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UROSCAN |
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| Year : 2013 | Volume
: 29
| Issue : 3 | Page : 268-269 |
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Is Paclitaxel-based chemotherapy the way forward in testicular cancer?
Vivek Venkatramani
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| Date of Web Publication | 29-Aug-2013 |
Correspondence Address:
 Source of Support: None, Conflict of Interest: None  | Check |
How to cite this article:
Venkatramani V. Is Paclitaxel-based chemotherapy the way forward in testicular cancer?. Indian J Urol 2013;29:268-9 |
de Wit R, Skoneczna I, Daugaard G, De Santis M, Garin A, Aass N, Witjes AJ, Albers P, White JD, Germa-Lluch JR, Marreaud S, Collette L. Randomized phase III study comparing paclitaxel-bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer: intergroup study EORTC 30983. J Clin Oncol. 2012 Mar 10;30(8):792-9
 Summary | |  |
This paper [1] reports the results of the EORTC 30983 trial that compared standard bleomycin, etoposide, cisplatin (BEP) with paclitaxel-BEP (T-BEP) therapy in intermediate-prognosis germ cell testicular cancer. Patients with metastatic germ-cell cancer (GCC), aged 16-50 years of age, and classified as intermediate-risk as per the International Germ Cell Cancer Consensus were recruited. [2] Patients were excluded if they had received chemotherapy previously or had compromised renal function (GFR < 40mL/min). In the standard BEP arm, cisplatin 20 mg/m 2 , days 1-5; etoposide 100 mg/m 2 , days 1-5 for four cycles, and bleomycin at a dose of 30 mg/m 2 weekly for 12 weeks were administered. The T-BEP arm received paclitaxel 175 mg/m 2 on day 1 prior to standard four-cycle BEP in addition. All patients in the T-BEP arm received granulocyte-colony stimulating factor (G-CSF) as primary prophylaxis, while in the standard BEP arm, it was used as secondary prophylaxis.
Patients with normal tumor markers and no clinical or radiological evidence of residual masses after chemotherapy were classified as having a "complete response." Those whose histopathology showed no evidence of malignancy after resection of a residual mass were also included in this group. Patients in whom viable malignancy was completely resected following chemotherapy were considered "disease free." "Incomplete response" was defined as incomplete surgical resection of a residual mass, continuing rise of tumor markers, or disease progression during or within 2 months of completion of chemotherapy. "Disease progression" was defined as a progressive rise in tumor markers or increase in tumor volume.
The sample size for the study was calculated assuming that T-BEP would increase 3-year progression-free survival (PFS) from 75% to 85% using 80% power and a two-sided α error of 0.05. Ninety-eight events were required to prove this and it was planned to recruit 498 patients. Randomization was performed by minimization to ensure balance with respect to histology and number allocated to each centre.
Though a sample size of 498 was planned, 337 patients from 12 countries were recruited due to the premature termination of the trial. This was due to logistical delays and the cessation of a free drug supply once paclitaxel became generic. The BEP arm had 169 patients, while the T-BEP arm had 168 patients. Twenty-six patients were ineligible. Both arms were well-matched and the median follow-up of patients was 5.3 years.
The primary end-point analyzed was the 3-year PFS. A 12% superior PFS was found in the T-BEP arm (P < 0.05), but the overall survival did not show any significant difference. With respect to response to treatment, the only significant difference observed was on per-protocol analysis (P = 0.0384). Complete response was seen in 71.6% in the T-BEP arm and 59.9% in the BEP arm.
Neutropenia and neutropenic fevers were more common in the T-BEP group despite the fact that all patients in this group received G-CSF as primary prophylaxis. Allergic reactions, mucositis, and diarrheas were also more common in this group.
The authors concluded that T-BEP appears to be a safe and effective option in intermediate-risk GCC with a statistically significant 12% superior 3-year PFS on analysis of eligible patients.
| Comments | | |
BEP has remained the standard of care for metastatic GCC for a long time. Patients in the poor prognosis group have a 5-year disease-free survival of 45% with this regimen [2] and despite various attempts, no other regimen have proven superior [3] Paclitaxel is a second-line agent in the management of GCC. In these cases, it has been used in combination with ifosfamide and cisplatin (TIP regime), [4] or gemcitabine and oxaliplatin (GOP regime). [5] In this population, a favorable response is seen in 50%-70% of cases with durable responses in a minority. [4],[5] Gemcitabine with paclitaxel has also been used as a 3 rd line agent following the failure of high-dose chemotherapy and bone marrow transplant with a 31% favorable response rate. [6] The combination of paclitaxel with high-dose etoposide, ifosfamide, and cisplatin (HD-VIP) in chemo-naïve poor risk testicular tumors showed promise with 2-year and 5-year survival rates of 77.6% and 75.2%, respectively. [7]
The EORTC conducted a phase I/II study in the intermediate prognosis population and concluded that a dose of 175 mg/m 2 was safe and effective. [8] This study was based on those results and shows a 12% increase in PFS in intermediate-risk patients who received T-BEP. These patients also showed a higher complete response rate that was significantly better on per-protocol analysis. However, there was no significant difference in the overall survival.
As highlighted by the authors, there are weaknesses in this trial. First, the calculated sample size could not be reached and this left the trial with a power of 74%. Second, 13 patients were deemed ineligible for analysis in each arm. Of these, more good-prognosis patients had been allocated to the BEP group and more poor-prognosis patients to the T-BEP group. This might have skewed the intention-to-treat analysis toward non-significance. This is supported by the fact that eligible and per-protocol analyses for both, PFS and response rate, do show a significant difference. Despite being given primary prophylaxis with G-CSF, patients in the T-BEP arm had a greater risk of leucocytopenia and leucocytopenic fever, which can be directly attributed to paclitaxel. In addition, T-BEP arm also had higher rates of allergic reactions, mucositis, and diarrhea. Furthermore, two deaths occurred in the T-BEP arm (one related to possible bleomycin-induced pulmonary toxicity and the second due to severe diarrhea) as opposed to none in the BEP arm. Fourth, although some investigators consider minimization equivalent to randomization, doubts remain whether complete elimination of bias is possible using this method.
Despite these weaknesses, this is the first, and so far, only randomized control trial reporting the use of paclitaxel as a first-line chemotherapeutic agent in GCC. Further trials are needed in this area, especially in the poor-prognosis category of patients, in whom the possible toxicity of this regimen may be justified if significantly better survival can be obtained.
| References | | |
| 1. | De Wit R, Skoneczna I, Daugaard G, De Santis M, Garin A, Aass N, et al. Randomized phase III study comparing paclitaxel-bleomycin, etoposide and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer: Intergroup study EORTC 30983. J Clin Oncol 2012;30:792-9. 
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| 7. | Hartmann JT, Gauler T, Metzner B, Gerl A, Casper J, Rick O, et al. Phase I/II study of sequential dose-intensified ifosfamide, cisplatin, and etoposide plus paclitaxel as induction chemotherapy for poor prognosis germ cell tumors by the German Testicular Cancer Study Group. J Clin Oncol 2007;25:5742-7.
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| 8. | de Wit R, Louwerens M, de Mulder PH, Verweij J, Rodenhuis S, Schornagel J. Management of intermediate-prognosis germ-cell cancer: Results of a phase I/II study of Taxol-BEP. Int J Cancer 1999;83:831-3.
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