ANOTHER FAILURE OF HIGH DOSE CHEMOTHERAPY FOR GERM CELL TUMORS

A randomized phase III study comparing standard dose BEP with sequential high-dose VIP plus stem-cell support in patients with poor-prognosis germ-cell cancer
02.12.10
Category: Scientific News
An intergroup European study did not demonstrate improved outcome of first-line high-dose chemotherapy

The development of effective chemotherapy such as cisplatin, etoposid, and bleomycin (BEP) has dramatically improved the prognosis of patients with metastatic non-seminomatous germ-cell cancer (GCC). However, patients with poor prognosis according to the International Germ Cell Cancer Collaborative Group criteria (IGCCCG) only achieve long-term survival rates of 50%–60%. In order to improve these results, the German Testicular Cancer Study Group (GTCSG) developed a dose intensification approach, consisting of one cycle of cisplatin, etoposide, and ifosfamide (VIP) with stem-cell mobilization followed by three to four sequential high-dose cisplatin, etoposide, and ifosfamide (HD-VIP) cycles each with granulocyte colony-stimulating factor (G-CSF) and peripheral blood stem-cell transfusion at 21-day intervals, in order to achieve an early dose intensification.

The aim of the study conducted by the European Organization for Research and Treatment of Cancer (EORTC) in collaboration with the GTCSG and the Spanish Grupo Germinal was to compare the efficacy of one cycle of standard dose VIP plus three cycles of HD-VIP followed by stem-cell infusion to four cycles of standard BEP in previously untreated patients with poor-prognosis GCC and to compare the toxicity of these two treatments. Results are published online on 17 November 2010 in the Annals of Oncology.

To show a 15% improvement in a 1-year failure-free survival (FFS), the study aimed to recruit 222 patients but was closed prematurely due to slow accrual. Between April 1999 and June 2007, 137 patients from 27 European oncology centers were included. Two sites were excluded due to poor data documentation. Of 131 patients included in the analysis, 11 were considered ineligible. The median follow-up of 4.4 years overall is similar in the two arms.

All 66 patients who were randomly assigned to BEP started the treatment. Of 65 patients allocated to HD-CT, 62 (95.4%) received the treatment. In the BEP arm, 93.8% of patients received four cycles of scheduled treatment compared with 75.4% in the HD-CT arm and as expected the main reason for this was toxicity. Toxicity was more severe in patients treated by HD-CT. Seven (5%) of 131 patients died during treatment. Three died of toxicity: two who were assigned to the HD-CT arm died of sepsis (one after the first cycle of standard dose VIP) and one on the BEP arm who died of cardiac failure. The other patients died of lung embolus (one) or malignant disease (three).

The dose intensity in the BEP arm was 97.7%, while the dose intensity in the HD-CT arm was 89.3%. One or more cycles were postponed in 25% of the patients in the BEP arm compared with 66% in the HD-CT arm. This was mainly due to patient wish or infrastructure problems and not toxicity.

There was no improvement in complete response rate for patients treated in the HD-CT arm compared with patients treated on the BEP arm (intention to treat 44.6% versus 33.3%). Overall, there was no difference in FFS between the two treatment arms. The 1-year FFS rate was 48% after BEP and 66.1% after HD-CT with a difference of 18.1% (P = 0.035). The 2-year FFS rate was 44.8% after BEP and 58.2% after HD-CT but this 16.3% (standard deviation 7.5%) difference was not statistically significant. Overall survival did not differ between the two groups. On BEP, 83% of patients survived 1 year 65.5% survived 2 years. For the HD-CT arm, the 1- and 2-year survival rates were 86.1% and 72.9%, respectively.

The assessment of the prognostic value of marker half-life was conducted in the subset of 116 patients with at least two treatment cycles for whom the marker half-life could be calculated (62 BEP and 54 HD-CT). Marker decline was not prognostic for FFS or overall survival. However, there was a borderline significant interaction between treatment and marker decline for FFS (P = 0.05) and a suggestion for a greater benefit from VIP in patients with satisfactory marker decline.

The authors concluded that there is no clear evidence that high-dose chemotherapy plus autologous hematopoietic stem-cell support given as part of first-line therapy increase survival in patients with poor-prognosis GCC. Although this randomized trial indicates about 10% absolute improvement at 2 years with HD-VIP, it was not possible to demonstrate a statistical significance of the difference due to early study closure.

The authors also noticed if not used in the first-line therapy, HD-CT will still remain important at relapse. An international collaborative group is working on a definition of favorable or unfavorable prognostic criteria for relapsing patients and this could have a significant impact on the success of choosing patients for conventional or high-dose salvage chemotherapy in the future. To maintain the highest chance of cure, patients with a poor prognosis or relapsed disease should be transferred to a specialized center without any delay to benefit from optimal interdisciplinary management and supportive care. In order to improve on the poor outcome for poor-risk GCC, further clarification of the role of HD-CT as well as new combinations of drugs should be investigated in well-designed clinical trials and this can only be achieved by close international collaboration.