Wednesday, October 26, 2016

Lu-177-PSMA-617: Another update


Because there is great interest in systemic therapies for metastatic prostate cancer, I want to provide readers with the latest news about the Lu-177-PSMA-617 trials in Germany.

I recently reported (see this link) on 74 patients – 31% had PSA declines greater than 50%. A new report by Rahbar et al. expands the patient base to include PSA data on 99 patients and toxicity data on 121 patients treated at 12 therapy centers.  After median follow-up of 16 weeks, and up to 4 therapy cycles:
·      45% had a PSA decline greater than 50%
o   40% after a single cycle
·      18/121 patients (15%) had serious or life-threatening hematotoxicity, affecting red blood cells (10%), platelets (4%), and white blood cells (3%)
·      Xerostomia (loss of saliva) occurred in 8%

This is a very encouraging PSA response. For comparison, only 13% had a PSA reduction greater than 50% in the Xofigo clinical trial. However in that trial, 66% had a 50%+ decline in bone alkaline phosphatase, which may be a better biomarker for bone metastases. The hematotoxicity was identical.

What we really want to know is whether the treatment increases survival, and whether it is any better than Xofigo in doing so. The potential benefit of Lu-177-PSMA-617 is that it can treat non-osseous metastases too. We await future clinical trials to prove its benefit.


Monday, October 3, 2016

Urinary and sexual healing improved by waiting to start salvage radiation

Salvage radiation adds to the side effects of surgery and may halt the progress made towards healing. Healing takes time. On the other hand, we have learned that adjuvant or early salvage radiation has better oncological outcomes than waiting, the earlier the better (see this link).  Two new studies help us better understand the trade-offs.

Zaffuto et al. examined the records of 2,190 patients who had been treated with a prostatectomy. Their urinary and sexual outcomes were evaluated based on whether they received:
  1. no radiation
  2. adjuvant radiation (prior to evidence of recurrence, usually administered 4-6 months following prostatectomy), or
  3. salvage prostatectomy (after PSA reached 0.2 ng/ml)

They also looked at outcomes based on when they were treated with radiation:
  1. Less than a year after surgery, or
  2. A year or more after surgery

With median follow-up of 48 months, the 3-year outcomes were as follows.

Erectile function recovery rates were:
  • 35.0% among those who received no radiation
  • 29.0% among those who waited to receive salvage radiation
  • 11.6% among those who had adjuvant radiation
  • 34.7% among those who waited for a year or more before initiating salvage radiation
  • 11.7% among those who had radiation within a year

Urinary continence recovery rates were:
  • 70.7% among those who received no radiation
  • 59.0% among those who waited to receive salvage radiation
  • 42.2% among those who had adjuvant radiation
  • 62.7% among those who waited for a year or more before initiating salvage radiation
  • 43.5% among those who had radiation within a year

Van Stam et al. looked at their database of 241 patients who were treated with salvage radiation and 1005 patients who only received a prostatectomy but no radiation afterwards. All patients were last treated between 2004 and 2015, and had up to 2 years of follow-up afterwards.

After adjusting for patient characteristics, they found that:
  • Salvage radiation patients had significantly worse recovery of urinary, bowel, and erectile function.
  • Patients who waited more than 7 months before receiving salvage radiation had better sexual satisfaction scores and better urinary function recovery.

So what is one to do: treat earlier for better odds of cancer control, or treat later for better urinary and sexual function recovery? We have seen that adjuvant radiation is rarely likely to be necessary, and that early salvage radiation can probably be just as effective. But what if PSA is already high and rising rapidly? One solution might be to use hormone therapy to halt the cancer progression while tissues heal. That may help with urinary function, but is apt to interfere with recovery of sexual function. This remains a difficult decision, which is why discussions with an experienced radiation oncologist should begin at the earliest detectable PSA (over 0.03 ng/ml) on an ultrasensitive test. Most of all, the patient must do the self-analysis to understand which trade-offs he is willing to make.

Sexual function was no worse when fewer external beam radiation treatments were used



The HYPRO trial was designed to detect whether hypofractionation (fewer radiation treatments) was inferior to conventional fractionation. Their previous report looked at outcomes on late-term urinary and rectal function. Here, they report on sexual function outcomes.

To briefly recap, 820 intermediate/high risk patients were randomly assigned to one of two external beam radiation treatment protocols:
  • Conventional fractionation: 78 Gy in 39 treatments
  • Hypofractionation: 64.6 Gy in 19 treatments
  • 39% had adjuvant hormone therapy lasting up to 6 months

It should also be noted that men were 71 years of age at the time of treatment.

After median follow-up of 37 months:
  • Among those with partial or full erectile function at baseline, erectile dysfunction occurred in 34.4% among those who had hypofractionation and 39.3% among those who had conventional fractionation. The difference was not statistically significant.
  • Orgasmic function among those who did not have hormone therapy was higher for the hypofractionation group. The difference was statistically significant.
  • Overall, sexual function scores declined after treatment, but there was no difference between two treatments.

Two other randomized clinical trials also reported no difference in sexual function. Both the Fox Chase trial (see this link) and the M.D. Anderson trial (see this link) found hypofractionation made no difference in sexual outcomes. This should give some comfort to patients and radiation oncologists considering hypofractionation.

Wednesday, September 28, 2016

Brachytherapy alone is enough for favorable intermediate risk patients

RTOG 0232 was a large clinical trial conducted to determine whether low dose rate brachytherapy (BT) alone was of equal benefit compared to external beam radiation therapy with a brachytherapy boost (EBRT+BT) in intermediate risk patients.

The study was conducted at 68 cancer centers in the US and Canada from 2003 to 2012. 588 intermediate risk men were treated. For the purposes of this study, “intermediate risk” was defined as:
  • Stage T1c – T2b, and
  • Either Gleason Score of 7 and PSA less than 10 ng/ml, or
  • Gleason score of 6 and PSA between 10 and 20 ng/ml
They did not collect detailed data and report separately those who would now be classified as “favorable intermediate risk” by the Zumsteg definition (Gleason score 3+4, less than half the biopsy cores positive, and otherwise low risk). However, Howard Sandler, the Principal Investigator, wrote:
It was deliberately a favorable intermediate group largely. At the time (2002) we felt that combination therapy was mandatory for the more advance patients and we weren’t comfortable randomizing to brachy alone for those patients.

So it is important that we do not generalize their findings to unfavorable intermediate-risk or high-risk patients.

The patients were treated as follows:
  • BT: 145 Gy of I-125 seeds or 125 Gy of Pd-103 seeds
  • EBRT+BT: 45 Gy of EBRT and a boost with 110 Gy of I-125 seeds or 100 Gy of Pd-103 seeds
After 5 years of follow-up:
  • Progression-free survival was 85% for EBRT+BT patients, 86% for BT patients (no difference)
  • Acute grade 3 (serious) side effects were suffered by 8%  in each group.
  •  Late-term grade 3 (serious) side effects were higher (12%) in the EBRT+BT compared to 7% in the BT group
o   Urinary side effects: 7% in the EBRT+BT group vs. 3% in the BT group
o   Rectal side effects: 3% in the EBRT+BT group vs. 2% in the BT group

So, the addition of external beam radiation added nothing to cancer control, at least out as long as 5 years. While side effects were low for both groups, combination therapy increased them.

We saw recently in an analysis of the patients at Cleveland Clinic who were treated exclusively with BT only (see this link, especially the section on intermediate risk), that progression-free survival was very good for “low intermediate risk” patients. Furthermore, Drs. Stone and Zelefsky agreed that the combination therapy is unnecessary for this group, especially when treated with a sufficient brachytherapy dose. Radiotherapy Clinics of Georgia has built a business out of treating even low-risk patients with the combination therapy. This is now proved to be an overtreatment that is needlessly toxic.


5-year SBRT trial: high cancer control, low toxicity

(9/10/2018)
Meier et al reported the results of a 5-year multi-institutional trial, (also reported at the 2017 ASTRO meeting), finding that SBRT had high rates cancer control and low toxicity.

This was a prospective clinical trial in which all 21 institutions treated 309 patients according to the same protocol. The institutions were community, regional and academic hospitals across the US. All patients were low (56%) or intermediate risk (44%). Of the 137 intermediate risk patients,  61% were favorable and 39% were unfavorable intermediate risk. The treatment was:
  • 40 Gy in 5 treatments to the prostate
  • 36.25 Gy to the seminal vesicles in intermediate risk patients
  • No concurrent or adjuvant androgen deprivation therapy was allowed.
At five years after SBRT treatment, the following oncological outcomes were reported:
  • 97.1% had no biochemical progression; that is, no increases in PSA to over 2 ng/ml from the lowest value achieved 
      o 97.3% for low risk patients, compared to 92.3% for IMRT historically
      o 97.1% for intermediate risk patients, compared to 91.3% for IMRT historically
           - 100% among favorable intermediate risk
           - 93.1% among unfavorable intermediate risk

By five years after SBRT treatment, the late toxicity outcomes were reported:
  • No grade 3 (serious) rectal side effects
  • Grade 2 rectal side effects in 2%
  • Grade 3 (serious) urinary side effects in 4 of the 309 patients (1.3%)
  • Grade 2 urinary side effects in 12%

These are certainly excellent outcomes, and are in-line with or better than retrospective SBRT studies that have previously been reported. So far, the longest running SBRT single institution study has been reported by Alan Katz (see this link). I’ve heard that a ten-year update is in the works. That will be as long and larger than the longest running IMRT trial.

SBRT is about half the cost of IMRT, and at only 5 treatments, is certainly a lot less bother for the patients. It has excellent outcomes even without adjuvant ADT in unfavorable intermediate risk patients. With large long-term studies now available, it is difficult to understand why some insurance companies still don’t cover it.

Toxicity equal for SBRT and conventional external beam radiation


There has been some question as to whether the toxicity of delivering very high doses of external beam radiation per treatment (or fraction) in fewer fractions (called “extreme hypofractionation” or SBRT) would be high compared to conventional dose rates per fraction. While SBRT practitioners have reported very low toxicity rates (see table in this link), there has always been some doubt because there may have been some bias in how patients were selected in the various studies.

The HYPO-RT-PC trial was the first trial ever to randomly assign patients to one kind of radiation or the other. Between 2005 and 2015, they enrolled 1200 intermediate-risk patients in Scandinavia to receive either:
  1.  Conventional fractionation: 78 Gy in 39 fractions
  2. SBRT: 42.7 Gy in 7 fractions

The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

There were a few differences from some US practices:
  • “Intermediate risk” was defined as one or two of the following 3 risk factors:

  1. Stage T1c-T3a (T3a is a high risk factor in the commonly used US definition)
  2. PSA> 10 ng/ml (PSA> 20 ng/ml is a high risk factor in the commonly used US definition)
  3. Gleason score ≥7 (Gleason scores greater than 7 are a high risk factor in the commonly used US definition)

  • 80% of the men were treated with a technology called 3D-CRT, which is seldom used for external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic.
  • SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

The toxicity results are based on 866 patients who had 2-year follow-up results. There were some differences in acute toxicity:
  • Acute urinary toxicity was 27.6% for the SBRT group and 22.8% for the conventional fractionation group, but the difference was not statistically significant.
  • Acute rectal toxicity was 9.4% for the SBRT group and 5.3% for the conventional fractionation group. The difference was statistically significant, but narrowed by 3 or 6 months.

Neither physician-reported toxicity nor patient-reported late-term toxicity differed by the fractionation schedule they received. By two years:
  • Late-term urinary side effects were reported by 5.4% of the SBRT group and 4.6% of the conventional fractionation group. The difference was not statistically significant.
  • Late term rectal side effects were reported by 2.2% of the SBRT group and 3.7% of the conventional fractionation group. The difference was not statistically significant.
  • Impotence was reported by 34% of both groups, up from 16% at baseline.
  • Patient-reported bother from urinary, rectal and sexual side effects were not different.

Given their use of the largely outmoded 3D-CRT technology, it was not surprising that acute toxicity would be elevated. I’m frankly surprised that late-term toxicity was not higher for SBRT.

They plan to present their findings on oncological outcomes at a future time.

Tuesday, September 20, 2016

Very early salvage radiation has up to 4-fold better outcomes and saves lives

Another  subject that has come up a lot recently is when to have salvage radiation. It is always a pressing decision for those 30% of prostatectomy patients who have detectable PSA after prostatectomy. We have seen (see this link) that a low PSA on an ultrasensitive PSA test, as low as 0.03, can be a predictor of full biochemical recurrence later. This latest analysis of this subject looked at how treating sooner rather than later was associated with better cancer control and survival.

Abugharib et al. examined the records of 657 men who had salvage radiation therapy (SRT) from 1986 to 2013 at the University of Michigan and the University of Texas Southwestern. They were all discovered to have detectable PSA following prostatectomy. Researchers were looking for evidence to confirm or contradict their hypothesis that earlier SRT had better outcomes.

They defined "earlier" in two ways:

1. At a lower PSA. Because of the treatment dates, there was relatively little data from ultrasensitive PSA tests. They divided PSA at the time of SRT into three categories:
  • 0.01-0.2 ng/ml - the "very early salvage" cohort
  • >0.2 - 0.5 ng/ml - the "early salvage" cohort
  • >0.5 ng/ml - the "later salvage" cohort (0.5 was selected because the median PSA was 0.4 ng/ml)
2. At an earlier time from completion of prostatectomy
  • < 9 months   
  • 9-21 months
  • 22-47 months
  • > 48 months
They looked at "outcomes" in four ways:
  1. freedom from biochemical recurrence (PSA> 0.2 ng/ml) after SRT
  2. freedom from starting salvage, life-long androgen deprivation therapy (ADT) after SRT
  3. freedom from detectable metastases after SRT
  4. prostate cancer specific survival
After a median follow-up of 9.8 years, they found:
  • The time in months since completion of prostatectomy had no bearing on any of the outcomes.
  • The PSA at which they were treated has a major impact on all outcomes.
  • The "early salvage" group had outcomes that were about twice as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
  • The "later salvage group" had outcomes that were about four times as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
  • 91% of the variance in biochemical recurrence after SRT was explained by the PSA at which patients were treated.
  • Adjuvant ADT, which was given to 24% of patients for a median of 6 months (range 4-24 months), was significantly associated with freedom from biochemical recurrence after SRT. There were 40% fewer failures. 
Researchers did not have data on PSA doubling time and velocity, and the number who had persistently elevated PSA, all of which almost certainly would affect outcomes. Perhaps such other variables as the length of the positive margins and the Gleason score there ought to be incorporated into a fuller analysis.

Patients who were treated at an early sign of detectable PSA  (0.2-0.5) were twice as likely to develop metastases and die of prostate cancer as those who were treated at the earliest PSA (below 0.2). Those who waited for PSA to rise above 0.5 ng/ml were four times as likely to develop metastases and die from prostate cancer compared to those treated when PSA first became detectable.

We have three large randomized clinical trials proving that outcomes are diminished by about half by waiting rather than treating within the first 6 months, even before there are detectable PSAs (called adjuvant radiation). But few elect to have adjuvant radiation, and the number has been declining (see this link). To avoid overtreatment and protect patients from perhaps unnecessary side effects of SRT, early salvage has emerged as a compromise.

The authors point out that it may take 7 months or more for adequate healing of urinary and erectile complications (see this link). Also, this is an important decision for the patient, which he ought not make hastily. Yet here, more than in the primary therapy decision, very early action can save lives. As a compromise, they suggest early use of neoadjuvant ADT (prior to SRT) which could slow the cancer down and give tissues more time to heal. The extra time may help the patient recover better urinary function, if not erectile function.

They recommend,
"Our data would suggest potentially a traditional cut-off of 0.2 to define biochemical failure may be too late, and that at the first sign of a detectable PSA that SRT (or SRT + ADT) should be initiated."
This remains a difficult decision, and the patient with a detectable PSA after surgery should begin discussions with a good radiation oncologist as soon as possible. Age and comorbidities enter into the decision as well. Unfortunately at these low PSAs, even the most accurate of the new generation of PET scans are incapable of finding distant metastases that might help rule out those cases where SRT would be futile. Nomograms and Decipher scores may help in cases where the decision is equivocal.