A Significant Percentages of Older Prostate Cancer Patients are Being Overtreated

An increasing percentage of older men with intermediate-risk and high-risk prostate cancers are undergoing treatments that carry risks of side effects that can significantly reduce the health-related Quality of Life (hrQoL) without extending life.

This trend, observed by researchers at Cedars-Sinai, is problematic because these men may not have life expectancies that would allow them to receive the benefits of more aggressive treatments. Their conclusion is based on results from a study supported in part by VA Merit Review and the Department of Veterans Affairs Health Services Research and Development Service, using resources and facilities at the VA Informatics and Computing Infrastructure (VINCI).

The study outcome was published in the peer-reviewed journal JAMA Internal Medicine.[1]

Key Statistics
Prostate cancer is the second-most common cancer in the U.S., exceeded only by breast cancer. The American Cancer Society estimates that in 2024, in the United States, about 299,010 new cases of prostate cancer will be diagnosed and about 35,250 patients will die of the disease [2]*

About one-eighth of U.S. men are diagnosed with prostate cancer at a median age of 67, according to the National Cancer Institute (NCI). [3]

Most patients have low-risk, slow-growing, localized tumors confined to the prostate gland, generally defined as prostate-specific antigen (PSA) less than 10 ng/mL, and Gleason grade group 1, which is unlikely to threaten their lives. The long-term prognosis for men diagnosed with low-risk prostate cancer is excellent.  Instead of immediate treatment, these low-risk patients can be monitored through active surveillance,** in which examinations and tests are performed on a regular schedule to make sure the disease is not progressing.

Active surveillance for low-risk prostate cancer has evolved in many ways. Low-risk and many cases of low-intermediate-risk prostate cancer are indolent, have little or no metastatic potential, and do not pose a threat to the patient in his lifetime. These cancers are termed clinically insignificant. [4]

“Use of active surveillance has increased over the last 15 years for men with low-risk prostate cancer, and it is now the most common treatment for these men,” explained Timothy Daskivich, MD, director of Urologic Oncology Research for the Cedars-Sinai Department of Urology and corresponding author of the new study.

Avoiding side effects
Active surveillance is a method of monitoring select men, with the option of switching to active treatment upon signs of progression. [5]

“This approach allows these patients to avoid the risks of urinary incontinence, erectile dysfunction, and other potential side effects of surgery and radiation therapy,” Daskivich added.

According to clinical guidelines, active surveillance should be more broadly implemented for eligible patients to avoid a decrease in health-related Quality of Life (hrQoL) from undergoing active treatment.[5] These guidelines always allow a change of course and pursue curative treatment if changing circumstances require this. [6]

However, while clinical guidelines actively endorse this method as the preferred management strategy for low-risk prostate cancer, its use in contemporary clinical practice remains incompletely defined.[7]

Limited life expectancy
Conservative management, which includes active surveillance or watchful waiting, is also recommended for men with limited life expectancies who likely will not live long enough to benefit from aggressive local treatment, even for higher-risk cancers. However, for these men, the trend is going in the opposite direction, as measured by the investigators’ analysis of extensive data from the Veterans Affairs health system. They found that for men with limited life expectancies and intermediate- and high-risk cancers, conservative management was being employed less often and that more were receiving aggressive local treatment with surgery or radiation.

“We found this pattern surprising,” Daskivich noted.

“Prostate cancer patients with life expectancies of less than five or 10 years were being subjected to treatments that can take up to a decade to significantly improve their chances of surviving cancer, despite guidelines recommending against treatment,” Daskivich said.

Analysis
For their study, the investigators analyzed medical data on 243,928 men in the Veterans Affairs health system who were diagnosed with localized prostate cancer between 2000 and 2019. [1]

The researchers estimated Life Expectancy by using the validated age-adjusted Prostate Cancer Comorbidity Index (PCCI), a claims-based tool to predict mortality in men with prostate cancer, and assessed treatment trends among men with limited Life Expectancy by using a stratified linear and log-linear Poisson regression in aggregate and across PCCI and tumor risk subgroups.[8]

The mean age of the patients participating in this study was 66.8 (8.0) years.

Among patients with average Life Expectancy of less than 10 years (20.5%), the proportion who underwent treatments such as surgery or radiation for low-risk prostate cancer rather than receiving active surveillance decreased from 37.4% to 14.7% (absolute change, −22.7%; 95% CI, −30.0% to −15.4%); but treatment for the intermediate-risk disease increased from 37.6% to 59.8% (22.1%; 95% CI, 14.8%-29.4%) with increases observed for favorable (32.8%-57.8%) unfavorable intermediate-risk disease (46.1%-65.2%). Among men with an average Life Expectancy of less than 10 years who were receiving definitive therapy, the predominant treatment was radiotherapy (78%). In this group of patients, the use of radiotherapy increased from 31.3% to 44.9% (13.6%; 95% CI, 8.5%-18.7%) for intermediate-risk disease, with increases observed for favorable and unfavorable intermediate-risk disease.

Among patients with an average life expectancy of less than five years (4.7%), treatment for high-risk disease increased from 17.3% to 46.5% (29.3%; 95% CI, 21.9%-36.6%). The predominant treatment was radiotherapy (85%), which increased from 16.3% to 39.0% (22.6%; 95% CI, 16.5%-28.8%).

Overtreatment
Solving the issue of overtreatment in higher-risk prostate cancer patients with limited longevity requires a multifaceted approach involving better estimation, communication, and integration of life expectancy into decision-making.

Together with his team, Daskivich proposed a trifecta method for communicating cancer prognosis to the patient. This method involves the physician discussing the likelihood of dying from prostate cancer with treatment versus dying from the disease without treatment at the endpoint of the patient’s life expectancy.

This approach personalizes the risk of the cancer that is relevant to each patient.

“Our goal is to encourage clinicians to make longevity part of the discussion about the best treatment options so that prostate cancer patients with limited life expectancies can make educated choices,” Daskivich explained.

“A patient may be given this data and choose to pursue surgery or radiation treatments regardless of a limited probability of benefit.  Another patient may take a different course.”

“Every individual is different, and statistical averages for lifespan, treatment effectiveness and cancer risk cannot predict outcomes with certainty,” Daskivich added.

“But patients should be allowed to make informed decisions with the best possible information,” he added.

Strength in cooperation
“The JAMA Internal Medicine study reflects a signature strength of Cedars-Sinai: the close cooperation among researchers and clinicians,” noted Hyung L. Kim, MD, chair of the Department of Urology at Cedars-Sinai.

“Many of our investigators are themselves clinicians, which ensures that their research addresses real-life problems in healthcare with an emphasis on finding solutions,” Kim concluded.

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Note: * According to the American Cancer Sociey, the number of prostate cancers diagnosed each year declined sharply from 2007 to 2014, coinciding with fewer men being screened because of changes in screening recommendations. Since 2014, however, the incidence rate has increased by 3% per year overall and by about 5% per year for advanced-stage prostate cancer.[2]
** Active Surveillance is the recommended option for men with pathologic Grade Group 1 (Gleason Score 3 + 3 = 6) prostate cancer without other intermediate-risk features [6] These prostate cancers are considered indolent and are generally not associated with fatal outcomes. As a result, treatment is, in most cases, not indicated. Furthermore, these low-grade cancers have an overall negligible risk of locoregional progression and metastasis to distant organs.[9]

Reference
[1] Daskivich TJ, Luu M, Heard J, Thomas I, Leppert JT. Overtreatment of Prostate Cancer Among Men With Limited Longevity in the Active Surveillance Era. JAMA Intern Med. Published online November 11, 2024. doi:10.1001/jamainternmed.2024.5994 [Article]
[2] Key Statistics for Prostate Cancer. American Cancer Society (ACS). Online. last accessed on November 11, 2024.
[3] Age and Cancer Risk National Cancer Institute (NCI). Online. Last Accessed on November 11, 2024
[4] Klotz L. Active surveillance for low-risk prostate cancer. Curr Opin Urol. 2017 May;27(3):225-230. doi: 10.1097/MOU.0000000000000393. PMID: 28267056.
[5] Shill DK, Roobol MJ, Ehdaie B, Vickers AJ, Carlsson SV. Active surveillance for prostate cancer. Transl Androl Urol. 2021 Jun;10(6):2809-2819. doi: 10.21037/tau-20-1370. PMID: 34295763; PMCID: PMC8261451.
[6] Pekala KR, Bergengren O, Eastham JA, Carlsson SV. Active surveillance should be considered for select men with Grade Group 2 prostate cancer. BMC Urol. 2023 Sep 30;23(1):152. doi: 10.1186/s12894-023-01314-6. PMID: 37777716; PMCID: PMC10541702.
[7] Cooperberg MR, Meeks W, Fang R, Gaylis FD, Catalona WJ, Makarov DV. Time Trends and Variation in the Use of Active Surveillance for Management of Low-risk Prostate Cancer in the US. JAMA Netw Open. 2023 Mar 1;6(3):e231439. doi: 10.1001/jamanetworkopen.2023.1439. PMID: 36862409; PMCID: PMC9982696.
[8] Daskivich TJ, Thomas IC, Luu M, Shelton JB, Makarov DV, Skolarus TA, Leppert JT. External Validation of the Prostate Cancer Specific Comorbidity Index: A Claims Based Tool for the Prediction of Life Expectancy in Men with Prostate Cancer. J Urol. 2019 Sep;202(3):518-524. doi: 10.1097/JU.0000000000000287. Epub 2019 Aug 8. PMID: 31009286.
[9] Linder S, Severson TM, van der Mijn KJC, Nevedomskaya E, Siefert JC, Stelloo S, Pomerantz MM, Freedman ML, van der Poel H, Jerónimo C, Henrique R, Bergman AM, Zwart W. Grade Group 1 Prostate Cancers Exhibit Tumor-defining Androgen Receptor-driven Programs. Eur Urol. 2023 Nov;84(5):455-460. doi: 10.1016/j.eururo.2023.05.032. Epub 2023 Jun 2. PMID: 37271632.

Featured image: Getty-images-zb9UG4FLvFk-unsplash. Licensed under the Unsplash+ License.

DOI: 10.14229/onco.2024.11.11.001