Ageism in the undertreatment of high-risk prostate cancer: how long will clinical practice patterns resist the weight of evidence?

Abstract

Age discrimination is defined as “the denial of privilege or other unfair treatment based on the age of the person who is discriminated against,” and is a topic that has been studied at length in the field of oncology. For instance, despite obtaining similar survival benefit as younger patients, elderly patients are less likely to receive either surgery or radiation therapy (RT) for oropharyngeal squamous cell carcinoma. With rectal cancer, patients older than age 65 are less likely to receive preoperative radiotherapy, which has been demonstrated to reduce local recurrence rates and is widely considered as the standard of care for intermediate and locally advanced disease. Alarmingly, age-based discrimination is especially prevalent in men with high-risk prostate cancer; some have noted that for men older than 75 years of age with high-risk prostate cancer, 67% received primary androgendeprivation therapy (ADT) or no therapy at all, and only 33% received any local therapy. With recent guidelines recommending against prostate-specific antigen screening and increased attention given to the role of active surveillance for low-risk prostate cancer, it is easy to lose sight of the fact that prostate cancer is a leading cause of cancer mortality in men, second only to lung cancer. Ultimately, the majority of men diagnosed with locally advanced or high-risk prostate cancer will succumb to their disease within 15 years with conservative treatment, regardless of their age at diagnosis. Yet numerous studies have demonstrated widespread undertreatment of high-risk prostate cancer in older men, despite the observation that older men are more likely to have high-risk disease and account for approximately half of deaths as a result of prostate cancer. Furthermore, undertreatment of high-risk prostate cancer is a growing problem, with an increasing use of primary ADT monotherapy over time. Given that an average 75-year-old man in the United States has a remaining life expectancy of 11 years, and that the 10-year cause-specific mortality from conservatively treated high-risk prostate cancer is approximately 26%, this represents a serious potential for age-dependent bias against therapy. Therefore, it is important to assess the potential benefits of both ADT and RT in the treatment of high-risk prostate cancer in elderly men. Randomized controlled trials (RCTs) performed by both the EORTC (European Organisation for Research and Treatment of Cancer) and RTOG (Radiation Therapy Oncology Group) in men who were an average of 70 years of age demonstrated that the addition of long-term ADT to RT for locally advanced prostate cancer resulted in up to a 16% absolute improvement in survival at 5 years. Initially it was unclear if the survival benefit was attributable to eradication of micrometastases with systemic therapy or to ablation of local disease that could later serve as a reservoir for metastasis. In findings from two subsequent RCTs (also in men with an average age of 70 years), adding RT to ADT demonstrated that improved local control with externalbeam RT contributed significantly to the observed survival benefits, with an absolute improvement in overall survival (OS) of 8% to 9% at 7 to 10 years. A third RCT with shorter follow-up and a smaller sample size also demonstrated improvements in clinical/biochemical progression–free survival and metastasis-free survival with the addition of RT to ADT. On the basis of these three trials, there is little question that for patients with locally advanced prostate cancer, use of ADT alone provides inadequate treatment with inferior outcomes in comparison to ADT with RT. These findings are now reflected in guidelines from the European Association of Urology, the American Urological Association, and the National Comprehensive Cancer Network, which, in essence, recommend that primary therapy with ADT alone should be considered only for patients who are not candidates for definitive therapy. How these results apply to older men who are not well represented in the prospective clinical trials is an area of critical unmet need that is in part addressed by the population-based observational study performed by Bekelman et al. Using SEER-Medicare data from patients who were treated between 1995 and 2007, the authors first restricted analysis to men similar to those enrolled onto the RCTs, focusing on men younger than 75 years of age with high-volume tumors, and their results demonstrate similar relative and absolute benefits for cause-specific and OS to those observed in the phase III trials with the addition of RT to ADT. This is an intuitive and reassuring finding: that the results observed in selected patients enrolled onto RCTs seem applicable to a similar group of men receiving care in the community. However, more importantly, the authors then extend their analysis to assess the generalizability of these findings to two groups who are not well represented in the RCTs: men with screendetected high-risk prostate cancer and elderly men older than age 75 years. Here, too, they observed substantial improvements with the addition of RT to ADT with a 50% reduction in the risk of dying as a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 7 MARCH 1 2015