Phase I/II Trial Of Docetaxel And Concurrent Radiation Therapy In Localized High Risk Prostate Cancer (AGUSG 03-10)

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 31 Mar 2009 - 2:00 PDT

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UroToday.com - Although systemic chemotherapy has traditionally been reserved for metastatic prostate cancer (1,2), several investigators have reported on the potential role of incorporating systemic therapy into a multimodal treatment approach in clinically localized high risk prostate cancer (3,4,5,6).

We have previously reported on the maximally tolerated dose of weekly docetaxel when administered concurrently with 3-D conformal radiation therapy (7) . In that study, patients received intensity modulated radiation therapy (72 Gy at 1.8 Gy/fraction), and the maximally tolerated dose of weekly docetaxel was found to be 20 mg/m2.

A subsequent report focused on the phase I aspects of utilizing the maximal tolerated docetaxel dose (20 mg/m2) in 20 patients treated concurrently with intensity modulated radiation therapy (72 Gy). Results were reported at a median follow-up duration of 11.7 months (8). In that earlier report on the present cohort, the radiosensitizer docetaxel administered weekly with concurrent IMRT was well tolerated. Grade 2 diarrhea and urinary toxicity occurred in 40% and 35% of patients, respectively, and there were no grade 3 or 4 acute or late gastrointestinal or genitourinary toxicities(8). Presently, we report the oncologic outcomes utilizing weekly docetaxel at a dose of 20 mg/m2 and concurrent intensity modulated radiation therapy (72 Gy at 1.8 Gy/fraction) in men with clinically localized high risk prostate cancer at a median follow-up duration of 36 months.

Patients received weekly docetaxel with concurrent daily external beam radiotherapy to a total dose of 72 Gy at 1.8 Gy / fraction. The docetaxel dose was 20 mg/m2 administered as a continuous 30 minute intravenous infusion. External beam radiation therapy was delivered using Clinac 600CD with 6 MV photons and multileaf collimator for intensity modulated radiation therapy (IMRT). Target volume simulation was determined by CT. All acute chemoradiation toxicities were graded using the Common Toxicity Criteria of the National Cancer Institute. Late toxicity was scored using the Radiation Oncology Group / European Organization for Research and Treatment of Cancer scoring scheme.

Twenty-six men have enrolled in and completed the chemoradiation protocol since April 2003. In all patients, the prostate was treated to a total dose of 72 Gy and all patients received concurrent weekly docetaxel. Twenty-three patients received concurrent androgen deprivation therapy (ADT) as 3-month depot (median, 3 doses).

Three patients experienced treatment interruptions: dehydration requiring inpatient hydration (n=2); NSAID induced GI bleed (n=1). An additional 2 patients required outpatient hydration (<24hrs) with no treatment interruption. The most frequently experienced toxicities were grade 2 diarrhea (30%), grade 2 fatigue (38%), grade 2 urinary frequency (35%), grade 2 constipation (23%), taste aversion (15%), and rectal bleeding (12%). No significant hematologic toxicity (grade 2 to 4) was encountered among the 26 patients.

At the time of this report, the median follow-up duration is now 36 months (range, 12 to 58 months). Twenty-five (96%) of 26 patients are alive. Five (19%) of 26 patients have experienced relapse (serologic, n=4; bone, n=1). Twenty patients have serum testosterone levels in the male reference range, and 6 patients are suppressed (suppressed testosterone level range, 12 to 124 ng/dl; median 66 ng/dl). The median follow-up duration for men with normalized serum testosterone levels is 42 months (range, 23 to 58 months). Relapse among men with normalized serum testosterone levels is 25%.

At this interim analysis, our study illustrates the feasibility and early efficacy of weekly docetaxel and concurrent IMRT.

References:

1. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med, 351:1513-1520,2004

2. Tannock IF, de Wit R, Bery WR, et al: Docetaxel plus prednisone ar mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med, 351:1502-1512,2004

3. Schmidt JD, Gibbons RP, Murphy GP, et al: Adjuvant therapy for clinical localized prostate cancer treated with surgery or irradiation. Eur Urol,29:425-453,1996

4. Zelefsky MJ, Kelly WK, Scher H, et al: Results of a phase II study using estramustine phosphate and vinblastine in combination with high dose 3-D conformal radiotherapy for patients with locally advanced prostate cancer. J Clin Oncol.,18:1936-1941,2000

5. Ben-Josef E, Porter AT, Han S, et al: Neoadjuvant estramustine and etoposide followed by concurrent estramustine and definitive radiotherapy for locally advanced prostate cancer: Feasibility and preliminary results. Int J Radiat Oncol Biol Phys,49:699-703,2001

6. Khil MS, Kim JH, Bricker LJ, et al: Tumor control of locally advanced prostate cancer following combined estramustine, vinblastine, and radiation therapy. Cancer J Sci Am,3:289-296,1997

7. Kumar P, Perrotti M, Weiss R, et al: Phase I trial of weekly docetaxel and concurrent 3-D conformal radiation therapy in the treatment of unfavorable localized adenocarcinoma of the prostate. J Clin Oncol,22:1909-1915,2004

8. Perrotti M, Doyle T, Kumar P, et al: Phase I/II trial of docetaxel and concurrent radiation therapy in localized high risk prostate cancer (AGUSG 03-10). Urol Oncol,26:276-280,2008

Written by Michael Perrotti, MD,1,^, Linda Abriel, RN, ANP1, Todd Doyle, MD2, and Michael Kolodziej3, MD as part of Beyond the Abstract on UroToday.com

From the Sections of Urologic Oncology1, Radiation Oncology2 and Medical Oncology3 , Saint Peter's Cancer Care Center, and Department of Surgery^, Albany Medical College, Albany, New York, USA

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