Showing posts with label salvage radiation. Show all posts
Showing posts with label salvage radiation. Show all posts

Saturday, June 29, 2019

Evidence for Dose Escalation in Adjuvant/Salvage Radiation

It is well known that prostate cancer is relatively radio-resistant compared to other kinds of cancer. While dose escalation (most recently by increasing the biologically effective dose using hypofractionated dose (more that 2.0 Gy per session) delivery or brachytherapy boost therapy) has become the mainstay in primary radiation therapy, doses delivered for adjuvant or salvage radiation has stayed about 10 Gy lower. Recently, Dr. King's analysis of the dose responsiveness of salvage radiation questioned this supposition (see this link). While his mathematical arguments provide us with intriguing plausibility, only clinical evidence from a randomized clinical trial can change practice.

We now have Level 1 evidence that expanding the adjuvant/salvage treatment field to include the pelvic lymph nodes improves the oncological outcomes in men with higher PSA at the time of salvage radiation.

Link et al. conducted a small, retrospective study among 120 locally advanced (stage T3/4) post-prostatectomy patients at the University of Heidelberg between 2009 and 2017. All were lymph node negative.

  • 43 received whole pelvic radiation therapy (WPRT)- 62% received 79.3 Gy to the prostate
  • 77 received radiation to the prostate bed only (PBO)- 70% received 79.3 Gy to the prostate
  • Biologically equivalent dose (2 Gy) to the prostate was 79.3 Gy ("high dose") if they had positive margins or PET/CT/MRI imaging-detectable prostate bed tumors (62% of patients), 71.4 Gy ("low dose") if they had negative margins (38% of patients).

Median freedom from biochemical failure was:

  • longer among those who got the higher dose: 76 months vs 21 months
  • longer among those who received WPRT vs PBO: 68 months vs 32 months

There is a lot of overlap in treatments, so it is impossible to tease out the effect that each had on the oncological outcomes. Almost all of those who received the escalated dose also had positive margins - a known factor for predicting success of adjuvant/salvage radiation. Also, almost all men who had adjuvant radiation had positive margins and dose escalation - adjuvant radiation has proven to be more successful than "wait-and-see" in 3 major randomized clinical trials.

Toxicity increased with both dose and size of the treatment field. Grade ≥ 2 toxicity was reported by:

  • 3.4% among those who received low dose and PBO
  • 12.5% among those who received high dose and PBO
  • 15.4% among those who received low dose and WPRT
  • 36.7% among those who received high dose and WPRT
  • No reports of Grade 3 gastrointestinal toxicity
  • 13% Grade 3 urinary toxicity among high dose patients, none among low-dose patients

This is a far cry from the randomized clinical trial we need for practice-changing dose escalation for adjuvant/salvage radiation. However, we can't rule out that there is no oncological benefit to dose escalation. It remains unknown what proportion of these high-risk patients would have done just as well with lower doses and smaller treatment fields. The increase in toxicity with dose and treatment field means that patients ought not jump into this without understanding the risks and discussing them with their radiation oncologists.

Wednesday, December 6, 2017

Use of mpMRI and PSMA PET/CT to aid in salvage radiation decision-making

Because the success or failure of salvage radiation (SRT) hinges upon whether micrometastases are already systemic at the time of treatment, evidence that the cancer is still local improves the odds that SRT will be successful.. One way of finding local tumors is to use multiparametric MRI (mpMRI). mpMRI can detect tumors down to about a limit of 4 mm, and may be able to find tumors even when their PSA output is low.

Sharma et al. at the Mayo Clinic retrospectively examined the records of 473 men who were treated with SRT and who had an mpMRI prior to treatment from 2003 to 2013. Among men with a pre-treatment PSA ≤ 0.5 ng/ml, 5-year biochemical failure was:

  • 39% among those with a negative mpMRI
  • 12% among those with a positive mpMRI

Adding mpMRI to the updated Stephenson nomogram (see this link) increased its predictive accuracy for PSA recurrence after SRT from 71% to 77%. Perhaps its accuracy would increase even further if the MRI was confirmed by a biopsy of the suspicious tissue to eliminate any false positives.

Like the detection of a positive margin in post-prostatectomy pathology, detection of a local tumor using mpMRI increases the probability that SRT will be successful. Although the radiation dose to the suspicious lesion can be boosted (see this link), it is unknown whether such a boost actually increases efficacy when the entire prostate bed is adequately treated. It is also unknown what effect it might have on toxicity. Moreover, it is hard to argue for a reduced dose elsewhere in the prostate bed because of the known limitation of mpMRI in detecting smaller tumors, and the multi-focal nature of prostate cancer spreading.

Emmett et al. at St. Vincent Hospital in Sydney performed a Ga-68-PSMA-11 PET/CT on 164 men with rising PSA (PSA range: 0.05-1.0 ng/ml) after prostatectomy who received SRT. After eliminating patients who also had systemic therapy, there were 140 evaluable patients. They had a pre-SRT PSA of 0.23 (interquartile range 0.14-0.35).  As expected, detection rates went up with increasing PSA;

  • <0.2 ng/ml: 50%
  • 0.20-0.29 ng/ml: 64%
  • 0.30-0.39 ng/ml: 67%
  • ≥0.40 ng/ml: 81% 
They only had 10.5 months of median follow-up, and defined a favorable PSA response to SRT as a decrease of at least 50% in PSA and a PSA ≤ 0.1 ng/ml (those receiving adjuvant ADT were eliminated from the follow-up PSA-response analysis). The results should be interpreted with caution because of the very short follow up and low sample sizes. A short-term PSA response only indicates local control, and may not endure if systemic micrometastases were present.

PET/CT was negative in 38% (62/164). 45% of those men (27/60) had SRT to the prostate bed, and 7/27 had SRT to the pelvic lymph nodes field too. In the "negative" detection group, 86% had a favorable PSA response to SRT. Unfortunately, more than half of the PET-negative men never received SRT. This should serve as a caution against over-reliance on PET/CT. PET/CT is not good at detecting micrometastases in the prostate bed. The prostate bed is also a difficult place to detect PSMA-avid cancer because of masking from urinary excretion. We also know little about the natural history of PSMA development in prostate cancer -- it  may very well be that earlier forms of the cancer that may not express PSMA may be most vulnerable to SRT. SRT should never be withheld from an area based solely on negative PSMA findings.

PET/CT was positive in the prostate bed only in 23% (38/164). All of them had SRT to the prostate bed, and 17/36 had SRT to the pelvic lymph node field too. In the "prostate-bed only" detection group, 81% had a favorable PSA response to SRT. Recent evidence indicates that pelvic lymph node SRT increases effectiveness (see this link). Radiation of the pelvic lymph nodes should be considered in spite of negative nodal PSMA findings.

PET/CT was positive in pelvic lymph nodes in 25% (41/164). 87% (26/30) of them had SRT to the prostate bed and to the targeted pelvic lymph nodes. In the "pelvic lymph node" detection group, 61.5% had a favorable PSA response to SRT. The entire pelvic lymph node field and not just isolated lymph nodes should receive SRT for the reasons stated above.

PET/CT was positive for distant metastases in 14% (23/164). Nevertheless, 60% (10/15) of them had SRT to the prostate bed (and, I suppose, to the entire pelvic lymph node field), and 6/10 had metastasis-directed SBRT too. In the "distant metastasis" detection group, only 30% had a favorable PSA response to SRT. Only 1 of the 6 who had metastasis-directed SBRT had a favorable PSA response. When there are known distant metastases, treatment of the prostate bed, pelvic lymph nodes, and of metastases remains a controversial treatment.

The PET/CT was a better predictor of SRT response than PSA, Gleason score, stage, or surgical margin status. The most valuable finding of this small, short-term analysis was that metastases can sometimes be detected at fairly low PSA (as low as 0.1 ng/ml), and it may be possible to rule out SRT in those cases. Conversely, when distant metastases cannot be detected, SRT success rates may be very good.

We will require longer follow-up, larger sample size, prospective studies to establish the utility of mpMRI and PSMA PET/CT in SRT decision making. The two imaging techniques are complementary - the MRI is not as PSA-dependent and is not masked by the urinary excretion of the radiotracer, while the PET scan is highly specific for cancer. Both are useless in detecting tumors with a dimension smaller than 4 mm, so it would be a mistake to think that what is detected is all there is.

Wednesday, November 22, 2017

When is whole pelvic radiation needed for salvage?

Patients who elect to have post-prostatectomy radiation for recurrent prostate cancer face a couple of important decisions:

(1) Should the radiation be limited to the prostate bed (PBRT)? OR
(2) Should one treat all the pelvic lymph nodes at the same time (whole pelvic radiation - WPRT)? And if so, is the oncological outcome likely to be better if one has androgen deprivation therapy (ADT) along with it?

There is an ongoing prospective randomized clinical trial (RTOG 0534) to help answer these questions. But results are not expected until the end of 2020. Meanwhile, the best we can do is look at how patients have done in the past. Ramey et al. conducted a retrospective analysis of 1861 patients treated at 10 academic institutions between 1987 and 2013. The treatments and patient characteristics were as follows:

  • All had post-prostatectomy PSA> 0.01 ng/ml (Median was 0.5 ng/ml)
  • All had post-prostatectomy Gleason scores ≥ 7
  • None had detected positive lymph nodes
  • 1366 had PBRT without ADT,  250 with ADT
  • 176 had WPRT without ADT, 69 with ADT
  • Median salvage radiation dose was 66 Gy
  • More than half of GS 8-10 patients got ADT, whereas most GS 7 patients did not
  • 60% had extraprostatic extension
  • 21% had seminal vesicle invasion
  • 60% had positive surgical margins

After a median follow-up of 51 months, the 5-year freedom from biochemical failure outcomes are shown in the following table.

             5-Year Freedom from Biochemical Failure

With ADT
Without ADT

Among GS 7:

With ADT
Without ADT

Among GS 8-10:

With ADT
Without ADT

WPRT with ADT had the best outcomes in total and in each Gleason score category. Two-thirds of salvage patients had 5-year cancer control with the combination, whereas only about half had oncological control without them. The differences were especially marked among those with GS 8-10. There was significant improvement even in men with GS 7; however, they did not have the data to ascertain whether they were GS 3+4 or GS 4+3. Adjuvant ADT improved outcomes whether it was used in conjunction with WPRT or PBRT. On multivariate analysis, both WPRT and ADT independently increased freedom from biochemical failure. Higher radiation dose, lower PSA, lower Gleason score, Stage T2, and positive surgical margins decreased the risk of failure.

Neither WPRT nor ADT made any difference in the rate of metastases, which were low at 5 years post-prostatectomy.

Toxicity and quality of life, which would be the only reasons not to give WPRT and ADT to all salvage radiation patients, were not evaluated in this study. Also lacking were data on duration and type of adjuvant ADT

This study is congruent with a couple of retrospective studies (see this link and this one), but incongruent with a couple of other retrospective studies (see this link and this one). The present study is the largest and most recent dataset of them, and corrects for the effects of other variables in a way that the two opposing studies did not.

We saw previously that adjuvant ADT has been proven in a randomized clinical trial to improve oncological outcomes of salvage radiation after prostatectomy (see this link).

While we await the more definitive data from RTOG 0534, this builds the case that both WPRT and ADT should be included in the salvage radiation treatment of men with prostatectomy-diagnosed Gleason scores of 8-10, and at least some of those with Gleason score of 7. There are several open questions:

  • Is there a benefit for GS 3+4, or only for GS 4+3 or higher?
  • Is there a benefit when higher salvage radiation doses (70-72 Gy) are used, or with hypofractionated protocols that raise the biologically effective dose?
  • What is the optimal duration of adjuvant ADT?
  • Would any of the newer hormonal therapies (e.g., Zytiga or Xtandi) or other systemic therapies improve outcomes?
  • What are the trade-offs with toxicity and quality of life?
  • What is the optimal treatment field for WPRT, and should it vary with individual anatomy and comorbidities, given its potential toxicity?
  • Can we use the newer PET scans or USPIO MRI to help decide if WPRT is necessary?
  • Can we identify any subsets (e.g., low PSA, stage T2, GS 3+4) that would not benefit from the additional treatment?

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.

Sunday, August 28, 2016

Genomic classifier can help identify patients who may not need adjuvant radiation.

A decision that tortures patients with adverse findings (positive margins, and/or stage T3/4) after prostatectomy is whether to jump into adjuvant radiation right away, or wait until PSA rises to 0.2 ng/ml before having salvage radiation. We want early treatment while the cancer is still local, but we don’t want to over-treat cancers that may never require treatment in one’s lifetime. Currently, only about 10% of post-prostatectomy patients with adverse pathology are getting adjuvant radiation. In a recent article, I noted that PSA, Gleason score, and stage may not adequately capture the risk of progression. Radiation oncologists commonly rely on tools like the CAPRA-S score or the Stephenson nomogram to predict the outcome of salvage radiation.

Karnes et al. in a study at the Mayo Clinic in 2013 retrospectively looked at the genomes of prostatectomy patients with adverse findings to see if they could predict whether they would progress to metastasis. Metastatic progression is used as a surrogate endpoint for prostate cancer mortality because of the very long natural history of progression. Even progression to metastases takes a very long time – 8 years median among those who progress. The researchers only followed the patient case files for up to five years, so we expect to see proportionately fewer metastatic cases. They found that a genomic classifier (GC), Decipher ™, could reliably predict those patients with adverse pathology after RP that would go on to develop metastases.

They performed GC analysis on tissue samples from a random sample of 256 patients who were at high risk of recurrence owing to any of several factors: PSA>20 ng/ml, GS≥8, pT3 or positive margins. They augmented the sample to include 73 patients who were known to eventually progress to metastases. They tracked whether patients progressed to metastasis within 5 years. Median time to metastases was 3.1 years. The researchers found that:
·      GC had a predictive accuracy of .79, which was significantly better than any of the clinicopathological risk factors or the Stephenson nomogram.
·      Independent of all other risk factors, every 10% increase in GC raised the risk of metastases by 58%.
·      60% had a GC score <0.4. They had a 5-yr cumulative incidence of metastases of only 2.4%.
·      20% had a GC score > 0.6. They had a 5-yr cumulative incidence of metastases of 22.5%.
·      While there was some correlation between Gleason score and GC score, 36% of those with GS≥8, had low GC scores and 77% of that subset remained metastasis-free.

Researchers at Thomas Jefferson University and the Mayo Clinic (Den et al.) performed a similar study, but they only looked at the cases of patients who had adjuvant or salvage radiation after RP. Because the patients had both RP and RT, we expect that the cytoreduction would slow down the rate of metastases, if not prevent them, if they weren’t already micrometastatic. The 188 patients in their study had positive margins or stage pT3, and were all treated with radiation after RP between 1990 and 2009. Their cases were analyzed for up to 5 years following RP.

They used the genomic classifier (GC) on prostatectomy tissue samples to classify them as low, average, and high GC scores. GC scores range from 0 to 1. Based on the Karnes et al. study, they classified low scores as 0-0.4, average scores as 0.4-0.6, and high scores as 0.6-1.  The researchers found:

·      Of all the risk factors comprising GC, CAPRA-S score, age, preoperative PSA, Gleason score, stage, surgical margins, time between RP and RT, and whether adjuvant or salvage RT was given, only three were helpful in predicting metastatic progression: GC, preoperative PSA, adjuvant RT, and CAPRA-S score. Of those, GC was the strongest predictor. Independent of all other risk factors, every 0.1 increase in GC raised the risk of metastases by 66%.
·      5-year rates of metastasis were:
o   0% in those with low GC score
o   9% in those with average GC score
o   29% in those with high GC score
·      In patients with GC score less than 0.4, there was no difference in incidence of metastases whether they received adjuvant or salvage radiation.
·      In patients with GC scores at or greater than 0.4, the 5-year cumulative incidence of metastases was:
o   6% if they received adjuvant radiation
o   23% if they received salvage radiation
·      The “survival concordance index,” a measure of how accurate a tool is for predicting survival (or in this case, metastases), was much greater for GC (0.83) than for the CAPRA-S score (0.66) or the Stephenson nomogram (0.67).

This study suggests that adjuvant radiation may be beneficial if the patient has a high GC score, while those with a low GC score can comfortably wait for salvage radiation.

In this study, all the tissue samples were from patients who went on to receive adjuvant or salvage radiation. What happens to patients who decide not to have radiation after RP?

One such study by Ross et al. of Johns Hopkins of the genomic classifier was presented at the 2015 Genitourinary Cancers Symposium. The sample of patients they studied had the following characteristics:
·      260 patients
·      Intermediate or high risk treated with surgery between 1992 and 2010
·      Undetectable PSA after surgery
·      No therapy prior to detected metastases
·      77% were stage pT3a, 28% were stage pT3b, 28% had positive margins, 20% were N(1), 36% were GS≥8
·      By 15 years, 38% had biochemical recurrence, 21% had metastases, and 9% died of prostate cancer.
·      Median GC score was .47 among those who had metastases, and .28 among those who didn’t.
·      The risk of metastases increased by 48% for every 10% increase in GC Score.
·      GC Score predicted metastases independent of other clinical risk factors.

Most men (79%) did not go on to have metastases, even after 15 years and even with no salvage radiation, again raising the issue of potential over-treatment if they had received adjuvant or salvage radiation. Clearly, we need a tool to help us better predict risk of metastatic progression.

Another small study by Klein et al. at the Cleveland Clinic looked at patients who did develop metastases within 5 years of surgery, and who had no adjuvant or salvage radiation. They found 15 such patients, called “rapid metastases,” who had been treated between 1987 and 2008. These were compared to 154 control patients who did not develop rapid metastases. The controls were nevertheless at very high risk for developing metastases; they were screened for the following characteristics:

·      Preoperative PSA>20 or stage pT3 or positive margin or GS≥8, and
·      N(0), and
·      Undetectable post-RP PSA, and
·      No neoadjuvant or adjuvant therapy, and
·      Minimum 5 years of follow up

The researchers found that GC could distinguish those who developed rapid metastases from those who did not, with an odds ratio of 1.48. They also found that GC was a better predictor than the CAPRA-S score or the Stephenson nomogram.

These studies corroborate a similar finding by Feng et al. in an earlier study. They found that among patients with biochemical progression (PSA≥0.2 ng/ml), GC was a better predictor of metastatic progression than other clinical or pathologic risk factors. 40% of those with high GC scores developed metastases within 3 years of biochemical recurrence, compared to only 8% among those with low GC scores.
Genome Dx wrote that the positive predictive value (PPV) of a GC score greater than 0.4 was 69 percent in the Karnes validation study. This means that more than two-thirds of the time, it correctly (albeit retrospectively) predicted those men who went on to suffer metastases. Conversely, it means that about a third of men with high scores might be over-treated, at least with 5 years of follow-up, if they relied on a high GC score to make their salvage treatment decision. Complicating the interpretation is the fact that the natural history of progression is quite long, and may be further delayed by the debulking of the tumor burden from the initial prostatectomy. So longer follow-up, say, 10 or 15 years, might reveal that it predicted progression better.
The negative predictive value (NPV) of 98.5% for a GC score < 0.4 is particularly impressive. However, we still have the problem of the long natural history of progression. While a GC score under 0.4 almost certainly rules out risk of metastatic progression in the next 5 years, we don't know how safe we are in a 10- or 15-year time frame.
Even with these uncertainties, it is a better decision tool than our other available alternatives.

All of the above studies were retrospective, but I am doubtful that a prospective study will be undertaken because of the very long time needed to obtain sufficient metastatic cases.

Cumulatively, these studies build a good case that Decipher™ can do a reasonably good job of discerning which patients with adverse postoperative pathology but undetectable PSA could reasonably forego adjuvant and salvage radiation. It seems to be less accurate at predicting which patients would require radiation to prevent metastases, although it is a better predictor than other tools we have at our disposal. I was hoping Genome Dx would supply the sensitivity, specificity, and positive and negative predictive value at various cut-offs, but they did not respond to my request.

At $4,000+ this is an expensive test. However, considering that a course of adjuvant or salvage radiation can cost over $30,000, and the potentially worse side effects associated with adjuvant radiation, this test seems to have a reasonable cost/benefit ratio. It is covered by Medicare, many private insurance providers, and there is a financial assistance program available.

This is a difficult decision even with a GC score in hand, and one that should only be made in a shared decision-making process between patient and doctor.

note: Thanks to Dr. Robert B. Den for allowing me to see the full text.

Saturday, August 27, 2016

Can salvage radiation therapy be safely and effectively completed in less time?

Salvage or adjuvant external beam radiation therapy for prostate cancer is usually a protracted affair, more so since we learned that a total dose of about 70 Gy was needed to be effective in the salvage setting. At the typical rate of 1.8 Gy to 2.0 Gy per treatment, it takes approximately 35 treatments sessions over the course of 7 weeks to complete. This is very costly and extremely time consuming. Can it be accomplished in less time without adding side effects or rendering it less effective?

Using fewer treatments for radiation therapy is called hypofractionation. Stereotactic body radiation therapy or SBRT is on the fastest end of the hypofractionation spectrum. It is accomplished in a blazingly fast five treatments. With its pinpoint accuracy, many radiation oncologists are using it for primary treatment at doses up to 8 Gy per treatment session. But that is also its drawback for salvage therapy – it may be too accurate. Because we don’t know exactly where in the prostate bed the cancer may be hiding, IMRT or 3D-CRT – radiation technologies with less abruptly ending margins – have been traditionally preferred. There has also been some concern that blasting the anastomosis (the place where the urethra has been cut and re-attached, and where most recurrences occur) with high intensity X-rays may be too much for the fragile tissue.

There are also several considerations that arise more in the salvage radiation therapy setting than in the primary therapy setting:
  • The bladder and rectum are no longer shielded by an intact prostate, so they are potentially exposed to greater spillover radiation. The prostate bed without the prostate is highly deformable, and rectal distension can change its shape markedly within seconds during the treatment. This increases the amount of toxic radiation absorbed by healthy tissues.
  • Only devices that continuously track prostate bed motion during, and not just at the start of, each treatment, and that operate with extremely fast treatment times may be able to avoid some of this. It is an open question as to whether this can be done with the entire prostate bed the way it is with the prostate in place. This becomes an important consideration only at higher dose rates.
  • It is unknown whether those late-responding tissues will suffer increased damage from the higher dose rates after longer follow-up.
  • As mentioned, the scar tissue of the anastomosis may become inflamed, leading to a higher risk of urinary retention or tissue destruction.
  • The bladder neck, which may be spared during primary radiation and surgery, receives a full dose during salvage radiation therapy, increasing the probability of bladder neck contracture, urethral strictures, pain and incontinence. These problems may be amplified at higher doses per treatment.
  • None of the studies (below) mention the effect on erectile function, which is probably already impaired from the surgery. Neurovascular bundles, if spared by surgery, are far more exposed during salvage radiation.

Ohri et al. at Thomas Jefferson University in Philadelphia developed a mathematical model based on known radiobiological parameters to help determine ways in which salvage radiation therapy can be optimized. Among other findings, they showed that moderate hypofractionation – increasing the dose to 2.5 Gy per treatment in each of 26 treatments – gave only modest improvements. However, increasing the dose to 6.5 Gy in each of 5 treatments increased the probability of tumor control while decreasing expected urinary and rectal toxicity – a win/win! But would this happen in real life?

(Update May 2023)   Peterson et al. reported the toxicity results of the RADICALS-RT trial. Patients getting salvage radiation were not randomized but received either 66 Gy in 33 fractions (417 patients) or 52.5 Gy in 20 fractions (217 patients).
  • In the first 2 years, Grade 1 or 2 cystitis was reported more often in the 66GY/33fx (30%) than in the 52.5Gy/20fx group (20%)
  • After 2 years, Grade 1 or 2 cystitis was reported more often in the 66GY/33fx (16%) than in the 52.5Gy/20fx group (9%) - not statistically different
  • All other toxicities were similar

(Update January 2020) Chin et al. retrospectively reviewed 112 patients treated post-prostatectomy in the UK. They were treated with 52.5 Gy in 20 fractions.  With 10 years of follow-up they reported:
  • 51% were free of biochemical failure.
    • 68% if treated when PSA≤ 0.2 ng/ml
    • 49% if treated when PSA> 0.2 ng/ml
  • 16% had distant metastases
  • 11% died of prostate cancer
  • 75% overall survival
Kruser et al. at the University of Wisconsin treated 108 consecutive patients with a moderately hypofractionated schedule – 2.5 Gy per treatment in each of 26 treatments. After 4 years of follow-up, they found:
  • Freedom from biochemical failure: 67%
  • Acute urinary toxicity: Grade 2: 6%, Grade 3: 1%
  • Acute rectal toxicity: Grade 2: 14%, Grade 3: 0
  • Late-term urinary toxicity: Grade 2: 15%, Grade 3: 0
  • Late-term rectal toxicity:Grade 2: 4%, Grade 3:0
These toxicities are nearly identical to those found by Goenka et al. at Memorial Sloan-Kettering Cancer Center using the traditional dosing schedule. The freedom from biochemical failure rate is also similar to other studies using 70 Gy across 7 weeks (e.g., Shelan et al.)

Now, a group at Sunnybrook in Toronto, Gladwish et al., report possibly even better results using a hypofractionation schedule of 3 Gy per treatment in each of just 17 treatments. After a median of 2 years of follow-up, they found:
  • Freedom from biochemical failure: 83%
  • Acute urinary or rectal toxicity, Grade 2 or higher: 20%
  • Late-term urinary or rectal toxicity, Grade 2 or higher: 6%
None of these were randomized clinical trials, so the results across studies are not strictly comparable. However, they do tell us that in well-selected patients treated at centers of excellence, that hypofractionation can reduce treatment times with acceptable safety and efficacy.

Can this be taken further? Ohri et al. conclude:
More aggressive hypofractionation, using a regimen of 6.5 Gy × 5, however, provided significant improvements in both tumor control and expected toxicity... Based on our findings, careful clinical study of more aggressive hypofractionated schedules may be warranted.”

There are a couple of such clinical trials that have taken them up on their challenge. One of them (NCT01923506) is currently enrolling patients at the City of Hope in Los Angeles. There are some peculiarities in this trial. They are treating with doses as high as 45 Gy across 5 treatments to the prostate bed – higher than anyone uses on the whole prostate for primary SBRT! And they are setting a goal of up to 33% of patients experiencing dose-limiting toxicity. I am surprised that their ethics board approved this. I hope the patients are informed that a toxic dose of Grade 3 or higher among 33% of the patients is far out of line from what they'd expect from conventional 70 Gy salvage IMRT I also hope that using such extreme parameters does not discourage future studies.

A more reasonable clinical trial is at the University of Southern California (USC). They are randomly assigning patients to salvage treatment with 5, 10 or 15 SBRT treatments over 1-3 weeks. The other clinical trial is at the University of Virginia (NCT01868386). They are looking only at moderate hypofractionation schedules ranging from 2.5 Gy in each of 26 treatments to 4.26 Gy in each of 10 treatments.

A trial at UCLA is discussed in detail here.

None of these clinical trials mentions the type of equipment, image guidance system, or whether neoadjuvant/concurrent/adjuvant ADT is allowed.

I know many patients will be eager to use a shorter, more intense treatment schedule for salvage radiation therapy based on the encouraging results of SBRT for primary radiation therapy, and the two trials of moderate salvage hypofractionation so far. I am hopeful that clinical trials will confirm their safety and benefit.

Wednesday, August 24, 2016

How early salvage radiation therapy can be used to prevent metastases and save lives

While several clinical trials have established that adjuvant radiation reduces the risk of biochemical recurrence, but only one looked at and demonstrated an improvement in metastasis-free survival and prostate cancer-specific survival. That one (see this link), only compared adjuvant radiation to “wait-and-see,” and a third of the men with a biochemical recurrence were never given salvage radiation. Some retrospective studies (see this link and this link) suggested that salvage radiation could improve metastasis-free and prostate cancer-specific survival, particularly if begun within 2 years of biochemical recurrence and when PSA doubling time (PSADT) is long.

Stish et al. examined the records of 1,106 patients who received salvage radiation therapy (SRT) at the Mayo Clinics between 1987 and 2013. They wanted to determine whether, with a large enough sample size and long enough follow-up, they could show patient characteristics and treatment variables that are associated with salvage radiation saving lives and increasing metastasis-free survival. With a median of 9 years of follow-up, they found that:
  • ·      64 percent had a second biochemical recurrence within 10 years after SRT
o   Biochemical recurrence was higher among men with higher stage, positive lymph nodes, higher Gleason scores, and shorter PSADTs prior to SRT.
o   Biochemical recurrence was lower among men with longer time to reach detectable PSA, those who had adjuvant androgen deprivation therapy (ADT) for more than a year, those who had an SRT dose ≥ 68 Gy, and those who received SRT since 2008.
  • ·      20 percent had distant metastases within 10 years after SRT
o   Incidence of distant metastases was higher among men with higher stage, positive lymph nodes, higher Gleason scores, and shorter PSADT prior to SRT.
  • ·      10 percent died of prostate cancer within 10 years after SRT
o   Prostate cancer mortality was higher among men with higher stage, higher Gleason scores, and shorter PSADT prior to SRT.
  • ·      23 percent died of all causes within 10 years after SRT
o   All-cause mortality was higher among men who were older, and those with higher stage, higher Gleason scores, and shorter PSADT prior to SRT.

As we’ve seen in so many radiation studies, adequate radiation dose (of about 70 Gy) and long-term ADT (see this link) are important for success of SRT. Outcomes are better when patients are treated when the disease has had less time to progress.

Now that use of SRT is declining, it is particularly important to show which patient and treatment variables may aid SRT in saving lives. Although current AUA/ASTRO guidelines advocate adjuvant and salvage RT, we have seen (see this link) that utilization is declining among men with adverse pathology after prostatectomy.

The authors performed a secondary analysis to determine whether it is safe to wait for a higher PSA prior to SRT. It is not. They arbitrarily used a cut-off of 0.5 ng/ml. Post-SRT biochemical recurrence, distant metastases, and prostate cancer mortality were all worse among those who did not receive SRT until PSA was over 0.5 ng/ml.

It’s important not to misinterpret this to mean that a patient can wait for his PSA to rise to 0.5 ng/ml before opting for SRT. This cut-off was chosen quite arbitrarily. Many patients were not diagnosed with a recurrence at lower PSA levels (this analysis includes patients treated as early as 1987), and ultrasensitive PSA did not become widely available until the 21st century. The authors clearly state,

This observation suggests that SRT at the lowest PSA level is most beneficial for long-term therapeutic efficacy.

Dr. Stish emphasized this point in a note to me:

We chose a PSA cutoff of 0.5 ng/ml to allow comparison with other previously reported studies that have cited this arbitrary point of dichotomy. As you read the paper, you will note that our data suggest salvage radiotherapy is most efficacious when the PSA is lowest, and in general we advocate for SRT to be considered at the earliest detectable values following prostatectomy.

As we have seen in several analyses, early SRT should be considered when the ultrasensitive PSA reaches 0.03 ng/ml (see this link). But “considered” doesn’t mean “chosen.” What is of critical importance is that the patient begin meeting with a radiation oncologist to discuss the many considerations, including positive surgical margins -- their size and Gleason score, stage T3/4, lymph node status, PSA stability, Decipher scores, and possible advanced PET studies to detect distant metastases. If they mutually determine that SRT is appropriate, discussions should include such variables as dose, hypofractionation (if any), pelvic lymph node treatment (if any), and adjuvant ADT type and duration.

 note: Thanks to Dr. Brad Stish for allowing me to review the full text and for answering questions.