International Journal of

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Oncology ScandRising Stars, Fading Stars, and Shooting Stars: New Trends in Prostate Cancer Management By Danny Y. Song, MD, Associate Editor In this edition of Oncology Scan, Associate Editor Danny Song reviews 3 very provocative papers affecting the management of prostate cancer at different points along its evolution. The first report, by Thompson et al (1), looks at finasteride, the “fading star” of prostate cancer prevention; the second report investigates hypofractionation, the “current passion” of radiation oncologists for treatment of localized disease; and the third paper looks at radium-223 (223Ra), the “rising star” in skeletal metastatic disease. These practice-defining papers are testament to the numerous, high-quality, clinical research initiatives currently underway in this disease.

Thompson et al. Long-term survival of participants in the Prostate Cancer Prevention Trial. N Engl J Med 2013. (1) Summary: In the Prostate Cancer Prevention Trial (1), 18,880 eligible men age 55 years with normal digital rectal examination findings and prostate-specific antigen (PSA) concentration of 3.0 ng/mL underwent randomization to receive either finasteride (a 5a-reductase inhibitor) or placebo for 7 years. Annual digital rectal examinations and PSA testing were performed, and biopsies were done if rectal examination findings became abnormal or PSA (adjusted for effect of finasteride) exceeded 4.0 ng/mL. Participants whose conditions were not diagnosed as prostate cancer during the course of the 7 years were offered an end-of-study biopsy. The median age of participants at the time of randomization was 63.2 years. Enrollment was completed in May 1997, and data collection and prostate cancer assessments continued until June 2004, providing up to 10 years of observation for most of the participants. Following prior analysis of the effect on prostate cancer prevention, a long-term follow-up study was performed to evaluate differences in mortality among patients who had a diagnosis of prostate cancer. The Social Security Death Index (SSDI) was used to enhance survival data; as a result, causespecific mortality could not be calculated, as SSDI does not include cause of death. Among all participants enrolled, prostate cancer was diagnosed in 10.5% of patients in the finasteride group, compared with 14.9% in the placebo group. The 15-year survival rate was 78.0% in the finasteride group and 78.2% in the placebo group, with an unadjusted hazard ratio for death of 1.02 (95% confidence interval [CI], 0.97-1.08). Among men in whom Int J Radiation Oncol Biol Phys, Vol. 89, No. 1, pp. 4e6, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.01.039

prostate cancer had been diagnosed, the hazard ratio for death in the finasteride group was 1.01 (95% CI, 0.85-1.20) and remained nonsignificant after adjustment for cancer grade, age, race, and family history of prostate cancer. When classified according to grade, the 10-year survival rates were 83.0% in the finasteride group and 80.9% in the placebo group among those with lowgrade cancers and 73.0% and 73.6%, respectively, among those with high-grade cancer (defined as Gleason score 7-10). There were no between-group differences (finasteride vs placebo) in the risk of death from high-grade prostate cancer; this remained true when considering only Gleason score 8 to 10 cancers (2). Comment: Prior results from this study showed a 24.8% relative reduction in the risk of prostate cancer diagnosis by the use of finasteride, but this was entirely due to a reduction in the risk of low-grade cancers. Of concern was an observed 26.9% relative increase in the risk of high-grade cancers in the finasteride group. Although subsequent analyses suggested this increase was observed because finasteride improved the sensitivity of PSA testing and biopsy for the detection of high-grade disease (3), the US Food and Drug Administration mandated that the labels of 5a-reductase inhibitors be revised to state that the drugs might increase the risk of high-grade prostate cancer and were not approved for prevention of prostate cancer. Concern regarding the potential for increased lethality of high-grade cancer among men receiving finasteride prompted the current analysis. The investigators acknowledge that the wide confidence interval for the hazard ratio meant that within the placebo group, neither a decreased risk of death up to 30% nor an increased risk up to 27% could be ruled out. As discussed in a previous Oncology Scan (4), analyses limited to survival effects of screening and, in this case, prevention, do not take into account the morbidity, quality of life, and cost considerations for patients developing metastatic disease, a consideration for which this study does not provide additional guidance. However, it now appears unlikely that finasteride will find a role as a routine preventive measure for prostate cancer. Pollack et al. Randomized trial of hypofractionated external-beam radiation therapy for prostate cancer. J Clin Oncol 2013. (5) Summary: Investigators at Fox Chase Cancer Center performed a phase 3 trial comparing 76 Gy in 2.0 Gy per fraction with

Volume 89  Number 1  2014 a hypofractionated regimen of 70.2 Gy in 26 fractions at 2.7 Gy per fraction (5). Their hypothesis was that if the a/b ratio for prostate cancer is 1.5 Gy, then the hypofractionated regimen would be equivalent to 84.4 Gy in 2.0-Gy fractions, resulting in a 15% reduction in biochemical and/or clinical failure. Normal tissues in the hypofractionated arm would receive the equivalent of 77.2 Gy in 2.0-Gy fractions, assuming an a/b ratio of 5.0 Gy. Intermediate- and high-risk patients were enrolled, with androgen deprivation therapy given for 2 years to the high-risk patients and for 4 months to most of the intermediate-risk patients. Intensity modulated treatment and ultrasonography-based image guidance were used, with slightly more generous planning target volume margins for the conventional arm (8 mm, 5 mm posteriorly) than for the hypofractionated arm (7 mm, except 3 mm posteriorly); the pelvic lymph nodes were treated in patients with high-risk disease. The median follow-up was 68.4 months, with 303 assessable patients. At 5 years, there were no differences in biochemical and/or clinical failure between the 2 arms, with 21.4% for conventional and 23.3% for hypofractionated patients. Both late gastrointestinal and genitourinary (GU) toxicity rates were not significantly different between treatment arms overall, but an unplanned subset analysis revealed that patients in the hypofractionated arm with pretreatment International Prostate Symptom Scale (IPSS) scores >12 had increased rates of grade 2 late GU toxicity compared with those with IPSS scores 12 (PZ.001). Comment: Hypofractionation has been a topic of great interest within the GU radiation oncology community ever since a relatively low a/b ratio for prostate cancer was suggested (6, 7). Given the design of the trial, one cannot determine whether the lack of improvement in efficacy in the hypofractionated arm was due to an inaccurate estimation of the a/b ratio or a lack of benefit to delivering doses beyond the w76 Gy range for patients with intermediate- and high-risk disease. This is one of a handful of published phase 3 randomized studies comparing hypofractionated with conventional treatment regimens. A randomized trial from Australia by Yeoh et al (8) showed improved freedom from biochemical failure by using a hypofractionated regimen in patients with T1 to T2 cancers. Another trial by Arcangeli et al (9) compared the effects of 62 Gy in 20 fractions to those of 80 Gy in 40 fractions for high-risk patients, with a study design assuming equivalent disease control within the 2 fractionation arms. Although an early analysis showed improvement in biochemical control with hypofractionation, with further follow-up this difference was no longer statistically significant. A third notable study, by Lukka et al (10) (Ontario Clinical Oncology Group), found increased biochemical failure rates with hypofractionation, but the authors noted that the biologically effective dose in the hypofractionated arm was comparatively inferior if the a/b ratio for prostate cancer was >0.85. In the Fox Chase study (5), the secondary finding of increased GU toxicity in patients with baseline IPSS scores >12 deserves confirmation in other studies and underscores the fact that not only is the a/b ratio for prostate cancer still not certain but that tolerances of normal tissues to hypofractionation also remain unclear. The results of a large noninferiority study performed by the Radiation Therapy Oncology Group (0415), as well as more mature results from both the Ontario Clinical Oncology Group and the UK Institute of Cancer Research (11), will hopefully shed further light on these issues.

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Parker et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013. (12) Summary: 223Ra is an alpha emitter that selectively targets bone metastases due to its chemical similarity to calcium (12). In the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study, men with metastatic castration-resistant prostate cancer (mCRPC) involving bone (without visceral involvement) were randomized in a 2:1 ratio to receive either 223 Ra or placebo, with all patients receiving best standard of care, including external beam radiation therapy as needed to localized sites of disease. 223Ra was administered intravenously every 4 weeks, at a dose of 50 kBq/kg of body weight, for a total of 6 injections. The primary endpoint was overall survival. The study was stopped after a planned interim analysis involving 809 of 921 enrolled patients showed a statistically significant improvement in survival for the 223Ra arm compared to patients in the placebo group. The final analysis confirmed a median survival improvement of 14.9 months versus 11.3 months (hazard ratio, 0.70, P

Oncology scan-rising stars, fading stars, and shooting stars: new trends in prostate cancer management.

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