Showing posts with label overall survival. Show all posts
Showing posts with label overall survival. Show all posts

Monday, January 29, 2018

New Study: Adjuvant Radiation Saves Lives vs. Salvage

A major new study adds to several other studies that show that, for men with adverse pathology, adjuvant radiation (ART) within 3-6 months of prostatectomy saves more lives compared to waiting until the PSA rises into the range of 0.1-0.5 ng/ml - salvage radiation (SRT).

Three previous randomized clinical trials have shown an advantage to adjuvant radiation over a "wait-and-see" approach. However, only one of them (SWOG  S8794) showed that there was an improvement in freedom from metastases and overall survival attributable to earlier treatment. That study was limited in its generalizability because only a third of the "wait-and-see" cohort ever received salvage radiation. ARO-96-02 was designed to detect differences in progression-free survival (which were significant), but it was underpowered to detect overall survival differences. EORTC 22911 was designed to detect differences in progression-free survival (which were significant), but although it had a larger sample size, overall survival did not improve. Sub-group analysis showed the survival benefit was limited to men under the age of 70. A recent meta-analysis of the three trials showed that freedom from biochemical failure, freedom from life-long ADT,  and freedom from distant metastases were significantly improved by adjuvant treatment. But less than half of the men in the wait-and-see arms ever received salvage radiation, and 20-40% of  them never suffered a recurrence. All three trials used salvage radiation doses that would now be deemed too low. ART utilization rates are at an all-time low of 17% in men with adverse pathology.

What we really want to know is: what is the downside of waiting until the PSA rises to some arbitrary level, say 0.2 ng/ml? That is the subject of three randomized clinical trials, but we will not have the findings for several years. Meanwhile, some researchers looked at historical data in a new way to determine whether there is any evidence that might aid in decision-making.

Hwang et al. have pooled the databases from ten top institutions: Massachusetts General, Cleveland Clinic, University of Michigan, Duke University, Washington University, Mayo Clinic, University of Chicago, University of Miami, Virginia Commonwealth University, and Thomas Jefferson University. There were 1,566 patients who were treated between 1987-2013. Patients either had fully contained prostate cancer (T2) with a positive margin or extraprostatic extension (T3a)/ seminal vesicle invasion (T3b) with or without a positive margin.

They used a statistical technique called "propensity score matching" that in some respects resembles what would have resulted from a prospective randomized trial. Every patient who had ART was matched, in terms of patient characteristics, to a patient who had SRT. Patients are chosen randomly from among those with matched characteristics.  Patients were matched on age at surgery, year of surgery, Gleason score, T stage, margin status, postoperative ADT, and pelvic nodal RT. In this way, they were able to generate 366 matched pairs of patients. This technique works quite well in predicting outcomes of prospective randomized trials as long as there is a large enough sample size, considerable overlap in patient characteristics (which there was) and there aren't any prognostic patient characteristics that were missed.

The researchers found that all measured outcomes were significantly better among those who received ART:

  • 12-year freedom from biochemical failure: 69% for ART vs. 43% for SRT
  • 12-year freedom from distant metastases: 95% for ART vs. 85% for SRT
  • 12-year overall survival: 91% for ART vs. 79% for SRT
  • Patients who suffered biochemical failure were more likely to have had SRT, have been stage T3b, have had higher Gleason score, had not been treated with lymph node radiation, and had not had postoperative ADT.
  • The advantage of ART was only lost if more than 56% of them would have been overtreated, but based on nomograms, no more than 46% would have been overtreated (using the assumption that 2/3 were GS 3+4 and 1/3 was GS 4+3).

Pending confirmation by the randomized clinical trials, this study is our best evidence to date that ART is preferable to SRT. However, there are a few very important caveats:

  • They defined SRT as treatment when the PSA is in the range of 0.1 - 0.5 ng/ml. (They actually call this "early" salvage -- a term I would prefer to reserve for radiation when the ultrasensitive PSA (uPSA) is below 0.10 ng/ml.) For uniformity reasons in this 10-institution study, any PSA below 0.10 ng/ml on an uPSA test was deemed "undetectable," and those treated at very low PSAs were considered to have had ART. They had to use those definitions in their analysis because of the heterogeneous data set with PSAs recorded as early as 1987 (before there were any ultrasensitive PSAs). Because the risk of overtreatment with ART is high (they estimate 33%-52%), it behooves patients to track their post-prostatectomy PSA with an ultrasensitive test. We have seen that for men with adverse pathology,  any uPSA over 0.03 ng/ml reliably predicts that it will keep going up to 0.2 ng/ml (see this link). In men without adverse pathology, only a convincing pattern of PSA rises is prognostic.
  • Adverse pathology in this study included anyone with positive margins, but others advocate that the length of the positive margin and the Gleason score at the margin are important considerations. A patient with focal positive margins and GS 6 at the margin may never need additional ART or SRT.
  • They lumped together men whose PSA was undetectable but then climbed higher and men whose PSA was persistently elevated after prostatectomy. Persistent PSA with adverse pathology is a clearer indicator that gross amounts of cancer were left behind and calls for some quick action.
  • The Decipher genomic test was not available throughout most of the study period. For those sitting on the fence, it may be a decisive factor.
  • The newer PET scans (Axumin and PSMA-based) can find metastases if PSA is greater than 0.2 ng/ml. Multiparametric MRI may be able to find sites in the prostate bed or among the pelvic lymph nodes where tumor size is longer than 4 mm. Because of the advantage of earlier treatment, most men will require treatment before metastases become detectable. Some will be overtreated if the cancer is already systemic.
  • Among very high risk patients (i.e., GS 8-10, seminal vesicle invasion (T3b) or invasion of nearby organs (T4), and very high persistent PSA) the probability that ART or SRT will be curative may be very low. Patients should understand what the population-based risk is from a nomogram.
  • The radiation doses delivered were at a median dose of 66 Gy. More recent evidence suggests that higher doses may be necessary to achieve a cure. The value of adjuvant ADT and whole pelvic radiation suggested here has also been suggested by a number of other studies.
  • This study excluded patients with detected positive lymph nodes. That is a clear indication for ART.
There are many factors to consider including comorbidities, continence and potency recovery. This will seldom be a straightforward decision. Patients with adverse pathology and uPSA over 0.03 ng/ml should be talking to a radiation oncologist and not a urologist.

Thursday, October 26, 2017

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.

Monday, October 16, 2017

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.

Friday, August 26, 2016

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.