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Treatment of Biochemical Recurrence After Prostatectomy: A Step Forward

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Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without antiandrogen therapy in recurrent prostate cancer. N Engl J Med 2017;376:417–28.

 
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Study Overview

Objective. To evaluate the impact on overall survival of adding antiandrogen (bicalutamide) therapy to radiation in patients with prostate cancer who have an elevated prostate-specific antigen (PSA) after radical prostatectomy (either as persistence or as a relapse) and no evidence of metastatic disease.

Design. Phase III, randomized, double-blind, placebo-controlled trial.

Setting and participants. The trial was designed by NRG Oncology (Philadelphia, PA), sponsored by the National Cancer Institute, and conducted at NRG Oncology member sites, which included community-based hospitals. Eligible patients had undergone radical prostatectomy and had disease that was originally assessed, on the basis of pathological testing, as tumor stage T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension of tumor beyond the prostatic capsule) without nodal involvement. Patients also had to have a detectable PSA level between 0.2 and 4.0 ng/mL at least 8 weeks after surgery. All the patients underwent abdominal and pelvic computed tomography (CT) and bone scans to rule out metastatic disease. Patients who received prior chemotherapy or radiation therapy for prostate cancer were excluded. Most patients had not received prior hormonal therapy for prostate cancer.

Intervention. All eligible patients received salvage radiation therapy within 12 weeks after randomization. Radiation was directed to the original prostatic site, the tumor resection bed, and the membranous urethra at a total dose of 64.8 Gy given in 36 daily fractions. In addition to the radiation therapy, patients were randomly assigned to receive either 150 mg of bicalutamide or 1 placebo tablet daily, beginning at the initiation of radiation therapy and continuing for 24 months. Tablets were administered in a double blind fashion. Follow-up evaluations occurred every 3 months for 2 years, then every 6 months for 3 years, and then yearly. Bone and CT scans were performed either at biochemical recurrence or as indicated clinically. If metastatic disease was detected on follow up or if the serum PSA level rose to more than 4.0 ng/mL, maximum androgen blockade was recommended.

Main outcome measure. The main outcome was overall survival rate at 12 years. Secondary end points were disease-specific death, distant metastases, local disease progression, non–disease-specific death, any prostate cancer progression including a second biochemical recurrence, and adverse events.

Main results. 840 patients were randomized between March 1998 and March 2003, with 760 patients eligible for evaluation (384 patients in bicalutamide group and 376 in placebo group). Demographic and tumor-related characteristics of the 2 groups were similar. In both groups the majority of patients were white (89.6% in bicalutamide arm; 86.2 in placebo), had Karnofsky performance status score of 100% (77.1 % in bicalutamide arm; 74.5% in placebo), and had positive surgical margin (75% in bicalutamide arm; 74.7% in placebo). Median age was 65 years, and median PSA level at trial entry was 0.6 ng/mL. The median follow-up among the surviving patients was 13 years.

A total of 21 patients in the bicalutamide group and 46 patients in the placebo group died from prostate cancer. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group and 71.3% in the placebo group (hazard ratio [HR] for death 0.77 [95% confidence interval {CI} 0.59 to 0.99; P = 0.04), resulting in a 23% relative reduction in the risk of death in patients who received bicalutamide. The 12-year incidence of death from prostate cancer was 5.8% in the bicalutamide group versus 13.4% in the placebo group (HR 0.49 [95% CI 0.32 to 0.74]; P < 0.001), resulting in a 51% lower rate of death from prostate cancer in bicalutamide patients. Post hoc subgroup analyses showed that the greatest overall survival benefit was seen in subgroups of patients with more aggressive prostate cancer, such as those with high PSA level at trial entry (1.5 to 4.0 ng/mL) or Gleason score of 7. There were too few patients with Gleason scores of 8, 9, or 10 to draw meaningful conclusions about this subgroup. There appeared to be a larger benefit in patients with positive surgical margins than in those with negative surgical margins.

Adherence to radiation therapy was similar between the 2 trial groups, and addition of bicalutamide to radiation therapy did not result in an increase in adverse events associated with radiation therapy, such as cystitis, colitis, or sexual dysfunction. The rates of hot flashes and cardiovascular deaths were not significantly higher in the bicalutamide group than in the placebo group. However, gynecomastia was reported significantly more frequently in the bicalutamide group (69.7%) than in the placebo group (10.9%, P < 0.001).

Conclusion. The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidence of death from prostate cancer as compared to the addition of placebo. This benefit appeared to be without a significant cost in terms of toxicity.

 

Commentary

Prostate cancer is the second most common cancer in men worldwide, with an estimated 1,618,000 cases and 366,000 deaths in 2015 [1]. The current lifetime risk of developing prostate cancer for men living in the United States is estimated to be 1 in 6 [2]. Most prostate cancers are diagnosed in the localized stage, which is often treated with radical prostatectomy. All prostate tissue is removed during a successful radical prostatectomy. Postoperatively, detectable serum PSA is indicative of residual prostatic tissue, which presumably represents disease recurrence. This elevation in PSA after surgery in the absence of systemic metastatic disease is termed bio-chemical recurrence. The current standard of care for patients who develop biochemical recurrence is salvage radiation therapy. The prognosis for these patients is related to initial tumor characteristics—grade, volume and local stage. However, approximately 50% of the patients who are treated with salvage radiation therapy for biochemical recurrence will have further disease progression and may ultimately die from prostate cancer [3,4]. This is especially true when aggressive disease features are present. Radiation therapy combined with androgen-deprivation therapy using GnRH agonists or antiandrogen therapy (bicalutamide, flutamide) prolongs survival among some men with an intact prostate. This combination represents a rationale approach to prolong survival among men who develop non-metastatic biochemical relapse after radical prostatectomy.

The study by Shipley and colleagues reports the long-term outcomes of a randomized trial comparing salvage radiation plus 2 years of antiandrogen therapy to salvage radiation and placebo. Starting daily bicalutamide 150 mg orally with salvage radiation and continuing for 2 years was associated with a 23% improvement in overall survival and a 51% lower rate of death from prostate cancer, as compared to the placebo group. The number needed to treat (NNT) with bicalutamide to prevent one death from prostate cancer over 12 years was 20. By comparison, standard treatment of prostate cancer with surgery or radiation has an NNT of 27, which demonstrates the magnitude of the benefit of addition of antiandrogen therapy to salvage radiation. The benefit appears to be greatest in patients with poor prognostic factors such as higher Gleason scores (8 to 10), a higher PSA level at entry (0.7 to 4.0 ng/mL), or positive surgical margins. In contrast, patients with lower Gleason score or negative margins seemed to benefit less from the addition of antiandrogen therapy to salvage radiation. Two years of bicalutamide was not associated with increased incidence of radiation-related toxicities or cardiovascular death. As expected, the primary adverse effect of bicalutamide was gynecomastia, which was seen in 70% of the men treated. This adverse effect can be distressing but can be mitigated by prophylactic radiation of the breast or by the administration of tamoxifen, which were not done as preventative measures in this trial.

While the addition of bicalutamide to radiation did show a clear benefit to overall survival, questions remain about whether bicalutamide is the best drug to use. As the authors note, at present GnRH agonists such as leuprolide are considered first-line hormonal therapy with radiation for most patients with prostate cancer, and bicalutamide at the dose used in this study (150 mg) is not approved. We do not know how GnRH agonists will perform either as a single agent or in combination with antiandrogen for patients who develop biochemical relapse, as the use of GnRH agonists with radiation therapy has not been evaluated in patients who develop biochemical relapse in randomized clinical trials. Two trials exploring the use of androgen deprivation therapy with salvage radiation therapy in patients with biochemical recurrence (Radiotherapy and Androgen Deprivation in Combination After Local Surgery–Hormone Duration [RADICALS-HD] and the Groupe d’Etude des Tumeurs Uro-Génitales [GETUG]-16 trial) have finished enrollment; however, we will have to wait until the overall survival data matures before drawing any meaningful conclusions from them [5,6]. We know that patients with certain aggressive disease features based on tumor stage, grade, and volume are more likely to develop biochemical recurrence. As such, it is logical to consider evaluating the role of androgen deprivation therapy with adjuvant radiation therapy in patients who are at high risk of biochemical relapse with the goal of prolonging survival and reducing the risk of metastases. The RADICALS (Radiation Therapy and Androgen Deprivation Therapy in Treating Patients Who Have Undergone Surgery for Prostate Cancer) trial, which is evaluating the role of androgen deprivation therapy after adjuvant radiation therapy in patients who are at high risk of developing biochemical relapse, will help to address this issue.

 

Applications for Clinical Practice

Adding an antiandrogen agent (bicalutamide) to salvage radiation therapy in this randomized, double-blind, placebo-controlled trial resulted in higher rates of overall survival, disease-specific survival, and metastasis-free interval than radiation therapy alone for patients who developed biochemical relapse after radical prostatectomy for pathological T2/T3 and node-negative prostate cancer. We eagerly await the results of clinical trials evaluating the role of GnRH agonists in combination with salvage radiation therapy in patients in this setting. Given the long natural history of prostate cancer and the relatively low event rate, such studies can take over a decade to show differences in overall survival. Thus, until such data is available, 24 months of bicalutamide in combination with salvage radiation should be considered the new standard of care for patients (especially those at high risk) who develop non-metastatic biochemical relapse after prostatectomy.

—Devalkumar Rajyaguru, MD, and Lori Rosenstein, MD,
Gundersen Health System, La Crosse, WI

References

1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol 2016 Dec 3.

2. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212–36.

3. Trock BJ, Han M, Freedland SJ, et al. Prostate cancer–specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 2008;299:2760–9.

4. Stephenson AJ, Scardino PT, Kattan WW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035–41.

5. Parker C, Clarke N, Logue J, et al. RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery). Clin Oncol (R Coll Radiol) 2007;19:167–71.

6. Carrie C, Hasbini A, De Laroche G, et al. Interest of short hormonotherapy associated with radiotherapy as salvage treatment for biological relapse after radical prostatectomy: results of the GETUG-AFU 16 phase III randomized trial. J Clin Oncol 2015;33:Suppl:5006 [abstract].

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