PCa Commentary
 

Adjuvant Androgen Suppression Following Radiotherapy: How Long?

There is no current consensus as to the optimal duration of androgen suppression (AS) for patients at risk for recurrence following primary radiotherapy, and consensus as to who should be treated is evolving. However, clinicians regularly must address this management issue despite lacking guidance from the perfect clinical trial. A case study highlights this question:

Mr. X, now 75, experienced an unimpressive gradual rise of his PSA value from 2.9 ng/mL in 1992 to 4.4 in August 2003 at which time his DRE showed firmness on the right (cT2b,‘97). A 6 core biopsy found four right sided cores positive for adenocarcinoma . The Gleason scores were 4 + 5, 4 + 3, 3 + 4, and 3 + 3. Radiotherapy to 74 Gy was given to the prostate and seminal vesicles. Lupron was commenced prior to radiotherapy (along with a short course of Casodex) and has been continued for one year. The current PSA is < 0.1 ng/mL. His question to his radiotherapist is “Is there an advantage to continuing androgen suppression longer, and, if so, for how long?”

Mr. X is at substantial risk for recurrence. The Partin tables and the Kattan nomogram, respectively, give estimates for organ confinement of 28% and 14%; for extracapsular extension, 58% and 46%; for seminal vesicle involvement, 8% and 24%; and for metastases to lymph nodes, 6% and 16%. He has a substantial likelihood of having pT3 prostate cancer.

Multiple trials have compared radiotherapy alone (or with 4 months AS) to XRT with immediate, adjuvant AS delivered for 3 years, or indefinitely. This man’s case fits - never exactly - into subsets of most of these trials.

D’Amico’s recent JAMA report (Aug.18,2004) of a trial of 6 months of AS with XRT versus no AS for men with clinically localized prostate cancer showed an overall survival benefit at five years for XRT + AS of 88% versus 78%. Androgen suppression was given on relapse in both arms and at five years follow-up freedom from the institution of this salvage AS was seen in 82% of treated men versus 57% who initially received no AS. The study categorized the 206 participants into four disparate groups encompassing intermediate- and high-risk men. Mr. X fits into the study as a member of group 2, ie those men having a Gleason score of > 7.

RTOG trial 92-02 (JCO 2003, Nov) studied men with cT2c-T4 disease with PSA values < 150 ng/mL and compared XRT delivered to the prostate and lymph nodes: one group receiving AS for 4 months with XRT, and a second in which an additional 24 months of AS were given. Taken as a whole this study population had more aggressive disease than Mr.X. However, a relevant subset analysis showed a survival advantage at five years for men with Gleason scores of 8 to 10: 81% versus 70.7%, P = .044.

Roach et al (Red Journal, June 2000) authored “Predicting long-term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials”. The several studies compared XRT combined with short-term AS to long-term AS. The analysis was categorized into four prognostic risk groups, one of which matched Mr. X, ie (group 3): men with T1-2NX and Gleason scores 8 - 10. Group 3, combined with a higher stage group 4, experienced a 20% higher survival at 8 years. One of these studies, 85-31, had compared immediate, indefinite AS to androgen ablation at relapse in cT1-T2 N1 or cT3 non-metastatic disease. The update (Pileich, [Abstract 381A] ASCO 2003,22) “at 7.3-year mean follow-up demonstrated significant improvement in overall survival, with estimated 10-year survival rates being 53% and 38% in the immediate and deferred treatment groups, respectively.” (Messing, reference, see below)

Horwitz et al (Red Journal, Mar. 2001) authored “Subset analysis of RTOG 85-31 and 86-10 indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced non-metastatic prostate cancer treated with radiation therapy.” Statistically significant improvements were found in biochemical disease free survival and freedom from distant metastases for men on long-term AS.

It is usually difficult to find relevant clinical trials that include participants having exactly the characteristics of a single patient of clinical interest, such as Mr.X. However, the trend in these quoted studies and others favor adding long-term AS to primary XRT in cases such as Mr. X as a means of achieving longer freedom from biochemical relapse and longer freedom from distant metastases. These benefits may easily be regarded as clinically desirable even if a survival benefit was not significantly demonstrated in some studies.

he critical issue really is at what price in terms of unwanted “side effects” are these benefits obtained? If an effective and congenial means of long-term androgen suppression were available, the question of duration of treatment may become mute. After all, in the prostate’s sister endocrine disease, breast cancer, oncologists have been prescribing Tamoxifen, a medication with a very acceptable side effect profile, for over twenty years to women with estrogen receptor positive disease encompassing a wide spectrum of risk of recurrence. Treatment has resulted in a substantial control of disease progression and a modest survival advantage.

[An excellent review article: “Early Versus Late Hormonal Therapy for Prostate Cancer”, by Miamoto and Messing, in Current Urology Reports 2004, 5:188-186]

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