

In a previously reported randomized Southeastern Cancer Study Group (SECSG) trial, three cycles of chemotherapy were found to be equivalent to four cycles in patients with favorable-prognosis germ-cell cancer. We have conducted a follow-up analysis of patients treated at Indiana University (Indianapolis, IN) to compare long-term survival between the two groups and to examine factors associated with survival. Sixty-nine patients with minimal-stage and 49 patients with moderate-stage disseminated germ-cell tumors were randomized to either three or four courses of bleomycin, etoposide, and cisplatin (BEP) administered every 3 weeks. Median follow-up time is 10.1 years (range, 7 months to 12.6 years). Ninety-two percent of patients have an actual follow-up time of > 5 years, and 97.5% of patients have an actual follow-up time of > 3 years. Survival analysis shows no significant difference between the two treatment groups in terms of overall (P = .80) or disease-free (P = .93) survival. Several clinical variables were examined by univariate analysis; only serum human chorionic gonadotropin (HCG) had an impact on survival. There were two disease-related deaths in 104 patients with HCG < or = 1,000 mIU/mL and five disease-related deaths in 14 patients with HCG greater than 1,000 mIU/mL (P < .001). Ninety-eight percent (95% CI, 95.2 to 100) of patients with favorable prognosis germ-cell tumor with an initial HCG of < or = 1,000 mIU/mL are alive without evidence of disease at 5+ years. With long-term follow-up, there is no statistically significant difference in survival between three or four cycles of BEP chemotherapy in patients with favorable prognosis germ-cell carcinoma. Serum HCG elevation of greater than 1,000 mIU/mL is a significant predictor of poor outcome in patients with otherwise good-risk disease.

Long-term follow-up of three randomized trials comparing idarubicin and daunorubicin as induction therapies for patients with untreated acute myeloid leukemia

Most clinical trials for acute leukemia have reported results after 2-3 years of follow-up. Comparisons between the original data and longer-term follow-up data may be of interest, particularly with regard to promising new therapies.In 1996, survival data were updated from three prospective, randomized comparisons of idarubicin and daunorubicin that began in 1984 and 1985. These were trials of the Memorial Sloan-Kettering Cancer Center (MSKCC), the U.S. Multicenter Study Group, and the Southeastern Cancer Study Group (SEG). The original results of these trials were reported in 1991 and 1992.The original results of the SEG trial demonstrated no significant difference between idarubicin and daunorubicin. The updated survival analysis showed similar results. The MSKCC trial revealed a significant advantage of idarubicin compared with daunorubicin in both the original and the updated analyses. The U.S. Multicenter trial found a significant difference favoring idarubicin in the original analysis, but the difference was not significant in the updated analysis.It is essential that the median length of follow-up be clearly stated in any clinical trial. When the results obtained with a particularly promising new drug or procedure are presented early in the course of study (within 1-2 years), the investigators should strongly consider a repeat evaluation after an additional 3-5 years of follow-up.

Combination chemotherapy with or without thoracic radiotherapy in limited- stage small-cell lung cancer: A randomized trial of the Southeastern Cancer Study Group : Johnson DH, Bass D, Einhorn LH, Crawford J, Perez CA, Bartolucci A et al. Division of Medical Oncology, 1956 Vanderbilt Clinic, Nashville, TN 37232-5536. J Clin Oncol 1993;11:1223–9

Combination chemotherapy with or without thoracic radiotherapy in limited- stage small-cell lung cancer: A randomized trial of the Southeastern Cancer Study Group : Johnson DH, Bass D, Einhorn LH, Crawford J, Perez CA, Bartolucci A et al. Division of Medical Oncology, 1956 Vanderbilt Clinic, Nashville, TN 37232-5536. J Clin Oncol 1993;11:1223–9

Combination chemotherapy with or without thoracic radiotherapy in limited-stage small-cell lung cancer: a randomized trial of the Southeastern Cancer Study Group.

The primary objective of this randomized prospective study was to compare the survival of limited-stage small-cell lung cancer (SCLC) patients treated with chemotherapy alone or chemotherapy plus thoracic radiotherapy (TRT). A secondary objective was to determine the effect of consolidation chemotherapy on survival. This multiinstitutional phase III study included 386 patients with limited-stage SCLC. All patients received cyclophosphamide 1,000 mg/m2, doxorubicin 40 mg/m2, and vincristine 1 mg/m2 (CAV) every 3 weeks for six cycles. Irradiated patients received 30 Gy in 10 fractions during weeks 1 and 2 of chemotherapy. Fifteen Gy in five fractions was administered during week 7 (total dose, 45 Gy). Following CAV, responding patients were randomized to receive two cycles of consolidation chemotherapy (cisplatin 20 mg/m2/d for 4 days plus etoposide 100 mg/m2/d for 4 days) or observation. Complete (46% and 38%; P = .14) and overall response rates (67% and 64%; P = .58) were not statistically significantly different. Although not significantly different, median (14.4 v 12.8 months) and 2-year survival (33% v 23.5%) rates favored the irradiated patients. Grade 4 hematologic toxicity was greater in irradiated patients (60% and 39%; P < .001). Patients given consolidation chemotherapy experienced superior median (21.1 v 13.2 months; P = .028) and 2-year survival (44% v 26%; P = .028) rates. The concurrent use of TRT and CAV chemotherapy as administered in this study failed to improve the survival of limited-stage SCLC patients compared with CAV alone. Life-threatening hematologic toxicities were more frequent with combined-modality therapy. The survival of limited-stage patients treated with CAV (with or without TRT) was improved with two cycles of cisplatin and etoposide consolidation therapy. Whether similar survival results could be achieved with cisplatin and etoposide alone requires additional study.

Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group : Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, et al. University Hospital, 926 West Michigan, Indianapolis, IN 46202. J Clin Oncol 1992;10:282-91

Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group : Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, et al. University Hospital, 926 West Michigan, Indianapolis, IN 46202. J Clin Oncol 1992;10:282-91

Postsurgical adjuvant chemotherapy with or without radiotherapy in women with breast cancer and positive axillary nodes: a South-Eastern Cancer Study Group (SEG) trial

In a prospective study of 622 women with breast cancer, those with one to three histologically positive axillary lymph nodes were randomised after mastectomy to receive cyclophosphamide 100 mg/m 2 orally on days 1–14, methotrexate 40 mg/m 2 intravenously on days 1 and 8, and fluorouracil 600 mg/m 2 intravenously on days 1 and 8 every 28 days for six cycles (CMF × six), or for twelve cycles of the same chemotherapy (CMF × 12). Those with ≥ four positive nodes were randomised to one of these two groups or to 5000 cGy of postmastectomy regional radiotherapy (RT) followed by six cycles of the same chemotherapy (RT + CMF × six). With about 10 years median follow-up, there was no significant difference in survival or disease-free survival among the three groups. There was evidence of decreased locoregional recurrence in patients with ≥ four nodes who received RT + CMF × six (relative risk 0.53, P = 0.067). Multivariate analysis indicated that the presence of ≥ four positive nodes (negatively) and the percentage of ideal (full) dose of CMF received (positively) were the strongest factors predictive of survival. This study shows no advantage for 12 over six cycles of CMF chemotherapy in women with breast cancer and positive axillary nodes. There was a suggestion of decreased locoregional recurrence but no improvement in survival with radiotherapy for women with ≥ four positive nodes.

Corynebacterium parvum versus bacille Calmette-Guérin adjuvant immunotherapy of stage II malignant melanoma.

Two separate studies have been reported comparing Corynebacterium parvum and bacille Calmette-Guérin (BCG) as adjuvant immunotherapy for stage II melanoma patients (The Milton S. Hershey Medical Center, 48 patients; Southeastern Cancer Study Group [SECSG], 162 patients). As the criteria for patient selection and drugs used were similar, we have pooled the data to analyze the effects of these two treatments. Both studies used BCG (Tice, Chicago, IL) 3 x 10(8) live organisms per treatment by Tine technique and C parvum (Burroughs-Wellcome, Triangle Park, NC) subcutaneous at a dose of 4 mg/m2 (SECSG) or 5 micrograms/m2 (Hershey) per treatment. The only difference in these studies was the frequency of immunization, with patients in Hershey receiving 22 doses and the SECSG patients receiving 55 doses during the 2-year period of treatment. Kaplan-Meier life-table analysis for the 210 patients shows a prolonged disease-free interval for patients treated with C parvum (P = .02, two-sided Mantel procedure). In similar fashion, patients treated with C parvum had an improved survival rate (from all causes) when compared with BCG-treated patients (P = .012). An analysis of the results for the 170 patients for which the number of positive nodes was available was performed using Cox's model, with nodes as a stratification variable and with covariates of place, treatment, age, and sex. In this analysis, an observed benefit for C parvum on the disease-free interval had a P value of .37 while the benefit of C parvum on the survival times (from all causes) had a P value of .04. When the same analysis was performed using only patients aged younger than 60 years, the observed benefit of C parvum on disease-free interval had a P value of .08 and the benefit of C parvum on survival times (from all causes) had a P value of .008.

Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol.

Between 1984 and 1989, 159 patients presenting with advanced germ cell cancer were entered on a randomized clinical trial comparing the efficacy and toxicity of etoposide and bleomycin and either standard-dose cisplatin (20 mg/m2 daily for 5 days) or high-dose cisplatin (40 mg/m2 daily for 5 days). Of the 159 patients, 153 were assessable for toxicity and response. As expected, patients receiving the high-dose cisplatin regimen experienced significantly more neurotoxicity, ototoxicity, nausea and vomiting, and myelo-suppression. Four patients (3%) died related to therapy. Despite the toxicity encountered, dose intensity was maintained. Overall, 84% of patients in the high-dose arm received 80% or more of the projected dose of cisplatin, etoposide, and bleomycin; and 90% of patients on the standard-dose arm received 80% or more of the projected dose. Of the 76 eligible patients randomized to receive the high-dose cisplatin regimen, 52 (68%) became disease-free with chemotherapy alone or with subsequent resection of residual teratoma or cancer. Of the 77 patients randomized to the standard-dose arm, 56 (73%) became disease-free with chemotherapy alone or with surgery. Median follow-up is now 24 months. Eleven patients (three high-dose and eight standard-dose) relapsed from disease-free status. Overall, 74% of patients receiving the high-dose cisplatin regimen are alive, and 63% are continuously free of disease. Of the patients receiving the standard-dose cisplatin regimen, 74% are alive, and 61% are continuously free of disease. This randomized prospective trial in advanced germ cell cancer achieved dose intensity of the most active single agent in this disease. This dose intensity did not translate into an improved survival or cure. We conclude that dose escalation of cisplatin beyond standard doses results in excess toxicity with no accompanying therapeutic benefit.

Serum tumor markers and patient allocation to good-risk and poor-risk clinical trials in patients with germ cell tumors

The allocation of patients with advanced germ cell tumors (GCT) to different treatment programs based on clinical characteristics is standard in the design of clinical trials today. Studies have shown that substantial differences exist between entry criteria and that these differences could influence the outcome of clinical trials. The factors contributing to these differences are not clear due to patient selection biases. Two hundred five unselected and consecutive patients allocated to and treated in good-risk and poor-risk treatment programs at Memorial Sloan-Kettering Cancer Center (MSKCC) were reassigned risk status by the Indiana University (IU) Classification. The results were compared with those of the Southeastern Cancer Study Group (SECSG). The results using both criteria indicated substantial agreement in total end results and the identification of good-risk patients. The results in poor-risk patients differed substantially, with 39 patients (19%) classified as poor-risk by MSKCC criteria and 66 (32%) by Indiana criteria. The major discrepancy occurred in IU Stage 7, in which 26 of 32 patients (81%) achieved a complete response. The major factor contributing to this difference in risk assignment was the use of serum tumor markers. Serum tumor markers must be incorporated into risk assignment criteria for GCT clinical trials to minimize the number of good-risk GCT patients in poor-risk trials.

Etoposide therapy for testicular cancer

During the past two decades, dramatic strides have been made in the treatment of metastatic testicular cancer. In the early 1970s, cisplatin, vinblastine, and bleomycin (PVB) produced durable complete remissions (CR) in approximately 70% of treated patients. In the early 1980s, etoposide emerged as the only drug with single-agent activity in cisplatin-refractory patients. Based on preclinical data demonstrating synergy of cisplatin plus etoposide, the two-drug combination proved to be a useful salvage therapy, curing approximately 25% of such patients. Further evaluation of etoposide as part of initial therapy by the Southeastern Cancer Study Group (SECSG) compared PVB with bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with metastatic germ cell tumors. Not only did BEP have significantly less toxicity, it proved to be superior to PBV in patients with advanced disease. Varying the dose and schedule of etoposide also may provide patients with potentially useful avenues of treatment. High-dose etoposide plus carboplatin in drug-refractory patients has produced durable CR in a cohort of treated patients; it is currently being evaluated as part of initial salvage therapy. The schedule dependency of etoposide in small cell lung cancer led us to evaluate daily oral administration of etoposide in patients refractory to previous etoposide therapy; objective response rates of approximately 15% to 25% were observed. In summary, etoposide remains an integral part of the treatment regimen for testis cancer. However, the incorporation of innovative dose and schedule combinations for etoposide may further improve its therapeutic index for this disease.

Effectiveness of Treatment for Non-Small Cell Lung Cancer

To the Editors: The article by Johnson and colleagues (1) alleges in its title that the Southeastern Cancer Study Group has shown a lack of survival benefit for thoracic radiotherapy among patients...

Improved survival in advanced Hodgkin's disease with the use of combined modality therapy

To compare the effectiveness of combined modality therapy and chemotherapy alone for the treatment of advanced Hodgkin's disease (Stages IIB-IV), records of 154 patients who achieved a complete or partial response to induction combination chemotherapy were analyzed. Sixty-seven patients received consolidation radiotherapy and 87 patients received no further treatment. Thirty of 154 patients participated in a prospective randomized trial of the Southeastern Cancer Study Group (SEG). Ten-year actuarial survival (Hodkin's disease deaths only) was 93% for the combined modality therapy patients compared with 59% for the chemotherapy alone patients ( p < 0.0005). Combined modality therapy patients had an 87% 10-year actuarial freedom from relapse as opposed to 56% for the chemotherapy alone patients ( p < 0.0005). Relapse occurred in 33 of the chemotherapy alone patients, 28 (85j%) being in sites involved at initial diagnosis. Seven combined modality therapy patients recured with only two true in-field failures. Multi-variate analysis demonstrated treatment (combined modality) as the only variable affecting outcome. Patients prospectively treated with combined modality therapy in the Southeastern Cancer Study Group trial also showed a statistically significant improvement in both survival and freedom from relapse compared with patients receiving chemotherapy only. There was no apparent increase in toxicity from using combined modality therapy compared with chemotherapy. Three chemotherapy patients and one combined modality patient developed acute leukemia.

Randomized comparison of two combination regimens versus minimal chemotherapy in nonsmall-cell lung cancer: a Southeastern Cancer Study Group Trial.

Patients with advanced nonsmall-cell lung cancer (NSCLC), good performance status, and no prior chemotherapy were randomized to receive one of three regimens: intravenous vindesine (V) 3 mg/m2 every 2 weeks; V 3 mg/m2 weekly for 5 weeks, followed by a dose every 2 weeks plus mitomycin (VM) 20 mg/m2 day 1 and then 15 mg/m2 every 6 weeks; or V at the more intensive dose rate plus cisplatin (VC) 120 mg/m2 with forced diuresis on days 1 and 29 and then every 6 weeks. A total of 435 patients were enrolled in the trial, with 410 (94%) assessable for prognostic characteristics and survival. Among the 375 patients assessable for response, only 58 (15%) achieved objective response. Single-agent V every 2 weeks was inactive (response rate less than 1%), effectively acting as a no-treatment arm. Among assessable patients receiving VM, 33 (27%) responded; among patients receiving VC, 24 (19%) responded. There was no statistically significant survival difference among the treatment arms, with median survival among those treated with V 14.8 weeks, VM 20.4 weeks, and VC 24.7 weeks; VC achieved borderline significance (P = .06) compared with V. In a prognostic factor analysis, treatment was not a significant factor (P = .447) for survival. Thus, in this large multicenter trial, neither a high-dose cisplatin combination nor a noncisplatin regimen (VM) with a comparable response rate had a significant survival advantage over minimal chemotherapy. New approaches are needed in advanced NSCLC.

Combination Regional Therapy for Extremity Sarcoma

Patients with extremity sarcomas were treated with a neoadjuvant therapy protocol that had originated within the Southeastern Cancer Study Group. Major objectives were to determine tolerance of therapy and its effects on tumor control and survival. After undergoing biopsy, patients received intra-arterial infusion with doxorubicin hydrochloride (Adriamycin) (30 mg every 24 hours) for 3 days and were allocated by institution to receive irradiation of 30 or 35 Gy in 10 fractions or 46 Gy in 23 to 25 fractions. Surgery was done within 7 to 10 days or 30 days pending irradiation dose. Postoperative chemotherapy was given to 31 patients. There were 60 patients, 29 women and 31 men with a median age of 48 years, with 53 soft-tissue tumors and 7 malignant bone tumors. Stages (American Joint Committee on Cancer) included stage IB, 2 patients; stages IIA and IIB, 9 patients; stage IIIA, IIIB, or IIIC, 39 patients; and stages IVA or IVB, 10 patients. Limb salvage surgery was done in 57 patients, including radical resection in 23 with large extensive tumors, wide local excision in 30, excision with narrow margins in 7, primary amputation in 3, and delayed amputation in 2 because of wound complications. There was one local recurrence in the 57 patients who had limb salvage surgery. Disease-free and overall survival at 48 months were 47% and 56%, respectively. We conclude that combined therapy for extremity sarcomas in a multicenter setting resulted in excellent local control, good function, and reasonable long-term survival in patients having limb salvage surgery.

Therapy of acute myelogenous leukemia in patients over the age of 50: A randomized southeastern cancer study group trial

In a randomized trial, 299 evaluable patients with acute myelogenous leukemia, age ⩾ 51, were initially randomized to cytosine arabinoside, 100 mg/m 2/day, by continuous intravenous infusion for seven days, plus either daunorubicin 45 mg/m 2/day × 3 (DA), or m-AMSA 200 mg/m 2/day × 3 days (MA). Complete remission (CR) rates were not significantly different, 47% for DA and 42% for MA. Toxicities were similar except that severe hepatic toxicity, serum bilirubin ⩾ 7 mg/dl, was more frequent in patients receiving MA (10%) than in patients receiving DA (4%), p < 0.05. Deaths during induction were significantly more frequent in patients receiving MA (38%) than in patients receiving DA (25%), p = 0.018. Patients achieving a CR received thioguanine, cytosine arabinoside, and daunorubicin (TAD) for three cycles as consolidation. Among evaluable patients, 82/102 (80%) stayed in CR during these three cycles. Patients were then randomized to either no maintenance or to DA every 13 weeks × 4 cycles, at a dose slightly lower than used for induction. Remission duration was similar for the two maintenance programs, 10.7 months for no maintenance and 8.5 months for DA. The percentage of patients evaluable for maintenance achieving three year relapse-free survival was similar for the two maintenance programs, 28% for no maintenance and 21% for DA. However, overall survival was significantly greater (40 vs 12 months, p = 0.007) for patients receiving no maintenance therapy, due to greater survival after recurrence in these patients. At each phase of the study there were substantial numbers of non-evaluable cases, often due to incomplete evaluation of remission status. Of the 379 patients initially entered into the trial, 35% obtained a complete remission. Of all the patients who achieved a complete remission, 61% were both evaluable and in remission upon completion of the maintenance phase. Of these patients who completed the maintenance phase in remission, 15% were relapse free survivors three years following initiation of maintenance therapy. Overall, only 3.2% of patients who entered the trial (35% × 61% × 15%) were continuous relapse-free survivors three years into the maintenance phase.

Thoracic radiation therapy: dosage and techniques

Combination chemotherapy (CC) deserves credit for the increase in survival for patients with limited small cell lung cancer (SCLC). However, the best CC is not clearly established. The definition of limited disease and the work-up to define limited disease has evolved over the last 20 years. Imaging studies are now more sophisticated (MRI and CT scan) and used more frequently. Although there is general agreement on what constitutes limited disease and what is not, the extent of the staging work-up, the issue of ipsilateral pleural effusion and supraclavicular disease continue to stimulate lively discussion. The last decade’s studies usually employed cyclophosphamide-based CC. Presently. platinum-etoposide (PE) CC is assuming increased importance at least in North America. However, in limited disease, no data compare the regimens directly. Integration of CC with thoracic radiotherapy (TRT) has warranted much attention. These issues have been addressed in 3 recent reviews [l-33. Three randomized North American studies, the SEG [4], the NCI-USA [5], and the CALGB [63, all support a survival benefit for the group receiving TRT. However, the British Medical Research Council (MRC) [7], the Finsen Institute [8] and the later Southeastern Cancer Study Group (SEG) trial did not show improvement for the TRT group. For all of these trials, the CC was cyclophosphamide-based, but the radiotherapy varied in many ways. TRT has been known to produce dramatic regression of primary tumors in SCLC. The failure of CC to durably control the bulk primary location and TRT’s local efficacy both suggested their combination. Comis reported local failure in 50-100% of cases [9]. The method of CC-TRT is another factor that influences toxicity for sure and may also be important in efficacy and survival, but the available information prevents reaching conclusions. There are major problems that interfere with retrospective literature analysis of this issue. The term‘local control’ is quite imprecise. Assessment of local control in most series has been based on clinicians’ assessment of chest X-rays. More recently bronchoscopy and CT-scanning

Randomized Phase II evaluation of iproplatin (CHIP) and carboplatin (CBDCA) in lung cancer. A Southeastern Cancer Study Group trial : Kramer BS, Birch R, Greco A, Prestridge K, DeSimone P, Omura G. University of Florida, Gainesville, FL. Am J Clin Oncol, Cancer Clin Trials 1988;11:643-5

Randomized Phase II evaluation of iproplatin (CHIP) and carboplatin (CBDCA) in lung cancer. A Southeastern Cancer Study Group trial : Kramer BS, Birch R, Greco A, Prestridge K, DeSimone P, Omura G. University of Florida, Gainesville, FL. Am J Clin Oncol, Cancer Clin Trials 1988;11:643-5

High-dose cytosine arabinoside and daunorubicin as primary therapy in elderly patients with acute myelogenous leukemia. A phase I-II study of the Southeastern Cancer Study Group.

We undertook a phase I-II trial in elderly (age greater than or equal to 60 years) untreated acute myelogenous leukemia (AML) patients using brief, intensive therapy to improve induction rates and overall survival in older AML patients. Twenty-one patients ranging in age from 60 to 81 years (median, 66 years) were treated using either a 4- or 5-day course of high-dose cytosine arabinoside, 3 g/m2 intravenously (IV) every 12 hours; followed by daunorubicin, 45 mg/m2/d IV bolus for 3 consecutive days. Thirteen patients were entered at the first dose level (a 4-day course or eight doses of cytosine arabinoside), whereas eight patients underwent therapy at the second dose level (a 5-day course or ten doses). Patients who achieved a complete remission received a repeat course of high-dose cytosine arabinoside and daunorubicin within 4 weeks of attaining remission. Seven patients had an antecedant history of a myelodysplastic syndrome. Infection was the major complication experienced by this elderly patient group, and included ten episodes of bacteremia or fungemia (four of which were fatal) and five cases of pneumonia (one fatality). Nine of the 21 patients (three of 13 at the first dose level and six of eight at the second dose level) achieved a complete remission. Median remission duration was 9 months (range, 4-19+ months). Although high-dose cytosine arabinoside plus daunorubicin was an effective antileukemic therapy, it is too toxic to recommend for most elderly leukemic patients.

Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol.

Four courses of PVP16B (cisplatin plus etoposide [VP-16] plus bleomycin) has been standard chemotherapy for disseminated germ cell tumors at Indiana University and the Southeastern Cancer Study Group (SECSG) since 1984. We began a random prospective phase III study in patients with favorable-prognosis (minimal and moderate extent) disseminated germ cell tumors comparing four courses of PVP16B over 12 weeks to the identical dose PVP16B administered in three courses over 9 weeks. The categories of minimal and moderate disease constitute approximately two thirds of all disseminated germ cell tumors that require chemotherapy. One hundred eighty-four patients entered this trial, and all patients have a minimal follow-up of 1 year. Overall, 106 of 107 (99%) minimal extent and 73 of 77 moderate patients (95%) achieved an initial disease-free status (NED), confirming the favorable prognostic categories. Eighty-six of 88 patients (98%) randomized to three courses and 93 of 96 randomized to four courses (97%) of PVP16B achieved disease-free status. There have been ten relapses (5%), with five on each arm. Currently, 81 of 88 (92%) and 88 of 96 (92%) patients randomized to three v four courses of PVP16B are continuously disease-free. This study confirms the high cure rate with PVP16B in favorable-prognosis germ cell tumors. The deletion of the fourth course of PVP16B significantly reduces the toxicity, cost, and inconvenience of this curative regimen. We conclude that three courses of PVP16B is the preferred regimen for favorable-prognosis germ cell tumors.