Why did biochemical control not translate into a survival increase after brachy boost therapy?

The first randomized clinical trial to prove that brachy boost (BB) therapy had better oncological outcomes among high risk patients was Sathya et al. (2005). After 5 years, 36% of those high-risk patients who received the brachy boost had a PSA recurrence vs. 66% of those who received external beam radiation (EBRT) only. In an update, the authors report that overall survival was not significantly different in the two groups. This seems to call into question whether PSA recurrence is a useful surrogate endpoint for survival, or if it is, under what circumstances?

Dayes et al. provided a 14-year median update on the original study and added further comments in this "Beyond the Abstract" essay. The 104 patients in the original study who were treated between 1992 and 1997 had the following characteristics and treatments:

• Median age was 66
• 60% were high risk, 40% intermediate risk
• All had a negative pelvic lymph node dissection, negative bone scan and CT
• Brachy boost (BB) comprised 35 Gy of Ir 192 over 48 hours plus 40 Gy of EBRT in 20 fractions for a total of 75 Gy [sic].
• EBRT-only compromised 66 Gy delivered in 33 fractions using 2DRT (an outmoded external beam technology).
• None received androgen deprivation as part of their radiation therapy, nor afterwards unless PSA reached 20 ng/ml.

As of the update on the 104 patients (with only 5 lost to follow-up):

• Mortality from any cause was 67% among the BB patients, 77% among the EBRT-only patients -- not significantly different
• Prostate cancer-specific mortality was 18% among the BB patients, 23% among the EBRT-only patients - not significantly different
• Incidence of metastases was 20% among the BB patients, 28% among the EBRT-only patients - not significantly different
• Improvement in PSA control was maintained: 47% higher rate of biochemical recurrence-free survival among the BB group

There was a biopsy given 2 years after treatment to 87 of the 104 men in the original study

• In the BB group, 24% had a positive biopsy and 6% were metastatic
• In the EBRT-only group, 51% had a positive biopsy and 6% were metastatic

The authors conclude:

Despite ongoing benefit with respect to biochemical disease control, long term follow up out to 2 decades failed to demonstrate improvements in other important outcomes such as development of metastatic disease, deaths from prostate cancer and deaths from any cause. 

Increased biochemical (PSA) control usually translates into increased survival later on. That correlation is well-characterized. So why did it not in this case?

This study, with a sample size of only 104 (51 BB, 53 EBRT-only), was not large enough to detect statistically significant survival differences. We note that directionally there was an improvement in survival even though the difference wasn't big enough for 95% confidence. Also, 40% were intermediate risk patients who are slower to have detectable metastases and are more likely to die of other causes. By contrast, the ASCENDE-RT trial of LDR brachy boost therapy recruited 398 men, 30% were intermediate risk, and may eventually be able to demonstrate overall survival differences with longer follow-up.

We have to acknowledge that the doses delivered in this study were below what is now considered curative, and the findings here are to a large extent irrelevant. I am at a loss to explain how a hot iridium implant could be left in a patient for 48 hrs without doing serious damage or cooking the prostate to a crisp.  Perhaps they used cooler implants back then.  I can only trust that Dr. Sathya is correct in not making a correction for the lack of fractionation, which would be typical. It seems the BB dose was sub-optimal as demonstrated by the fact that in a quarter of men, the cancer was left alive in the prostate. EBRT-only was worse - leaving cancer alive in the prostates of twice as many men. Although they dissected some pelvic lymph nodes that they could find, we now know that even with improved modern lymph node detection methods, we miss 44% of positive lymph nodes (see this link). The 6% who were metastatic might have been caught with some of our new PET scans. So, in both groups, there was a lot of cancer left behind. Many high-risk radiation patients today would have had whole-pelvic radiation and would have had hormone therapy for up to two years. This highlights the importance of expanding the treated area, using escalated doses, and adding systemic therapy when the probability is high that the cancer might have escaped the prostate.

Even though BB wasn't curative for many high risk patients, it is disappointing that death was not delayed by reducing the tumor burden. There are several clinical trials of treating the prostate (with surgery or radiation) even after metastases have been detected, thereby hoping to prolong survival by reducing the load of cancer cells. Metastasis-directed radiation is sometimes given in this hope as well. Both of those therapies decrease PSA, at least temporarily. But only treating PSA serves no purpose if that is the only outcome. If this study is any indication, the cancer will catch up and replace the killed cells with no net survival benefit. I hope that is not the case.

How anticipating regret and quick decisions can lead to poor decision making

An essay in the New England Journal of Medicine describes the cognitive components of regret. They opine that regret always involves self-recrimination and not just disappointment over poorer than expected outcomes.

They breakdown treatment regret into different causes:

• "Process Regret" occurs when patients do not consider information about all available choices before making a decision.
• "Role Regret" arises when a patient gives in to pressure from others to change his decision.
• Active decisions can lead to more regret than passive decisions when the outcome turns out poorly.
• "Omission Bias" is the tendency to avoid active decisions, even when in our best interest.
• "Commission bias" may occur when the patient is distraught and believes that immediate decisive action is needed.
• Regret is lower when things are going poorly anyway; higher when there is a downturn of fortunes.

But there is another kind of regret that is equally counterproductive. In fact, it can lead to our making poor treatment decisions. "Anticipated regret," the fear of future self-recrimination, can cripple the patient's decision process, and ironically lead to "treatment regret" farther down the road. They offer the following advice to physicians, but I think that we as peers should heed it as well:

"We should recognize that anticipated regret can leave a patient mired in decisional conflict, unable to choose. For these patients, it is vital to bring anticipated regret to the surface by openly discussing their fears and helping them gain a clear perspective on the risks and benefits of their options in order to move forward. To mitigate the possibility of future experienced regret, we as doctors can try to reduce the emotional temperature and, when feasible, avoid having patients make their decisions while in a hot state. Except in the most urgent circumstances, physicians can set in motion a deliberate process, exploring all treatment options to avert process regret. When patients are heavily influenced by others in making a decision, we can also be alert to the possibility of role regret.

Here's their essay.

My personal belief is that regret - either of the past or anticipated - is a destructive emotion that causes distress. The best way I know to avoid it is by practicing Mindfulness to keep us in the present moment as much as possible and less in an a past that we can no longer change or a future that we cannot reliably anticipate.

I have also come to believe that no doctor ought to accept as final any prostate cancer primary treatment decision made by a low, intermediate or high risk patient within a month of receiving his diagnosis, and preferably within 3 months. The emotional temperature has too strong an effect on decision making, and time is our friend in this regard. Similarly, doctors should insist that second opinions have been acquired.

A new study by Hirasawa et al. confirms others that demonstrate that waiting 6 months or more (median 7.6 months) from biopsy to surgery among patients with localized prostate cancer (low risk to high risk) had no effect on 5 year rates of biochemical recurrence. It also had no effect on whether nerve bundles were spared, pathological upgrading or upstaging, positive margins, or positive lymph node detection. A similar study has demonstrated the same thing when the eventual treatment choice was radiation, comparing  those who waited more than 3 months with those who had treatment within 3 months,. There is no medical reason to rush this primary treatment decision.

Does Lu-177-PSMA-617 increase survival?

We have enthusiastically reported the encouraging outcomes of the early clinical trials of the radiopharmaceutical Lu-177-PSMA, most recently at this link. Based on reduction in PSA, it performs well. But medicines have no real benefit if all they do is treat PSA. We want medicines that increase survival.

Rahbar et al. reported the outcomes of 104 patients treated with Lu-177-PSMA-617 at University Hospital Muenster, Germany. All patients had metastatic castration-resistant prostate cancer (mCRPC) and had already received docetaxel and at least one of abiraterone or enzalutamide. After the first of an average of 3.5 cycles, they had the following outcomes:

• 67% of patients had some PSA decline
• 33% of patients had a PSA decline of at least 50%
• Median overall survival was 56 weeks (13 months)

The authors conclude:

177Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced mCRPC pretreated with chemotherapy, abiraterone and/or enzalutamide. 

But is this conclusion justified? It's hard to know without a prospective clinical trial where patients are randomized to receive the radiopharmaceutical or standard-of-care. The best we can do is look at the overall survival from clinical trials involving patients with symptomatic mCRPC. In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link), overall survival was:

• 14 months with Xofigo
• 11 months with placebo

The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival. There have been a couple of small trials of "third-line" medicines after docetaxel and abiraterone were used.

In a non-randomized trial among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

• 9 months with cabazitaxel

In a Danish study among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:

• 5 months with enzalutamide

So these data suggest that Lu-177-PSMA-617 may have prolonged life more than third-line treatment with another taxane or another hormonal agent. However, we expect much cross-resistance between abiraterone and enzalutamide, and resistance building up with prolonged use of taxanes. It is always hazardous to compare patient outcomes or declare success when they have not been randomized. Certainly there is enough suggestive data to warrant a Phase 3 randomized clinical trial.