Management of Poor Prognosis Germ-Cell Tumors
abstract & commentary
Synopsis: The Spanish Germ-Cell Cancer Group has used intensive alternating drug combinations in poor-prognosis metastatic germ-cell cancer. Bleomycin, vincristine, methotrexate, and cisplatin (BOMP) is alternated with etoposide, ifosfamide and cisplatin (EPI). Actuarial two-year overall survival was 64%, which may be superior to the 48% expected based on the International Germ-Cell Consensus Classification Group experience.
Source: Germa-Lluch JR, et al. Ann Oncol 1999;10: 289-293.
Germ-cell tumors are curable in about 80% of cases thanks to the introduction of cisplatin-based combination chemotherapy regimens. However, the spectrum of disease presentations is quite wide. The major problem under investigation for the patients with good prognosis tumors is how little therapy is enough. The major problem under investigation for the patients with poor prognosis tumors is can any amount of therapy be enough.
The field achieved a major organizational advance when an international group of investigators got together in 1996 and developed a set of consensus criteria for distinguishing prognosis in patients with metastatic germ-cell tumors.1 Patients with poor prognosis germ-cell tumors are now agreed to be those with mediastinal primary or non pulmonary visceral metastases or any of the following poor prognosis markers: alpha-fetoprotein levels greater than 10,000 ng/mL, beta-human chorionic gonadotrophin levels greater than 50,000 iu/L (10,000 ng/mL), or lactate dehydrogenase levels more than 10 times the upper limit of normal. About 16% of patients with nonseminomatous germ-cell tumors fall into this category (no patients with seminoma have a poor prognosis) and the five-year survival is about 48%.
The Spanish Germ-Cell Cancer Group has developed and tested an intensive six-drug combination chemotherapy program for patients with poor prognosis germ-cell tumors consisting of alternating combinations of drugs. Methotrexate is given on day 1 as a 100 mg/m2 intra-venous bolus followed by 200 mg/m2 by continuous infusion over 12 hours. Vincristine 2 mg is given intra-venously after the methotrexate infusion. Bleomycin 30 mg is delivered as a 12-hour or 24-hour continuous infusion on day 2. Cisplatin 100 mg/m2 iv is given on day 3. Bleomycin 30 mg is also given on days 8, 22, and 29 of the 35-day cycle. On days 15-18, etoposide 120 mg/m2, ifosfamide 1300 mg/m2, and cisplatin 25 mg/m2 are given. Cycles were repeated until the patient achieved a complete response, stable residual radiographic abnormalities were noted, or disease progressed. Bleomycin was stopped after 12 weekly injections.
Thirty-eight patients were entered on the study from 13 centers (i.e., around 3 patients/center). Eighteen (47%) achieved a complete response to chemotherapy alone; four additional patients (10.5%) had residual disease resected; and another four patients (10.5%) had marker-negative stable residual masses. Thus, 58% achieved a complete response to therapy and another 10.5% may have achieved a significant response. After a median follow-up of 41 months, two-year overall survival is 64%. Toxicity was mainly hematopoietic; 70% of patients experienced grade IV granulocytopenia. It is possible that this treatment is more effective than standard bleomycin, etoposide, and cisplatin (BEP) in poor-prognosis patients.
Commentary
A number of different approaches have been taken to try to improve the treatment outcome for patients with poor prognosis germ-cell cancer. The agreement about what constitutes poor prognosis disease is a recent development; therefore, much of the literature is confusing because of inclusion of patients who may not actually have poor prognosis features. Nevertheless, a review of the experiences to date in trying to improve therapy in this disease may be instructive.
Doubling the dose of cisplatin in BEP from 100 to 200 mg/m2 showed greater toxicity, but no increase in response rate or disease-free survival. Induction regimens using weekly cycles of bleomycin, vincristine, and cisplatin (BOP) followed by consolidation with a distinct drug combination has shown some promise,2 but randomized studies have not been conducted. Horwich and colleagues modified BOP by substituting carboplatin on weeks 2 and 4 and consolidating treatment with three cycles of BEP. This C-BOP/BEP regimen appeared active in pilot studies and is being tested in a nonrandomized phase II study by EORTC. Kaye and colleagues conducted a randomized study comparing three cycles of BOP given every 10 days followed by three cycles of etoposide, ifosfamide, cisplatin, and bleomycin (VIP-B) against four cycles of BEP followed by two cycles of EP without the bleomycin.3 The more intense arm was more toxic but not more effective.
Alternating combinations have also been tested in a number of centers. Alternating BEP with cisplatin, vinblastine, and bleomycin (PVB), which entails alternating use of etoposide and vinblastine in different cycles, did not improve survival.4 Bower and colleagues at Charing Cross Hospital have been using an alternating intensive regimen called POMB/ACE (cisplatin, vincristine, methotrexate, and bleomycin alternating with actinomycin D, cyclophosphamide, and etoposide) for nearly 20 years and have achieved overall three-year survival of 75% in a group of poor prognosis patients.5 This regimen from the Spanish Germ-Cell Cancer Cooperative Group (BOMP/EPI) is similar to POMB/ACE and also appears to achieve results better than expected with BEP. However, randomized studies are in progress to evaluate the more intensive alternating regimens against the standard regimen.
Another important approach to improving outcome in poor prognosis germ-cell tumors is the use of primary high-dose therapy with hematopoietic stem cell support. The German Testicular Cancer Study Group has developed a sequential high-dose combination regimen of cisplatin, etoposide, and ifosfamide given with granulocyte colony-stimulating factor and peripheral blood stem-cell support for four cycles every three weeks.6 Of 141 evaluable patients, 82 (58%) achieved a complete response and 32 (23%) have achieved partial remission with marker normalization. The early death rate was 8%. The projected five-year overall survival rate is 74%. It is not completely clear if patients receiving high-dose therapy as primary treatment are better off than those receiving intensive therapy without stem-cell support.
New agents are also being introduced into the treatment of germ-cell tumors including paclitaxel and gemcitabine. Their integration into effective combination programs may represent a path to successful treatment of poor prognosis patients.
Regardless of the treatment approach to poor prognosis patients, a disturbing new prognostic factor was recently elucidated, the site of treatment. Collette and colleagues examined the outcome of patients entered into the EORTC randomized study comparing BOP/VIP-B to BEP/EP (cited previously) as a function of the number of patients treated at a particular center.7 They found that patients of similar poor prognosis treated on the same protocol had significantly different outcomes based on whether they were treated at an experienced center or an inexperienced center. The cut point separating experienced and inexperienced was five patients. Centers entering at least five patients on the study over a four-year period achieved two-year overall survival rates of 77% while those entering less than five patients achieved two-year overall survival rates of 62% (P = 0.006). Significant differences in the dose intensity of delivered therapy were detected when the groups were compared.
This is not the first example of the impact of center experience on treatment outcome. Prior data have suggested that allogeneic transplant centers need to treat at least six patients per year in order to acheive the optimal outcome. One wonders the degree to which negative results in large cooperative group studies are related to experience. Data analysis from multi-institutional studies should probably include exploratory analysis to assess whether site of treatment influences outcome. Of course, such differences may not always be related to deviations from protocol or altered delivery of treatment. Some centers may see sicker patients. No matter what the reason, significant deviation in treatment outcome based on the treatment center should probably be a stimulus to examine the patient population and treatment practices at the center. The radiation oncologists are way ahead of the medical oncologists in the area of monitoring treatment delivery.
References
1. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997;15:594-603.
2. Horwich A, et al. Eur J Cancer Clin Oncol 1989;25: 177-184.
3. Kaye SB, et al. J Clin Oncol 1998;16:692-701.
4. deWit R, et al. Br J Cancer 1998;78:828-832.
5. Bower M, et al. Ann Oncol 1997;8:477-483.
6. Bokemeyer C, et al. Semin Oncol 1998;25 (suppl 4):24-32.
7. Collette L, et al. J Natl Cancer Inst 1999;91:839-846.
When patients with poor prognosis nonseminomatous germ-cell tumors are treated with standard bleomycin, etoposide, and cisplatin (BEP) chemotherapy, the expected five-year survival is what?
a. 22%
b. 48%
c. 64%
d. 77%
e. 92%
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