Testosterone Replacement Therapy (TRT) after Radiation Therapy

Many urologists these days are fairly comfortable prescribing testosterone replacement therapy (TRT) for men who have had a radical prostatectomy and whose PSA has stayed at undetectable levels for some time. However, considerations may be somewhat different after radiation therapy.

Pastuszak et al. looked at the records of 98 men (median age 70) who were treated at 4 institutions with TRT after primary radiation therapy (brachytherapy or external beam). After a median follow up of 41 months, they found:

• ·      Testosterone increased from 209 ng/dl to 420 ng/dl
• ·      Median PSA was 0.08 ng/ml at baseline, and 0.09 ng/ml at end of follow-up (p=0.05)
• ·      PSA of high-risk patients increased from 0.10 ng/ml to 0.36 ng/ml (p=0.02)
• ·      Biochemical recurrence was found in 6.1 percent.

The authors note in an accompanying article that the biochemical recurrence rate was actually lower than expected based on historical data of men not given TRT after radiation therapy.

While it seems safe to give TRT after radiation, the authors caution:

“Nevertheless, the safety of testosterone therapy in the setting of prostate cancer can only be truly demonstrated in the setting of a prospective, controlled trial, an effort that, to date, has been limited by difficulties with patient accrual. Until such a study is available, the burden remains on the physician to judiciously select men for testosterone therapy, and perhaps more importantly, to regularly monitor them with appropriate testing and examination.”

It is important to also note that the men selected for TRT in this study had a very low PSA at baseline, which is an appropriate selection criterion. An issue that can arise with TRT after radiation is that the testosterone might aggravate some incipient BPH that might cause PSA to rise even though the cancer is eradicated. In that case, monitoring PSA as an indicator of biochemical failure can become problematic.

Some studies have noted that for reasons that remain poorly understood, natural testosterone production may be depressed temporarily after radiation (Pickles et al.) It may be a better strategy to wait for a natural rebound in serum testosterone than to supplement immediately. Supplementing will stop the natural production of testosterone by the testes, and it may sometimes cease permanently as a result.

The other interesting issue raised by the lower than expected recurrence rate found by this study is the hypothesis that normal levels of testosterone are required to keep healthy prostate tissue healthy. Clinical trials are in place to test this hypothesis.

The optimal brachytherapy ADT pre-treatment for intermediate risk patients depends on whether they are “favorable” or “unfavorable.”

Anthony D’Amico has been advocating breaking up the intermediate risk category into “favorable” and “unfavorable,” and now offers yet another circumstance where the optimal treatment is different for each of the two groups, this time with brachytherapy.

First, let’s get clear about his definitions. He starts with the current NCCN definition of intermediate risk:

• Clinical stage T2b or T2c, or
• A PSA level of 10 to 20 ng/ml, or
• A Gleason score of 7

(If multiple risk factors are present in a specific patient, the clinician may optionally deem such a patient to be high risk.)

D’Amico advocates for the intermediate-risk sub-grouping proposed last year by Zumsteg et al. (from the Memorial Sloan-Kettering Cancer Center):

Favorable Intermediate Risk:

• NCCN intermediate risk, as defined above, but only those with
• Predominant Gleason grade 3 (i.e., Gleason score 3 + 4 = 7), and
• Percentage of positive biopsy cores < 50%, and
• No more than one NCCN intermediate risk factor

Unfavorable Intermediate Risk:

• NCCN intermediate risk, as defined above, plus
• Predominant Gleason grade 4 (i.e., Gleason score 4 + 3 = 7), or
• Percentage of positive biopsy cores ≥ 50%, or
• Multiple NCCN intermediate risk factors

Keane et al. did a retrospective study using the dataset at Harvard of intermediate risk men treated with brachytherapy between 1997 and 2013. In that cohort, 1,902 fell into the “favorable intermediate risk” category, and 608 fell into the “unfavorable intermediate risk” category. After a median 7.8 years of follow-up, there 29 deaths attributable to prostate cancer. They found that:

·      Among “favorable intermediate risk” patients, there was no significant difference in prostate cancer mortality due to using ADT before brachytherapy vs, brachytherapy alone.

·      Among “unfavorable intermediate risk” patients, there was a significant decrease in prostate cancer mortality if they were pre-treated with ADT rather than if there was a combination therapy with external beam radiation (adjusted hazard ratio=0.34)

The authors conclude:

“Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men.”

There are a few of important caveats:

·      This was a retrospective database analysis and not a randomized clinical trial, so the conclusions must be taken as provisional. This analysis is especially prone to selection bias: patients were chosen for their treatment based on an assessment of its probability of success.

·      There were only 29 deaths from prostate cancer in the follow-up period, so it is difficult to project what might have happened as the patients were tracked longer.

·      This study did not include a subgroup treated with all three therapies – early ADT and external beam RT and a brachytherapy boost. We saw in the ASCENDE-RT trial that that triple combination was very potent.

In spite of those caveats, there is nevertheless evidence of something very interesting happening here – the two subgroups that we had previously been treating equivalently respond, in fact, to very different treatment protocols.

We have seen in earlier studies (Castle et al. and Edelman et al.) that ADT confers no benefit when added to external beam radiation treatment unless the Gleason score is at least 4+3 or there is a large volume of cancer. This study provides evidence that that is also true for brachytherapy.

Unfavorable intermediate risk prostate cancer, on the other hand, seems to respond very well to the addition of ADT to brachytherapy. There is a randomized clinical trial (RTOG 0815) designed to determine if there is a benefit to adding ADT to dose-escalated external beam RT for intermediate risk patients as a whole, and sub-group analyses for unfavorable intermediate risk patients if there is a specific benefit. Zumsteg et al. demonstrated a benefit in a retrospective analysis.

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.

Trends in the use of radiation for primary therapy

Two separate database analyses have now reported an increasing trend in adoption of SBRT, while brachytherapy use has been declining.

In an analysis of the National Cancer Data Base, Baker et al. reported that use of SBRT increased from <1% in 2004 (it was first used for prostate cancer in 2003) to 8.8% of low-risk patients treated at academic centers in 2012. Similarly, Halpern et al., in an analysis of the SEER/Medicare database,  found that SBRT was the fastest-growing of all radiation therapies between 2004 and 2011, but it only accounted for 1.6% of all men treated with radiation in that database. They also found that adoption was highest among low-risk patients: 54% of those using it had a Gleason score of 6. The median cost was $27,145.

Proton beam therapy use also increased. It accounted for 2.3% of all radiation therapy utilization. Half of those using it had a Gleason score of 6. It had the highest cost of all radiation therapies at $54,706.

Brachytherapy use, on the other hand, is on the decline. It accounted for 28% of all primary radiation therapies. Compared to other radiation therapies, a higher proportion of those utilizing it had a low Gleason score: 64.2% of those utilizing it had a Gleason score of 6. It was the lowest cost of all radiation therapies at a median cost of $17,183.

It is unclear how combination therapies of EBRT with a brachytherapy boost were counted in The SEER/Medicare database analysis. Orio et al. reported that in their analysis of the National Cancer Data Base, use of such combination therapy in intermediate and high-risk patients declined markedly between 2004 and 2012. They found that among intermediate and high-risk patients, 66% were treated with EBRT alone, 20% were treated with brachytherapy alone, and only 14% were treated with the combination. Use of combination therapy declined from 15% to 8% in academic centers, and from 19% to 11% in non-academic centers. We will have to see if the results of the ASCENDE-RT randomized clinical trial last year (discussed here) reverses this trend.

IMRT took the lion’s share of all radiation therapies at 68.1%. Relative to the other radiation therapies, it was most likely to be used by patients with higher Gleason scores: almost two-thirds of patients using it had Gleason scores of 7 or greater. I suspect that it continues to be the treatment of choice in older patients, who tend to have more progressed prostate cancer at the time of diagnosis. Next to proton therapy, it was most expensive, costing a median of $37,090. Hypofractionation may be able to cut the cost if it is widely adopted.

It should be noted that the high rate of utilization of brachytherapy, SBRT and proton therapy among low risk patients has historical roots. Those therapies were originally tried in low risk patients before we had results from Active Surveillance trials. While proton therapy and brachytherapy are given as boosts to IMRT, their use as monotherapies has not been established in intermediate and high-risk patients. SBRT, as both a boost and a monotherapy, is in trials for the higher risk categories, but many institutions still do not offer it for that purpose, and insurance may be reluctant to cover it.

It is sad to witness the decline in brachytherapy utilization, especially considering it is the lowest cost alternative. But that works to its detriment as well: new practitioners are not attracted to its relatively low profit potential. With the passing of Peter Grimm this year, it has lost one of its greatest proponents. The generation of brachytherapists who developed its modern techniques at the University of Washington Seattle have mostly dispersed and some have retired. It is a very specialized therapy, requiring years of practice to get superlative results. I expect we will continue to lose our best practitioners, and patients will find it increasingly difficult to find.