This month’s column focuses on recent reports in the literature pertaining to prostate cancer. The studies summarized below cover such topics as the first radioisotope to show a survival benefit in men with bone metastases, the importance of an accurate biopsy reading by a pathologist who specializes in urology specimens, the inappropriate use of intensity-modulated radiotherapy by physicians who self-refer patients for radiation, overuse of imaging modalities in men with low-risk prostate cancer, and data suggesting that acute kidney injury is associated with current use of androgen deprivation therapy.
Radium-223 Improves Survival in Castration-Resistant Prostate Cancer
Radium-223 (Xofigo), a radioactive isotope, improved survival in men with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, according to results of a randomized, phase 3, double-blind, placebo-controlled pivotal trial. The study was halted early, when an interim analysis showed a clear survival benefit for radium-223. Updated results of the trial were published in the New England Journal of Medicine.
Radium-223 homes to the bone, where it emits alpha particles that cause DNA damage, sparing normal tissue. The drug has a half-life of 11.4 days, which is much shorter than other alpha-emitting isotopes. Radium-223 was approved by the US Food and Drug Administration earlier in 2013 based on this study, which is the first to show a survival benefit for an alpha-emitting isotope in CRPC.
The trial enrolled 921 participants randomized 2:1 to receive radium-223 intravenously every 4 weeks for 6 cycles or placebo in combination with the best available standard care. Best available standard care included radiotherapy, antiandrogen therapy, estrogen, estramustine, and ketoconazole; men who were taking antiandrogen therapy at baseline continued it during the trial.
Median age was 71 years; 94% were white; 87% were Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 58% had previously received docetaxel; 54% were taking opioids for pain relief; 44% were taking nonopioids for pain relief.
Overall survival (OS) was the primary end point. At the time of the interim analysis, when 314 deaths had occurred, median OS was significantly in favor of radium-223: 14 months versus 11.2 months, respectively (P = .002). An updated analysis in the New England Journal of Medicine, when 528 deaths were reported, confirmed that radium-223 achieved a significant OS benefit, with a median OS of 14.9 months for patients treated with radium-223 versus 11.3 months for the placebo group (P <.001). Patients treated with radium-223 were 30% less likely to die: 54% died versus 64% in the placebo group (P <.001).
Median time to first symptomatic skeletal event—a key secondary end point—was significantly improved with radium-223: 15.6 months versus 9.8 months, respectively (P <.001).
Adverse events, including grade 3 or 4 adverse events, serious adverse events, and drug discontinuations due to adverse events, were numerically lower in the group treated with radium-223. The most commonly reported adverse events (at least 5% frequency) with radium-223 included nausea, diarrhea, vomiting, and peripheral edema. The most common hematologic laboratory abnormalities were anemia, thrombocytopenia, and neutropenia.
In an accompanying editorial in the New England Journal of Medicine, Neha Vapiwala, MD, and Eli Glatstein, MD, University of Pennsylvania, Philadelphia, wrote that the properties of radium-223, including its half-life and safety, make it an important new anticancer weapon. They noted that it is not clear what the ultimate role of radium-223 will be; perhaps it will be combined with other agents to further improve outcomes. Additional trials combining radium-223 with other drugs, including docetaxel, are being planned.
Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
Gleason Scoring May Provide Better Management and Prognosis
The Gleason score (GS) assigned at a comprehensive cancer center allowed better biochemical failure risk stratification and prognostic information for patients treated with external-beam radiotherapy compared with the GS of the referring institution. A confirmatory second pathologic review (SPR) at a dedicated comprehensive cancer center by a pathologist who specializes in genitourinary (GU) malignancies led to a change in overall GS grouping in 13% of patients. An SPR performed at Fox Chase Cancer Center (FCCC) changed the National Comprehensive Cancer Network risk group assignment in 144 men (9%): 92 men (64%) to lower risk and 52 (36%) to higher risk.
"These changes all have the potential to alter management and prognosis. The GS assigned based on the SPR provided greater prognostication of biochemical failure risk. Patients may benefit from national standards encouraging an SPR at a comprehensive cancer center,” wrote the authors. Natasha C. Townsend, MD, of FCCC, was lead author. At present, nationwide standards do not call for an SPR at a comprehensive cancer center.
This retrospective study, published in the July 2013 issue of the Journal of the National Comprehensive Cancer Network, is the largest regarding the impact of an SPR on the GS and the only report on the impact of an SPR on the GS in patients treated with radiotherapy.
Several studies, as well as anecdotal reports, note discordance rates of up to 40% between the GS assigned by a general pathologist and the GS subsequently assigned by a GU pathology specialist. Taken together, studies to date suggest that central review by a specialist in GU pathology will provide a more accurate estimate of the GS than that assigned by general pathologists.
The retrospective study included 1649 men diagnosed with prostate cancer based on a transrectal ultrasound–guided prostate biopsy at a referring institution. Patients were treated with radiation therapy alone (no androgen deprivation therapy) between 1994 and 2007. Pathology slides of all patients diagnosed at a referring institution were reviewed at FCCC by an oncologic pathologist with special expertise in GU pathology. Follow-up comprised serial prostate-specific antigen (PSA) determinations every 6 months and annual digital rectal examinations. Biochemical failure was determined by the American Society for Radiation Oncology definition (PSA nadir plus 2 ng/mL).
Median follow-up was 64 months, and median follow-up PSA interval was 6.2 months. Median age of patients was 68 years. About 80% had stage T1/2 prostate cancer and PSA <10 ng/mL.
Overall, the GS assigned by FCCC upgraded 8% of patients and downgraded 6% of patients compared with the GS assigned by their referring institution. Among patients originally assigned to GS 6 by the referring institution, 8% were upgraded to the intermediate category (ie, GS 7). A greater impact was observed in patients originally assigned to GS 7 by the referring institution; 20% were downgraded by FCCC to GS 6 and 2% upgraded to GS 8-9. The authors note that the greatest impact of an SPR by FCCC was in the group of men originally assigned to GS 8-9: 58% were downgraded to GS 6 (12%) or GS 7 (88%).
The data show an improvement in overall prediction of biochemical failure with the GS assigned by FCCC compared with the GS assigned by the referring institution. “Overall, these data support a routine SPR, preferably at a dedicated comprehensive cancer center with a pathologist specializing in the diagnosis of prostate cancer,” the authors wrote.
Townsend NC, Ruth K, Al-Saleem T, et al. Gleason scoring at a comprehensive cancer center: what’s the difference? J Natl Compr Canc Netw. 2013;11(7):812-819.
Campaign Reduces Unnecessary Tests for Low-Risk Prostate Cancer
The rate of unnecessary cancer imaging scans for low-risk prostate cancer was drastically reduced by a joint campaign in Sweden aimed at curtailing those tests. Such tests account for a significant proportion of healthcare funds in the United States. The campaign was initiated in 2000 by the Swedish County Councils and the National Prostate Cancer Register of Sweden to reduce inappropriate diagnostic imaging in men with this cancer.
Men diagnosed with low-risk prostate cancer are unlikely to harbor metastases. Despite guidelines and quality measures from various policy organizations and professional societies that stipulate that extensive cancer scans for metastases are discouraged for these patients, many physicians continue to order these scans, said lead author Danil V. Makarov, MD, assistant professor at NYU Langone Medical Center, New York City.
The authors note that imaging is important to detect metastases in men with high-risk prostate cancer. However, most prostate cancer is diagnosed at an early stage, when it is unlikely to have spread.
The study was a collaboration between Makarov; his colleague at NYU, Stacy Loeb, MD; investigators at Memorial Sloan-Kettering Cancer Center; and Swedish investigators at Uppsala University Hospital and the Karolinska Institute. The authors examined the records of almost 100,000 Swedish men diagnosed with prostate cancer from 1998 to 2009. Imaging rates at institutions in Sweden were published and compared with best practices, giving providers an incentive not to be cited for ordering unnecessary imaging tests for low-risk prostate cancer. These data were also presented at urology meetings in Sweden.
During the study period, the percentage of inappropriate scans among patients with low-risk prostate cancer dropped from 45% at the beginning of the campaign to 3% at the end. But the rate of appropriate scans for high-risk patients also dropped from 63% to 47% over the study period.
Makarov said that it is important to emphasize the appropriate use of scans, along with the inappropriate use. He believes that the Swedish campaign demonstrates that targeted educational efforts can reduce the number of inappropriate tests. Such efforts could be implemented at urology conferences and in collaboration with the government, he suggested.
In the US, inappropriate prostate cancer imaging ranges from 22% to 62%, depending on the geographic region, according to a study published in 2012.
Makarov DV, Loeb S, Ulmert D, et al. Prostate cancer imaging trends after a nationwide effort to discourage inappropriate prostate cancer imaging. J Natl Cancer Inst. 2013;105(17):1306-1313.
Medicare Report on Costly Radiation Therapy for Prostate Cancer
Another study reveals the growing use of expensive treatment for prostate cancer. In July 2013, the Government Accountability Office (GAO) released a report, “Medicare: Higher Use of Costly Prostate Cancer Treatment by Providers Who Self-Refer Warrants Scrutiny,” requested by bipartisan leaders in Congress.
The report focused on specialty urology groups’ use of intensity-modulated radiation therapy (IMRT) from 2006 to 2010. The report showed that IMRT utilization among self-referring groups increased by 456% over the study period. IMRT utilization among non–self-referring physicians decreased by 5%, in line with national recommendations calling for judicious use of IMRT for treating prostate cancer.
The number of IMRT services performed by limited urology groups increased by 609%, while use by true multispecialty groups decreased 3.8%.
Along with these trends, IMRT spending by self-referral groups increased by approximately $138 million, compared with a $91 million decrease in non–self-referral groups.
These increases in IMRT utilization among self-referring practices were not attributable to patient preferences, age, geographic area, or patients’ health status. The report concludes that financial incentives were a major factor responsible for increased referrals for IMRT. Moreover, financial incentives were responsible for self-referral groups not ordering other appropriate but less expensive treatments, such as brachytherapy, prostatectomy, and active surveillance when appropriate.
These factors result in higher costs to Medicare and beneficiaries, and the costs when driven by providers’ financial interest are difficult to justify, states the GAO report.
Congress is currently considering a law called “Promoting Integrity in Medicare Act of 2013” that addresses the findings of the GAO to improve patient care and save billions of dollars in Medicare funds.
US Government Accountability Office. Medicare: Higher Use of Costly Prostate Cancer Treatment by Providers Who Self-Refer Warrants Scrutiny. July 2013. http://www.gao.gov/products/GAO-13-525. Accessed August 5, 2013.
Hormone Therapy and Kidney Damage
The risk of acute kidney injury was increased in men with nonmetastatic prostate cancer treated with androgen deprivation therapy (ADT), according to a retrospective analysis reported online in the Journal of the American Medical Association. Current use of ADT more than doubled the odds of acute kidney injury compared with men who did not receive ADT. The highest rate of acute kidney damage was reported with combined use of gonadotropin-releasing hormone (GnRH) agonists and antiandrogens. Effects were also seen with estrogen, other combination therapies, and GnRH monotherapy.
ADT will remain a mainstay of treatment for nonmetastatic prostate cancer, but these findings should raise concern about potential effects on the kidney. Hormonal therapy should be used judiciously to avoid potentially serious adverse events, the authors noted.
ADT is widely used to treat men with prostate cancer, but can lead to serious adverse events. For example, metabolic disturbances induced by the hypogonadal state achieved by ADT are known to increase the risk of heart disease and diabetes. Reducing testosterone to castrate levels may also affect blood vessels in the kidney and cause estrogen deficiency, leading to adverse effects on renal tubular function. This association has not been well studied previously, the authors noted.
The renal effects of ADT were analyzed in a nested case-control study of men with nonmetastatic prostate cancer. The study was based on a national hospital database that included 10,250 men followed up for a mean of 4.1 years. Of these men, 232 developed acute kidney injury at a rate of 5.5 per 1000 patient-years; 40 men (17.2%) never received ADT. Controls were 2721 patients who did not develop acute kidney injury.
Overall, current ADT use increased the likelihood of developing acute kidney injury by 2.48 compared with controls. The association was consistently elevated, with the highest odds during the first year of treatment with ADT. Past treatment with ADT did not increase the risk of acute kidney injury.
Lapi F, Azoulay L, Niazi MT, et al. Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer. JAMA. 2013;310(3):289-296.