Ageism in Prostate Cancer Treatment

We’ve all heard the age-related treatment recommendations of doctors. Comments like:

• “I don’t recommend surgery for patients over 70.”
• “Active surveillance is only for older men.”
• “Radiation is only for older men.”
• “After a certain age, there’s no point in doing anything beyond hormone treatment.”
• “There’s no need to test PSA or perform digital rectal exams on men over 70.”

Some such statements have some evidence behind them, some are historical relics, and some are neither. In fact, there is a distinct lack of evidence about prostate cancer treatments in older men.

Radical treatment for low-risk disease remains controversial at any age. However, the question remains: can treatment of high risk or locally advanced prostate cancer provide a survival benefit in the elderly?

In an editorial in the Journal of Clinical Oncology titled “Ageism in the treatment of high-risk prostate cancer: how long will clinical practice patterns resist the weight of evidence?” Shumway and Hamstra made the following points:

• Two-thirds of high-risk patients over 75 years of age receive only primary androgen deprivation therapy (ADT) or no treatment at all, and that has been increasing over time.
• Older men are more likely to be diagnosed with high-risk disease, and account for half of all prostate cancer-specific deaths.
• The average life expectancy of a 75-year-old US man is 11 years, and the 10-year cause-specific survival of high-risk men conservatively treated (i.e., without radical treatment) is 74%, so many doctors are hesitant to treat. The patient is more likely to die with the cancer than of the cancer.

On the other end of the risk spectrum, older men with low-risk disease are often over-treated. Daskivich et al. found that men with low- or intermediate-risk disease and co-morbidities that lowered life expectancy to under 10 years were often aggressively treated, yet there was no survival benefit to such treatment. Indeed, the survival benefit to immediate radical treatment of low-risk men of any age has been called into question by the PIVOT study.

Kowdley et al. argued that it is not chronological age, but physiological age that should be assessed in making a cancer surgery treatment decision. They further argue that it is overall health status, rather than age that must be assessed in the screening decisions. This runs counter to the AUA recommendation on prostate cancer screening, which argues against screening men over 70 years of age.

Surgery vs. Expectant Management in Older Men

A Japanese study last year by Mitsuzuka et al. looked at 333 matched pairs of men treated with prostatectomy. In each pair, one was older than 70 years of age, one was younger. They were matched on pre-operative factors (i.e., PSA, positive cores, Gleason score, clinical stage, and risk group). They turned out to be very similar on post-operative pathology as well (i.e., stage, Gleason score, positive margins, and lymph node invasion). The older group had higher cancer volume, however.

After 5 years of follow up, the biochemical recurrence-free survival was not significantly different between the younger men and the older men, 83% and 80%, respectively. Five-year

prostate cancer-specific survival and overall survival were similar as well.

It should be noted that a similar matched pair analysis from Cleveland Clinic by found that biochemical recurrence-free survival was 85% lower in the older cohort. Neither study reported on adverse events associated with radical surgery in the elderly.

A randomized clinical trial of prostatectomy compared to watchful waiting, the PIVOT trial, did not find a statistically significant survival difference in the older cohort. After 12 years of follow up, 8% of men aged 65 years and over who were only watched died of prostate cancer compared to 6% who had surgery. The difference was not statistically significant. Among men under 65 who were only watched, 9% died of prostate cancer, compared to 5% among those surgically treated. The difference between younger and older men was again not statistically significant. The difference may be clinically significant for high-risk older men, but the PIVOT trial was underpowered for that subgroup, so no determination can be made.

Another randomized clinical trial of prostatectomy or watchful waiting in Scandinavia with 18 years of follow up, SPGC-4, found no survival benefit to surgery among prostate cancer patients 65 years of age or older; however, there was a significant reduction in the risk of metastases with surgery. A Swedish study, Nilsson et al., found that age at the time of surgery predicted long-term urinary incontinence with a relative increase of 6% per year. Age at time of surgery also affects expected erectile function, according to Alemozaffar et al.

Liu et al. at Johns Hopkins used a Monte Carlo technique to simulate outcomes from active surveillance vs. surgery by age. They found that active surveillance had a net benefit in terms of quality-of-life years for low-risk prostate cancer patients older than 74 in excellent health, older than 67 in average health, and older than 54 in poor health. Yet, in 2009, twice as many men over 70 years of age had a radical prostatectomy compared to expectant management(26% and 13%, respectively) according to figures quoted by Maurice et al.

In the absence of data from larger randomized clinical trials, and the known risks of surgery in the elderly, such decisions much be approached carefully, especially among those with significant co-morbidities. NCCN recommends against surgery in low- or intermediate-risk men with life expectancy under 10 years.

Palliative Radiation/Conservative Treatment in the Elderly

The use of palliative radiation in elderly cancer patients has been decreasing over the years. In addition, its use decreases steadily by age, raising questions about under-treatment of the elderly. The following data were found by Wong et al. in the SEER/Medicare database:

Many kinds of conservative treatment for prostate cancer, i.e., treatment without curative intent, also seem to be under-utilized among the elderly. Conservative treatments may include ADT, chemotherapy, spinal surgery, and palliative radiation to metastases.

Echoing the findings of Wong et al. in all cancer patients, Lu-Yao et al. analyzed the SEER/Medicare database and found that only 7% of high-grade prostate cancer patients over 75 years of age received palliative treatment beyond ADT, compared to 21% of high-grade patients between 66 and 74 years of age.

Radiation Plus Hormone Therapy in High Risk/Locally Advanced Older Men

Bekelman et al. published the results of a set of analytic studies designed to determine whether the combination of androgen deprivation therapy (ADT) and radiation therapy (RT) confers a survival benefit in older men with high risk or locally advanced prostate cancer over treatment with ADT alone. While two randomized clinical trials (RCTs) – NCIC CTG and SPGC-7 – have proven a survival benefit to the combined treatment in the age groups they studied, older men were under-represented in those studies. In spite of that convincing evidence, 40% of high-risk, elderly men are treated with ADT alone. Lacking evidence from RCTs, Bekelman et al. mined the SEER/Medicare databases to see if any convincing evidence could be gleaned from them. They looked at three cohorts:

•  The “RCT cohort” was matched as closely as possible to the two available RCTs on this subject. These men were:

o   65 to 75 years of age, and

o   Stage T2 (organ confined) and Gleason score 5 to 7 or Gleason score 8 to 10, or

o   Stage T3 and any grade

o   4,642 were treated with ADT alone; 8,282 with ADT + RT

• The “Elderly cohort” was defined as:

o   76 to 85 years of age, and

o   Stage T2 (organ confined) and Gleason score 5 to 7 or Gleason score 8 to 10, or

o   Stage T3 and any grade

o   8,694 were treated with ADT alone; 5,546 with ADT + RT

• The “Screen-detected cohort” was defined as:

o   65 to 85 years of age, and

o   Screen-detected, stage T1c and Gleason score 8 to 10

o   2,017 were treated with ADT alone; 2,260 with ADT + RT

·      Other variables collected were: co-morbidities, race, ethnicity, marital status, census tract median income, and the size of their urban area.

(Note: The RCT and Elderly cohorts include some men who were not high risk because of database limitations.)

Their findings are summarized below:

Compared to the younger men in the two RCTs, older men had about the same or greater reduction in prostate cancer-specific mortality and in all-cause mortality when they were treated with RT in addition to ADT.

Dr. Bekelman added the following comment:

“I generally think that doctors and patients should discuss the individual treatment decisions that older men face, including the evidence showing the benefits and risks of treatment.  For older men with prostate cancer, radiation therapy is well tolerated. There are risk factors that might increase risks of urinary or bowel toxicity, like prior history of transurethral resection of the prostate or inflammatory bowel disease, but these co-morbidities are independent of age. Age alone should not preclude patients and their physicians from considering curative cancer treatment.”

Conclusions

Taking these studies together, some generalizations can be made:

• Older men are generally under-represented in clinical trials for prostate cancer treatments.
• Older men who are low risk are generally over-treated, while those whose prostate cancer is high risk, locally advanced, or metastatic are generally under-treated.

As the baby-boom generation in the US ages, it will become particularly important to address these concerns. It behooves patients, their families, and their doctors to consider each case individually, and not make decisions based on chronological age alone.

Note: Thanks to Dr. Bekelman for allowing me to see the full text of his study, and for supplying important summary comments.