Trial Of Adjuvant Chemotherapy With Paclitaxel, Estramustine, And Oral Etoposide Combined With Long-Term Androgen Suppression Therapy And Radiotherapy

How should patients with high-risk prostate cancer be optimally treated? In large part because of PSA screening, increasing numbers of patients are diagnosed with low risk, T1c disease. Yet, a significant number of patients continue to die of prostate cancer, with over 28,000 prostate cancer deaths estimated in the US for 2008 . Many of these prostate cancer deaths occur in patients who have high risk features noted at presentation. The Radiation Therapy Oncology Group (RTOG) has been interested in pursuing strategies aimed at this cohort of patients (Primarily Gleason score 8-10, with Gleason Score 7 and PSA > 20 at presentation also eligible).

A recent article, "Phase III Multi-Institutional Trial of Adjuvant Chemotherapy with Paclitaxel, Estramustine, and Oral Etoposide Combined with Long-Term Androgen Suppression Therapy and Radiotherapy Versus Long-Term Androgen Suppression Plus Radiotherapy Alone For High-Risk Prostate Cancer: Preliminary Toxicity Analysis of RTOG 99-02," reported an attempt to improve survival rates in this cohort of patients. In this trial, the control arm was modeled after RTOG trial 92-02, where a regimen of 2 years of androgen suppression + RT was shown to produce improved survival rates when compared with a regimen of short term (4 months) of androgen suppression + RT for patients with Gleason Score 8-10 prostate cancers. This study has just been updated with 10 year follow-up in a recent report.

The rationale for this study involved the hypothesis that adding cytotoxic chemotherapy to the long term AS + RT regimen would improve survival rates by being used in an adjuvant fashion, after the initial period of AS +RT, in an effort to reduce the number of hormone refractory clones earlier in the disease process, rather than waiting for clinically apparent hormone refractory disease to develop.

A chemotherapy regimen of paclitaxel, estramustine, and etoposide was utilized. Almost 400 patients were accrued to the trail between 2000-2004 at institutions in North America. Unfortunately, the study closed early because of toxicity concerns related to the chemotherapy. Specifically there was excess thromboembolic toxicity thought to be related to the chemotherapy regimen, and most likely the agent estramustine. This report by Rosenthal et al. discusses the toxicity concerns and reports. It is too early to analyze efficacy endpoints from the study, although this analysis is planned for the future.

Although RTOG trial 99-02 closed prematurely because of toxicity concerns, a successor trial, RTOG 0521 , opened in 2005, and has accrued approximately 470 patients by December 2008. It uses the same basic schema, with a regimen of long-term (2 yrs) of AS + RT in the control arm, and AS+ RT with cytotoxic chemotherapy in the experimental arm. In this trial, the chemotherapy is delivered with docetaxel and prednisone, based on reports showing this regimen to be well tolerated and efficacious in hormone refractory disease. This trial is ongoing, and results are not available. It builds on the basis of RTOG 99-02. The report referenced here shows how an initial toxicity report from a protocol concept can be useful in guiding the development of subsequent studies.

The ongoing RTOG 0521 study, and subsequent analysis of the RTOG 99-02 study, will help to address the question of whether the use of cytotoxic chemotherapy earlier in the disease process will help to improve survival rates, when added to standard therapy, for gentlemen diagnosed with high-risk, but non-metastatic, prostate cancer.

References

Jemal, A, Siegel, R, Ward, E, et al: Cancer Statistics, 2008. CA Cancer J Clin 2008; 58:71-96.

Rosenthal SA, Bae K, Pienta KJ, Sobczak ML, Asbell SO, Rajan R, Kerlin KJ, Michalski JM, Sandler HM : Phase III Multi-Institutional Trial of Adjuvant Chemotherapy with Paclitaxel,Estramustine, and Oral Etoposide Combined with Long-Term Androgen Suppression Therapy and Radiotherapy Versus Long-Term Androgen Suppression Plus Radiotherapy Alone For High-Risk Prostate Cancer: Preliminary Toxicity Analysis of RTOG 99-02. Int J Radiat Oncol Biol Phys. 2008 Nov 4. [Epub ahead of print].

Horwitz, EM, Bae, K, Hanks, GE, Porter, A, Grignon, D, Brereton, H, Venkatesan, V, Lawton, C, Rosenthal, SA, Sandler, HM, and Shipley, WU: Ten-Year Follow-up of RTOG 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer. J Clin Oncol 26:2497-2504, 2008.

Radiation Therapy Oncology Group: RTOG 0521: A Phase III protocol of Androgen Suppression (AS) and 3DCRT/IMRT vs. AS and 3DCRT/IMRT followed by chemotherapy with docetaxel and prednisone for localized, high-risk, prostate cancer. www.rtog.org. http://www.rtog.org/members/protocols/0521/0521.pdf

Tannock, IF, deWit, R, Berry, WR, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-1512.