Showing posts with label recurrence after prostatectomy. Show all posts
Showing posts with label recurrence after prostatectomy. Show all posts

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?

Thursday, July 6, 2017

First US randomized clinical trial of oligometastasis-directed SBRT

In a recent commentary (see this link), we saw that some clinicians are making unsubstantiated claims of cancer control from treatment of oligometastases (less than 5 detected metastases). Only a randomized clinical trial (RCT) can prove that there is any benefit to such treatment. Johns Hopkins has announced the first such RCT in the US.

Stereotactic body radiation therapy (SBRT) is the treatment of choice because it is precise, as well as convenient for the patient (usually completed in 1-5 treatments). It is important to distinguish between two different situations that may involve oligometastases:
  1. Metastasis-directed SBRT after primary treatment (prostatectomy or prostate radiation) and any local salvage radiation has failed. This is sometimes called "metachronous" treatment of recurrent prostate cancer.
  2. Radiation to the prostate and oligometastases in newly-diagnosed men, or men who are radiation- or surgery-naive but have progressed to castration-resistance.
  3. Radiation to metastases for the purposes of pain palliation, or to prevent fractures or spinal compression.
In addition, the situation may be different depending on whether the oligometastases are in the visceral organs, bones, extra-pelvic lymph nodes, pelvic lymph nodes, or some combination of these.

Phuoc Tran is the lead investigator of the "ORIOLE" RCT (NCT0268058) at Johns Hopkins described at this link. It is a small, Phase 2 trial for men in situation A described above. It has some noteworthy characteristics:
  • 36 men will receive SBRT, 18 men will receive standard-of-care treatment
  • Oligometastases are diagnosed by bone scan and CT
  • Patients will be balanced based on whether initial treatment was surgery or radiation, whether they've had hormone therapy, and whether the PSA doubling time was less than 6 months.
  • The primary outcome will be radiographic or PSA progression (by >25% over nadir and by > 2 ng/ml) after 6 months.
  • To be deemed successful, the treatment will have to reduce this measure of progression by 50%
There are several interesting secondary objectives of this RCT:
  • identification of additional metastases using the DCFPyL PET/CT
  • toxicity of treatment reported by doctors
  • pain palliation reported by patients
  • local control of metastases (see below)
  • Number of circulating tumor cells (CTC)
  • Genomic analysis of CTCs
  • Immune (T cell) response to treatment
  • Time until patients have to start life-long hormone therapy
We will see if the radiation activates a systemic T-cell response that may destroy cancer cells beyond the treated tumors (the abscopal effect).

It may seem odd that detection of fewer than 5 metastases by the DCFPyL PET/CT (developed at Johns Hopkins and now in expanded trials) is not a qualifying criterion. Perhaps they will change that for the Phase 3 trial. Or perhaps they want to prove the concept with a bone scan/CT because it will be several years before that PET scan (so far, the most accurate) is widely available and covered by insurance or Medicare. If it works for bone scan/CT-detected oligometastases, it will certainly work for DCFPyL PET-detected metastases.

Update (August 2017): Dr. Tran has made the following change in protocol:
We did change the criteria recently to allow men who had detectable disease on DCFPyL to enroll on the trial, BUT only if the DCFPyL did not show anything more than what is visible on conventional CT-AP and bone scan.  Our thought was that this would allow some patients of the "future" if you will (as PSMA-targeted imaging will be the SOC in 3-5 years) to be included on the trial, but because we do not allow men on the trial with DCFPyL scans that show us more than what is on conventional , we feel that still holds to original concept. 

It is also important to note what is not an objective of this early clinical trial. The outcome we most want to know is whether SBRT treatment of metastases extends overall survival. This 6-month trial will not tell us that. There is no doubt that local control will be excellent, but stopping the progression of 1-3 metastases does not necessarily mean that the cancer has been slowed down systemically at all. Certainly, PSA will fall as an immediate result of treatment. For those who are used to monitoring PSA as a measure of their cancer's systemic progression, this can be confusing. It's worth taking a moment to recall what serum PSA comes from in detectably metastatic disease. PSA is a protein on the surface of prostate cancer cells (and healthy prostate cells too.) It doesn't leak out into the blood from prostate cancer unless a tumor forms with its own blood supply. Tumor blood supply tends to be leaky, and so PSA is detected in the blood serum. Larger tumors with more blood supply put out more PSA. So irradiating those tumors and shrinking them is likely to eliminate the PSA they put out. But what about the micrometastases that do not yet have appreciable blood vessels? If there are thousands of them, will it matter that serum PSA was reduced for 6 months? No one knows the answer to that question and this Phase 2 study will not provide the answer. I hope they will provide radiographic progression-free survival separate from PSA progression-free survival.

For the answers to our most important questions we will have to look forward to the outcomes of some of the other RCTs that have longer follow-up than 6 months.

  • The CORE RCT (active, no longer recruiting) at Royal Marsden Hospital in London will have 5 years of follow-up (completion in 2024), and will include freedom from widespread metastatic disease and overall survival among the outcomes looked at. 
  • The STOMP RCT at University Hospital in Ghent had 2 years of follow-up looked at time to lifelong hormone therapy as its primary outcome (reviewed here). 
  • The PCX IX RCT (among castration-resistant patients) at Jewish General Hospital in Montreal will have 5 years of follow-up (primary outcome in 2025) and has radiographic progression-free survival as its primary outcome. 
  • The French RCT (recruiting, study completion in 2022) will look at radiographic progression-free survival with follow-up up to 3 years. 
  • The FORCE RCT at the University of Michigan (primary completion in 2022) will compare systemic treatment with ADT and any of Taxotere, Zytiga or Xtandi (at the discretion of the treating physician) to similar systemic treatment plus metastasis-directed SBRT for men with mCRPC who have not yet had any of those advanced systemic therapies. They will evaluate progression-free survival after 18 months. "Progression" is defined as alive and at least a 20% increase (and at least 5 mm net increase) in the size of tumors or any new metastases. They will detect metastases via bone scan/CT, However, they will also test whether PSMA-based PET indicators are as useful in among men with mCRPC as it is in men with newly  recurrent disease.

Tuesday, December 20, 2016

Recurrent PC (non-metastatic, hormone sensitive) after curative therapies exhausted? Here are some clinical trials to look at.

A perplexing situation is what to do after one has tried one or more potentially curative therapies (e.g., prostatectomy plus salvage radiation including pelvic lymph nodes), and there are no detectable metastases, but PSA keeps rising. The TOAD randomized clinical trial demonstrated that survival is improved by starting on hormone therapy (intermittent or continuous) as soon as recurrence is observed. Chemo has not proved to increase survival until after multiple metastases are detected (CHAARTED). Waiting for metastases to appear and spot treating them  has not proved to be beneficial either (see this link).

There may be hope in participating in clinical trials. There aren't many. There is a trial for the earlier use of Xtandi therapies, as well as trials for novel therapeutics, like apalutamide and Prostvac, which have been very promising in early trials. Here's a current list that you may wish to discuss with your medical oncologist:

Advanced hormonal therapies:

Apalutamide:at University of Texas, Houston (a larger trial is no longer recruiting)
Apalutamide/ degarelix/abiraterone at 8 locations
Xtandi at 172 locations
Xtandi at University of Colorado, Denver

Immunotherapy/PARP inhibitor:

Prostvac at NIH
Durvalumab + Olaparib at MSK
Olaparib - recurrent - Johns Hopkins & Thomas Jefferson U.

MAO inhibitor:

Phenelzine at USC

Wednesday, August 24, 2016

Probability of remaining recurrence-free after salvage radiation

In 2007, Stephenson et al. published a nomogram that predicted the probability of success of salvage radiation after post-prostatectomy biochemical failure. Biochemical failure was defined as a PSA≥0.2 ng/ml. Memorial Sloan Kettering Cancer Center has made the nomogram publicly available at this link. But that data was put together before ultrasensitive PSA tests became widely available, and before three randomized clinical trials demonstrated an advantage to adjuvant radiation over waiting. Several studies now suggest (see this link) that early salvage may provide the same benefit as adjuvant radiation therapy, but with less risk of overtreatment.

Tendulkar et al. have now updated the Stephenson nomogram.. The original nomogram was based on 1,540 patients treated between 1987 and 2005 at 17 tertiary care facilities. All patients had a confirmed PSA ≥0.2 ng/ml before SRT. Outcomes were based on 6-year progression-free probability after SRT. The updated nomogram is based on 2,460 patients treated between 1987 and 2013 at 10 academic medical centers. It included post-op ultrasensitive PSA test results for some (18 percent) of the patients, but only 18 patients were treated at a PSA≤0.05 ng/ml. The nomogram predicts 5- and 10-year probability of freedom from biochemical failure (PSA≥0.2 ng/ml) after SRT. The authors also constructed a nomogram that predicts 5- and 10-year probability of incidence of metastasis. Their model has a predictive accuracy of about 68 percent for freedom from biochemical failure, and 74 percent for incidence of metastasis.

Update (3/27/2018): Cleveland Clinic now has a more convenient online version of this nomogram on their website:

The tables below approximate the nomogram for predicting the 10-year probability of remaining free of biochemical failure after SRT treatment.

Risk Factor
Score (points)
Yes: 0      No: 49

Gleason score
6: 0      7: 54        8: 70        9/10: 90

Extraprostatic Extension
No:0        Yes:22

Surgical Margins
Positive: 0         Negative: 27

Seminal Vesicle Invasion
No: 0      Yes: 24

Pre-RT PSA (ng/ml)
0.05: 2.5    0.1: 5   0.2:10    0.3: 15        0.5: 25     1.0: 50   1.5: 75

Radiation dose (Gy)
≥66 Gy: 0   <66 Gy: 17

Total points

Total points

As an example, take the case of a man who, after his prostatectomy, had a Gleason score of 9 (=90 points), seminal vesicle invasion (=24 points), margins were negative (=27 points), PSA before SRT was 0.5 ng/ml (=25 points), and his radiation oncologist plans on treating him with a dose of 65 Gy (=17 points) without ADT(=49 points). His total score is 90+24+27+25+17+49= 232. This corresponds to about a 15% probability of success. The doctor and his patient probably would not consider this SRT treatment, given the risk of adverse side effects.

Now, let’s suppose the same man is treated earlier when his PSA is only 0.05 ng/ml (2.5 points) and his radiation oncologist proposes a dose of 70 Gy (=0 points) with ADT beginning two months before SRT (=0 points). His total score is 90+24+27+2.5+0+0= 143.5. This corresponds to about a 55% probability of success. This SRT treatment is a lot more tempting.

Because of database limitations, they could not incorporate PSA doubling time or increases in their model. They also could not include the duration of ADT use or more precise radiation dosage. With more data, a genomic classifier (Decipher®) also might improve the predictive accuracy of their model. Together with other factors like co-morbidities, risk of adverse effects and life expectancy, this nomogram should prove useful in helping the patient and doctor decide whether SRT is worthwhile.

Note: Thanks to Dr. Rahul Tendulkar for providing me with the full text of his original article.