Dose-escalated radiation therapy doesn’t impact survival within ten years

Zaorsky et al. conducted a meta-analysis of 12 randomized clinical trials covering data on 6884 patients treated with external beam radiation at various dose levels. Their goal was to determine whether increasing the delivered biologically effective dose made a difference in 5 or 10 year metastasis-free survival, prostate cancer specific survival, or overall survival.

They found that dose-escalated radiation had the following effects:

• ·      10-year freedom from biochemical failure improved by 9.6% in low-risk men.
• ·      10-year freedom from biochemical failure improved by 7.2% in intermediate-risk men.
• ·      There was no corresponding improvement in metastasis-free survival, prostate cancer specific survival, or overall survival out to 10 years.
• ·      Dose escalation was not correlated with increases in acute toxicities.
• ·      Late-term gastrointestinal toxicities increased in patients treated with 3D-CRT.
• ·      Late-term toxicities were lower among patients treated with IMRT despite higher dose levels.

The abstract makes no mention of dose-escalated radiation treatment of high-risk men. We discussed some conflicting  survival data on higher risk patients in a previous commentary (see this link). As we saw, even at the higher risk levels, ten years follow-up was not long enough to detect difference in survival due to dose escalation.

The authors conclude:

“Thus, freedom from biochemical failure is a poor surrogate of overall patient outcomes for trials of RT.”

This is an unwarranted conclusion from the data presented in the abstract. We discussed the issue of surrogate endpoints (like freedom from biochemical failure) and length of follow-up in a previous commentary (see this link). For a newly diagnosed intermediate-risk man, the time frame for development of distant metastases could easily be upwards of 10 years, and a lot longer for low-risk men. The only valid conclusion one can draw from their analysis is that 10 years is too short a time frame to detect any effect of dose escalation on metastasis-free survival, prostate cancer survival or overall survival in these risk groups. Their analysis makes the argument for using surrogate endpoints, rather than against them. Given the long natural history of prostate cancer progression in these risk groups, how else can we gauge the impact of dose escalation within a practical followup timeframe?

The other interesting conclusion is that dose escalation, when delivered with IMRT technology, had no impact on acute or late-term toxicities. This argues for IMRT-delivered dose escalation: since it did not increase toxicity risk, and may increase long-term cancer control, there is no reason not to use it. This holds true even among low risk men who, for whatever reason, have elected not to engage in active surveillance. It also holds true for men with fewer than ten years of life expectancy who, for whatever reason, have elected not to engage in watchful waiting.

Does early salvage radiation save lives?

Several studies have tried to address the issue of whether adjuvant radiation actually increases prostate cancer survival in the long term compared to waiting. They all showed that biochemical progression-free survival could be improved by earlier treatment, but it remained questionable whether that would eventually translate into a survival benefit.

After 10 years of follow-up, the randomized clinical trial ARO 96-02 found that neither metastasis-free survival nor overall survival was significantly improved by adjuvant radiation. However, the study was underpowered to reliably detect those results.

After 10 years of follow-up, the randomized clinical trial EORTC trial 22911 found that adjuvant radiation did not significantly improve overall or metastasis-free survival, although there may be benefit for men less than 70 years of age, or those with positive margins.

There was only one study, SWOG S8794, which after 12.6 years of follow-up, demonstrated a significant improvement in both overall and metastasis-free survival among patients who had adjuvant radiation compared to patients who waited. However, the difference did not hold up when patients who received adjuvant radiation were compared to those who received salvage radiation. The difference was possibly attributable to the fact that very few patients in the wait-and-see arm ever got salvage radiation.

None of those three studies used radiation doses that are now considered to be adequate for curative adjuvant or salvage radiation.

So, with highly equivocal findings from the best studies we have available so far, how is the patient to make a decision as to whether it is worthwhile to undergo the potential side effects of early salvage radiation? This is the question that Hsu et al. at the University of California San Francisco set out to answer by looking for evidence in their large CaPSURE database. They identified 305 patients who had radiation after surgery, and who had such high-risk features on their surgery pathology report as:

• ·      Positive surgical margins, or
• ·      Gleason score 8-10, or
• ·      Stage T3 or T4

In that group, they found

• ·      76 men who had undetectable PSA and received adjuvant radiation within 6 months of surgery.
• ·      229 men who had salvage radiation after reaching a PSA>0.1 ng/ml, or after 6 months post-surgery. This group comprised:

o   180 who had early salvage radiation before PSA reached 1.0 ng/ml

o   49 who had late salvage radiation after PSA reached 1.0 ng/ml

After a median elapsed time of over 6 years after surgery, the researchers found:

• ·      Overall, 98% were still alive.
• ·      Overall, 12% had progressed to metastases or death.
• ·      Adjuvant and salvage radiation patients had comparable high-risk features.
• ·      Men who had salvage radiation had an all-cause mortality rate 2.7 times higher than men who had adjuvant radiation.
• ·      Men who had salvage radiation had a prostate cancer-specific mortality rate 4.0 times higher than men who had adjuvant radiation.
• ·      Ten year estimated prostate cancer-specific mortality was:

o   12% among men who had adjuvant radiation.

o   16% among men who had early salvage radiation.

o   29% among men who had late salvage radiation.

• ·      Late salvage radiation carried increased risk of prostate cancer-specific mortality and all-cause mortality.
• ·      Early salvage radiation had about the same mortality risk as adjuvant radiation.

The conclusion is that early salvage radiation, while PSA is still below 1.0 ng/ml, had the same survival benefit as adjuvant radiation, but without the risk of overtreatment. However, waiting until after PSA reached 1.0 ng/ml significantly increased the risk of metastases and prostate cancer mortality.

The PSA threshold used in this study, 1.0 ng/ml, is quite high and well beyond the limit used for the definition of biochemical recurrence (0.2 ng/ml). It may turn out to be the case that this higher threshold is a more useful definition of biochemical recurrence than the current definition. However, the follow-up period here is short (median 6 years), as it may require 20 or 30 years for a survival benefit to show up when a lower threshold is used. It should also be noted that the definition of “adjuvant” radiation used in this study included therapy begun anytime before PSA reached 0.1 ng/ml, while there may be greater survival advantage when adjuvant radiation is begun at a lower level measured on an ultrasensitive PSA test.

While this study provides evidence for early salvage radiation, its retrospective nature makes it subject to selection bias: there may have been specific reasons why the patients were selected to receive adjuvant, early salvage or late salvage radiation. The abstract of the study makes no mention of the radiation doses used, whether androgen deprivation was used along with the radiation, the use of radiation to pelvic lymph nodes, or whether age and co-morbidities were significantly different. We await the results of ongoing randomized clinical trials to provide more reliable information.

Is overall survival a useful endpoint for evaluating therapies for intermediate risk patients?

In a recent commentary, we looked at the utility of surrogate endpoints in evaluating therapies. In an abstract presented at ASCO, Malouf et al. examined the large National Cancer Data Base to determine whether there is an association between the use of brachytherapy (BT), external beam radiation (EBRT), or a combination of both (CT) and overall survival in intermediate risk patients.

They found records on 122,405 patients treated from 2004-2013 who were staged IIA. IIA is an AJCC risk category that is similar to the NCCN intermediate risk category, except that it excludes those clinically staged with cancer in both lobes (stage T2c). The average age of the patients at diagnosis were:

• ·      EBRT: 69 years of age
• ·      BT and CT: 66 years of age

The study provides no information about the radiation doses used.

The average survival, and the percent who survived 10 years were:

• ·      EBRT: 109 months, 61.5%
• ·      BT: 116 months, 72.9%
• ·      CT: 116 months, 73.1%

Survival differences were statistically significant between EBRT cohort and those who received the two other therapies.

The authors conclude:

“The method of radiotherapy used contributes to the survival of patients with stage IIA prostate cancer, with brachytherapy with or without EBRT having improved survival. Careful selection of the proper treatment regimen should be used.”

Now, when we look at US actuarial tables, we see the expected survival for a 66 year-old man is 16.93 years (203 months), and 14.81 years for a 69 year-old man (177 months). So the men treated with EBRT should have lived 26 months less; yet they lived only 7 months less – a relative survival gain for some unknown reason. It is also unknown why overall survival in both cohorts was so much less than actuarial expectations.

Using the Memorial Sloan Kettering nomogram for life expectancy where intermediate risk cancer has been diagnosed but not yet treated, and assuming no significant co-morbidities or risk factors, and allowing only for the difference in age, the expected 10-year survival statistics for untreated prostate cancer are as follows:

Among the 66 year old men (BT and CT cohorts):

• ·      71% would still be alive, which is close to the observed 73% among those who were treated
• ·      20% would have died of other causes
• ·      9% would have died of prostate cancer

Among the 69 year old men (EBRT cohort):

• ·      67% would still be alive, which is somewhat higher than the observed 63% among those who were treated
• ·      25% would have died of other causes
• ·      8% would have died of prostate cancer

What we learn from this is that for a man who has a life expectancy of ten years or less, watchful waiting may be a better choice than radical treatment.

We see that it is impossible to attribute the difference in the overall survival to prostate cancer, let alone to any of the treatments received. What we needed to know is prostate cancer-specific mortality, and we have no idea from their analysis how, if at all, it was affected. Because of the very low rate of prostate cancer-specific mortality at 10 years, even in untreated patients, it takes a very long time to be able to detect differences in the efficacy of various treatments based on this endpoint; hence, the importance of surrogate endpoints. The authors’ conclusions are completely unfounded based on the data they presented.