What is the right choice?

James Fleck & Laura Albaneze: Anticancerweb 19(04), 2017

In young adult male, testicular cancer is the most common solid tumor, with a high curability rate, even in advanced disease. International criteria have been used for risk stratification. The most employed are those developed by Indiana University (IU) and the Memorial Sloan Kettering Cancer Center (MSKCC). The first used only clinical and imaging criteria and the second included tumor markers into a recursive algorithm. In 1997, the International Germ Cell Cancer Collaborative Group, taking advantage of a database composed of more than 5000 cases of germ cell tumors, developed a new classification system represented in the table below:

PT = Primary Tumor, AFP = Alfa-fetoprotein, HCG = Human chorionic gonadotropin, LDH = Lactate dehydrogenase, NA = Not applied  

The new international classification provided a downstaging in regrouping patients of the database. Using the new criteria only 16% of the patients were classified as poor prognosis, whereas 27 to 37% were considered high risk based on previous IU classification.

The importance of risk / benefit assessment is amplified in experimental models with curative intent. The clinical trial E3887 was a landmark to support the best treatment choice for advanced testicular cancer. Originally coordinated by the Eastern Cooperative Oncology Group (ECOG), the study further included the Southwest Oncology Group (SWOG) and Cancer and Leukemia Group B (CALGB) becoming an Intergroup Trial. Patients were randomly assigned to receive 4 cycles of BEP (Bleomycin + Etoposide + Cisplatin) or 4 cycles of VIP (Etoposide + Ifosfamide + Cisplatin). From October 1987 to April 1992, 304 patients classified as advanced disseminated germ cell tumors were recruited according to Indiana University criteria. Subsequently, 283 patients were regrouped according to parameters established by the new international classification. 

In 1998, the Journal of Clinical Oncology published the 2-year progression-free survival (PFS) and overall survival (OS) for BEP (PFS = 60% and OS = 71%) and VIP (PFS = 64% and OS = 74%), which did not differ significantly. In 2003, the journal Cancer published mature data on 5 year-OS obtained with BEP and VIP treatments in the three prognostic subgroups of the international classification, as expressed in the table below:

After a mean follow-up of 7.3 years and analyzing the entire group of patients, there was no significant difference in the outcomes PFS (BEP = 58% and VIP = 64%) and OS (BEP = 67% and VIP = 69%). Patients treated with VIP had higher hematological toxicity, despite the recommended use of prophylactic G-CSF. In conclusion, BEP scheme remained the international standard in the treatment of advanced testicular cancer. Regarding risk / benefit assessment, two issues should be considered: The first is bleomycin-related pulmonary toxicity. The use of 99Tc-DTPA lung scintigraphy revealed alveolocapillary injury after a bleomycin cumulative dose around 256 mg, which would nearly correspond to the dose achieved by the end of the third BEP-cycle. Additional studies will be needed to correlate pulmonary scintigraphy findings with any clinically relevant expression of lung disease. However, up to now, in the presence of lung comorbidities, bleomycin should be avoided and, therefore, this specific group of patients would be better candidate to VIP as first-line therapeutic option. The second question consists of an unusual group of patients whose tumor marker decreasing rate does not correspond to that expected after the first cycle of chemotherapy. Since it is a predictive factor of worse prognosis, dose-dense chemotherapy could be an alternative treatment for this unfavorable profile. The results of the GETUC-13 study are promising, although they are still supported only by a surrogate (PFS).

References:

International Germ Cell Consensus Classification. A prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol. 15: 594–603, 1997 

Nichols CR, Catalano PJ, Crawford ED, et al. Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: An Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study, J Clin Oncol. 16:1287–1293, 1998

Stuart Hinton,Paul J. Catalano,Lawrence H. Einhorn, et al: Cisplatin, Etoposide and Either Bleomycin or Ifosfamide in the Treatment of Disseminated Germ Cell Tumors: Final Analysis of an Intergroup Trial, Cancer 97:1869 –75, 2003

Evandro de Azambuja, James Freitas Fleck, Sérgio Saldanha Menna Barreto and Renato Duarte Cunha: Pulmonary epithelial permeability in patients treated with bleomycin containing chemotherapy detected by technetium-99m diethylene triamine penta-acetic acid aerosol (99m Tc-DTPA) scintigraphy, Annals of Nuclear Medicine19 (2): 131–135, 2005 

Azambuja E; Fleck, JF; Batista, RG and Menna Barreto, S: Bleomycin lung toxicity: who are the patients with increased risk? Pulmonary, Pharmacology and Therapeutics18(5):363 – 366, 2005

Fizazi K, Flechon A, Le Teuff G, et al. Mature results of the GETUG 13 phase III trial in poor-prognosis germ-cell    tumors (GCT). Abstract 4504, American Society of Clinical Oncology meeting, 2016