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

Published:November 05, 2008DOI:


      Long-term androgen suppression plus radiotherapy (AS+RT) is standard treatment of high-risk prostate cancer. A randomized trial, Radiation Therapy Oncology Group trial 9902, was undertaken to determine whether adjuvant chemotherapy with paclitaxel, estramustine, and etoposide (TEE) plus AS+RT would improve disease outcomes with acceptable toxicity.

      Methods and Materials

      High-risk (prostate-specific antigen 20–100 ng/mL and Gleason score ≥7; or Stage T2 or greater, Gleason score 8, prostate-specific antigen level <100 ng/mL) nonmetastatic prostate cancer patients were randomized to AS+RT (Arm 1) vs. AS+RT plus four cycles of TEE (Arm 2). TEE was delivered 4 weeks after RT. AS continued for 2 years for both treatment arms. RT began after 8 weeks of AS began.


      The Radiation Therapy Oncology Group 9902 trial opened January 11, 2000. Excess thromboembolic toxicity was noted, leading to study closure October 4, 2004. A total of 397 patients were accrued, and the data for 381 were analyzable. An acute and long-term toxicity analysis was performed. The worst overall toxicities during treatment were increased for Arm 2. Of the 192 patients, 136 (71%) on Arm 2 had RTOG Grade 3 or greater toxicity compared with 70 (37%) of 189 patients on Arm 1. Statistically significant increases in hematologic toxicity (p < 0.0001) and gastrointestinal toxicity (p = 0.017) but not genitourinary toxicity (p = 0.07) were noted during treatment. Two Grade 5 complications related to neutropenic infection occurred in Arm 2. Three cases of myelodysplasia/acute myelogenous leukemia were noted in Arm 2. At 2 and 3 years after therapy completion, excess long-term toxicity was not observed in Arm 2.


      TEE was associated with significantly increased toxicity during treatment. The toxicity profiles did not differ at 2 and 3 years after therapy. Toxicity is an important consideration in the design of trials using adjuvant chemotherapy for prostate cancer.
      To read this article in full you will need to make a payment
      ASTRO Member Login
      ASTRO Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Jemal A.
        • Siegel R.
        • Ward E.
        • et al.
        Cancer statistics, 2008.
        CA Cancer J Clin. 2008; 58: 71-96
        • D'Amico A.V.
        • Whittington R.
        • Malkowicz S.B.
        • et al.
        Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer.
        J Clin Oncol. 1999; 17: 168-173
        • Pilepich M.V.
        • Winter K.
        • Lawton C.A.
        • et al.
        Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—Long-term results of phase III RTOG 85-31.
        Int J Radiat Oncol Biol Phys. 2005; 61: 1285-1290
        • Bolla M.
        • Gonzalez D.
        • Warde P.
        • et al.
        Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin.
        N Engl J Med. 1997; 337: 295-300
        • Bolla M.
        • Collette L.
        • Blank L.
        • et al.
        Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomized trial.
        Lancet. 2002; 360: 103-106
        • Hanks G.E.
        • Pajak T.F.
        • Porter A.
        • et al.
        A phase III trial of long term adjuvant androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: The RTOG protocol 92-02.
        J Clin Oncol. 2003; 21: 3972-3978
        • Horwitz E.M.
        • Bae K.
        • Hanks G.E.
        • et al.
        Ten-year follow-up of a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer: RTOG 92-02.
        J Clin Oncol. 2008; 26: 2497-2504
        • Smith D.C.
        • Esper P.
        • Strawderman M.
        • et al.
        Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer.
        J Clin Oncol. 1999; 17: 1664-1671
        • Cox J.D.
        • Stetz J.
        • Pajak T.F.
        • et al.
        Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC).
        Int J Radiat Oncol Biol Phys. 1995; 31: 1341-1346
        • Pienta K.J.
        • Fisher E.I.
        • Eisenberger M.A.
        • et al.
        A phase II trial of estramustine and etoposide in hormone refractory prostate cancer: A Southwest Oncology Group trial (SWOG 9407).
        Prostate. 2001; 46: 257-261
        • Smith D.C.
        • Chay C.H.
        • Dunn R.L.
        • et al.
        Phase II trial of paclitaxel, estramustine, etoposide, and carboplatin in the treatment of patients with hormone-refractory prostate carcinoma.
        Cancer. 2003; 98: 269-276
        • Meluch A.A.
        • Greco F.A.
        • Morrissey L.H.
        • et al.
        Weekly paclitaxel, estramustine phosphate, and oral etoposide in the treatment of hormone-refractory prostate carcinoma.
        Cancer. 2003; 98: 2192-2198
        • Berry W.R.
        • Hathorn J.W.
        • Dakhil S.R.
        • et al.
        Phase II randomized trial of weekly paclitaxel with or without estramustine phosphate in progressive, metastatic, hormone-refractory prostate cancer.
        Clin Prostate Cancer. 2004; 3: 104-111
        • Fizazi K.
        • Le Maitre A.
        • Hudes G.
        • et al.
        Addition of estramustine to chemotherapy and survival of patients with castration-refractory prostate cancer: A meta-analysis of individual patient data.
        Lancet Oncol. 2007; 8: 994-1000
        • Flaig T.W.
        • Tangen C.M.
        • Hussain M.H.
        • et al.
        Randomization reveals unexpected acute leukemias in Southwest Oncology Group prostate cancer trial.
        J Clin Oncol. 2008; 26: 1532-1536
        • Tannock I.F.
        • deWit R.
        • Berry W.R.
        • et al.
        Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
        N Engl J Med. 2004; 351: 1502-1512
        • Dearnaley D.P.
        • Sydes M.R.
        • Graham J.D.
        • et al.
        Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: First results from the MRC RTO1 randomised controlled trial.
        Lancet Oncol. 2007; 8: 475-487
        • Kuban D.A.
        • Tucker S.L.
        • Dong L.
        • et al.
        Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer.
        Int J Radiat Oncol Biol Phys. 2008; 70: 67-74


      Commenting Guidelines

      To submit a comment for a journal article, please use the space above and note the following:

      • We will review submitted comments as soon as possible, striving for within two business days.
      • This forum is intended for constructive dialogue. Comments that are commercial or promotional in nature, pertain to specific medical cases, are not relevant to the article for which they have been submitted, or are otherwise inappropriate will not be posted.
      • We require that commenters identify themselves with names and affiliations.
      • Comments must be in compliance with our Terms & Conditions.
      • Comments are not peer-reviewed.