Showing posts with label adjuvant ADT. Show all posts
Showing posts with label adjuvant ADT. Show all posts

Wednesday, September 9, 2020

Adding ADT to external beam radiation only benefits unfavorable risk patients

In 2013, Zumsteg et al. proposed a refinement in the NCCN "intermediate risk" classification into two subcategories, "favorable intermediate-risk (FIR)" and "unfavorable intermediate-risk (UIR)." Based on retrospective studies with short follow-up, they discerned that the two subgroups had divergent prognoses when treated with external beam radiation and adjuvant androgen deprivation therapy (ADT). Since then, others have found that it is also a useful division for deciding whether brachy boost therapy is beneficial (see this link), or whether it is beneficial to add ADT to brachytherapy (see this link). Some FIR patients may be suitable candidates for active surveillance.

It has also been found to be a useful division in terms of prognosis following surgery, brachytherapy, and SBRT (see this link). Some clinical trials use the definition to distinguish  "favorable risk" (low risk or FIR) from "unfavorable risk" (UIR or high risk).  Since 2016, NCCN has incorporated the distinction in its risk stratification system.

The NCCN definitions are as follows:

The NCCN intermediate-risk group is currently defined as having any of the following:
- Stage T2b or T2c, or
- PSA 10- 20 ng/ml, or
- Gleason score = 7 
(If multiple risk factors are present, the clinician may optionally deem it high risk)

Unfavorable Intermediate Risk (UIR):
- NCCN intermediate risk, as defined above, plus
- Predominant Gleason grade 4 (i.e., Gleason score 4+3), or
- Percentage of positive biopsy cores≥ 50%, or
- Multiple NCCN intermediate risk factors

Favorable Intermediate Risk (FIR):
- NCCN intermediate risk, as defined above, but only those with
- Predominant Gleason grade 3 (i.e., Gleason score 3+4 or 3+3), and
- Percentage of positive biopsy cores <50%, and
- No more than one NCCN intermediate risk factor

Now, it has been found to be a useful distinction in an unplanned secondary analysis of a randomized clinical trial, with 17.8 years of median follow-up. Such a long follow-up is unusual for a clinical trial and gives us the ability to see significant numbers of mortality and metastases even in intermediate-risk patients. The trial, RTOG 9408, was originally conducted among 1,068 intermediate-risk patients who received 66.6 Gy to the prostate (low by today's standards) and 46.8 Gy to the pelvic lymphatics. Half the patients received 4 months of adjuvant ADT, and half received none. They lacked biopsy core information on 16%, who are excluded from their analysis. Zumsteg et al. found that adding 4 months of ADT:

  • more than doubled 15-year metastasis-free survival and prostate cancer-specific survival among UIR patients. Mean overall survival was 0.7 years longer with ADT.
  • had no statistically significant effect on 15-year metastasis-free survival, prostate cancer-specific survival, or overall survival among FIR patients
  • it took about 6 years for the differences to start to be noticeable.

Given all the retrospective studies we've seen before that all point to FIR vs UIR as a useful and significant distinction, this is not surprising. It did take a lot of work to review pathology reports on almost a thousand patients, and the authors are to be commended for doing so. If it spares some FIR men from being overtreated, it was a worthwhile effort.

Thursday, June 4, 2020

Importance of Adding ADT to Brachy Boost Therapy for Men with Unfavorable-Risk Prostate Cancer

Last month, we looked at Level 1 evidence (highest level, superseding all previous studies) that for unfavorable risk patients, brachy boost therapy (BBT) [external beam therapy (EBRT) with a brachytherapy boost to the prostate] has better results when accompanied by 18 months of androgen deprivation therapy (ADT). (see this link)

Now a meta-analysis has reaffirmed that finding. The two studies were probably submitted for publication at about the same time, which explains why the meta-analysis doesn't include data from RTOG 01.03 RADAR. In the Jackson et al. meta-analysis (and Medpage summary), there were:
  • 6 randomized trials of EBRT with or without ADT comprising 4,663 patients.
  • 3 randomized trials of EBRT with or without a BBT comprising  718 patients.
    • One of those trials included ADT, the other two did not
Their analysis found that ten-year overall survival was:
  • improved by 30% by the addition of ADT to EBRT
  • not improved by the addition of BBT to EBRT (at least when ADT was not included)
  • The addition of ADT had a bigger impact than the addition of BBT
  • The trial that included both ADT and BBT had the best results
Because this meta-analysis included trials with men from different risk levels, it gives no direction about which therapy is best for favorable- vs unfavorable-risk men. DART 01/03 GICOR proved that adjuvant ADT only provides an added benefit to EBRT in high-risk men (vs intermediate risk men). Furthermore, BBT did not benefit and did add toxicity to favorable-risk patients (see this link).

Some of the trials did not include radiation doses now considered curative. It also did not look at ADT duration.


Sunday, April 19, 2020

Long-term adjuvant ADT improves results of brachy boost therapy in unfavorable-risk prostate cancer patients

TROG 01.03 RADAR, begun in 2003, was a  (partly) randomized clinical trial to help optimize therapy of unfavorable-risk patients. It explored such topics as use of Zometa, radiation dose escalation, and optimal duration of androgen deprivation therapy (ADT) when given along with ("adjuvant" to) radiation therapy (RT).
  • Zometa did not delay progression, which is similar to the STAMPEDE trial finding among men with metastatic hormone-sensitive prostate cancer when it was used without Celebrex. 
  • The external-beam radiation (EBRT) doses they explored (66 Gy, 70 Gy and 74 Gy) were below today's standard of care (78 Gy-82 Gy), so have become irrelevant to current practice. 
  • The assignment to various radiation doses was not randomized. 
  • The benefit of long-term ADT (28 months vs 4 months) with dose-escalated EBRT in unfavorable-risk patients was proved by the DART 01/05 GICOR trial
Based on the Kishan et al. study, brachy boost therapy may be the preferred treatment option for high-risk patients So we will turn our focus to the only outstanding question that this major trial can still shed light on - what duration of adjuvant ADT is necessary when unfavorable-risk patients are treated with high dose rate brachy-boost therapy (HDRBBT)?

Joseph et al. reported the 10-year outcomes of the TROG 01.03 RADAR trial conducted at 24 sites in Australia and New Zealand. From 2003 to 2007, patients were randomized on 6 vs 18 months of adjuvant ADT . There were 1,051 evaluable unfavorable-risk patients defined as:
  • Stage T2b-4 or
  • Stage T2a and Gleason score≥7 and PSA≥10 ng/ml
  • NCCN risk groups: 31% unfavorable intermediate-risk, 66% high-risk
  • Patients with positive pelvic lymph nodes (stage N1) or distant metastases (stage M1) on a bone scan/CT were excluded
The HDRBBT treatment given to 237 patients consisted of:
  • 46 Gy in 23 treatments of EBRT followed by 19.5 Gy in 3 HDR brachy treatments (biologically equivalent to 88 Gy if given as EBRT-only)
  • All patients received 6 months of adjuvant ADT (Lupron) starting 5 months before EBRT 
    • Half were randomized to get 12 extra months of ADT (total =18 months) 
  • Pelvic lymph nodes were not treated
Distant progression (radiographic progression on a bone scan/CT) was the primary endpoint. The 10-year outcomes for those receiving HDRBBT were:

  • 20% distant progression (25% less than 74 Gy EBRT)
  • 2% local progression (71% less than 74 Gy EBRT)
  • 15% bone progression (31% less than 74 Gy EBRT)
  • 9% prostate cancer-specific mortality (25% less than 74 Gy EBRT)
  • 23% all cause mortality (31% less than 74 Gy EBRT)
  • Distant progression was reduced by 39% by the longer ADT treatment. It was statistically significant even after adjustment for potentially confounding risk factors.
  • Longer ADT was beneficial independent of RT dose, whether EBRT or HDRBBT
  • 13% of men receiving HDRBBT suffered urethral strictures vs 4% of men receiving 74 Gy EBRT (for full toxicity data, see this report)
  • The cumulative incidence of transition to castration resistance was significantly lower in men receiving 18 months of adjuvant ADT with RT (in an earlier report)

This establishes the importance of adding long-term (18 months) ADT for all unfavorable risk patients receiving radiation as a primary treatment. The adjuvant ADT gave better outcomes independent of the radiation dose. The Nabid et al trial proved that 18 months is as useful as 36 months in high-risk patients. But rather than slavish adherence to a single number, NCCN recommends 18 months to 3 years of adjuvant, at the discretion of the doctor.

The patient may wish to get more if:

  • there are multiple high-risk features (e.g., GS9-10, PSA>20, T3/4, PNI, rare histology, genomic risk)
  • there is suspicion of lymph node metastases, especially from advanced PET scans
  • side effects are very tolerable

The patient may wish to get less if:

  • there are lower risk features (e.g., GS 6-8, PSA<10, T2, no genomic risk)
  • advanced PET scans (Axumin or PSMA) are negative
  • side effects are onerous
  • treatment is entirely extremely hypofractionated (HDR brachy or SBRT monotherapy)
  • an additional systemic treatment (e.g., docetaxel, Zytiga, Xtandi, Erleada, or Nubiqa) is used experimentally

In an earlier observational meta-analysis (see this link), adjuvant ADT did not seem to add benefit to brachy boost therapy. This once again shows the limitation of observational studies. Only randomized clinical trials can provide the definitive proof we desire for decision-making.

Some patients think they can delay the transition to castration-resistance by eliminating or reducing the amount of ADT used with their RT. This shows that does not happen. Castration resistance is a consequence of genomic breakdown that always occurs as the cancer evolves. It may be facilitated by eliminating the hormone-sensitive cells and leaving only castration-resistant cells (this is called "competitive release"). By eliminating cancer cells as early as possible (before metastases have been detected) using HDRBBT and long-term adjuvant ADT, there is an opportunity to cure the disease. We are learning that cancer cells signal other cancer cells via extracellular vesicles to become like them. Even if it does not cure the patient, the profound reduction of the cancer load has a bigger effect on castration resistance than drug resistance does. This phenomenon was also noted in the TOAD randomized clinical trial (see this link). After there are metastases, an "evolutionary" personalized strategy (like this one) may be preferable.

Tuesday, October 23, 2018

Whole pelvic salvage radiation + short-term ADT improves oncological results

We didn't expect to see this for another two years, but they hit their recruitment goal early and were able to provide 5-year results. Alan Pollack, the lead investigator, presented the preliminary findings of NRG Oncology/RTOG 0534 (or SPPORT) trial at the ASTRO meeting, and in Medpage Today. It proved that salvage whole pelvic radiation (sWPRT) with short term ADT  (STADT) is superior to either prostate-bed only salvage radiation (PBRT) or prostate-bed only salvage radiation with short term ADT.

They randomly assigned 1,792 men with a recurrence after prostatectomy in 2008-2015 at 460 locations in the US, Canada, and Israel to one of 3 therapies:
  1. sWPRT+STADT
  2. PBRT + STADT
  3. PBRT
  • ADT consisted of 4-6 months of a combination of an anti-androgen and an LHRH agonist starting 2 months before salvage radiation.
  • Radiation dose to the prostate was 64.8-70.2 Gy at 1.8 Gy per fraction.
  • Radiation dose to the pelvic lymph nodes was 45 Gy at 1.8 Gy per fraction.
  • The treated pelvic lymph node area was per RTOG guidelines and did not include the recently recommended expansion
The oncological results were:
  • 5-year freedom from progression (biochemical or clinical) was 89% for sWPRT+STADT, 83% for PBRT+STADT, and 72% for PBRT (all significantly different). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
  • 8-year incidence of metastases was 25 for sWPRT+STADT (HR=0.52), 38 for PBRT+STADT (HR=0.64), and 45 for PBRT (sWPRT+STADT was significantly better than the other two)

The reported toxicity results were:
  • GI grade 2 or higher: 7% for sWPRT+STADT vs. 2% for PBRT
  • Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT
  • Bone marrow grade 3: 2.6% for sWPRT+STADT vs. 0.5% for PBRT
  • Late term bone marrow grade 2 or higher was 4% for sWPRT+STADT

There were some caveats. The researchers found that the benefit of salvage whole pelvic treatment and ADT was not maintained in men with very low PSA. There are further analyses expected based on patient risk characteristics and genomic biomarkers. We previously saw in a retrospective study that prostatectomy Gleason score had a significant influence. With better PET scans now, we can have more assurance that whole pelvic radiation is necessary. But at very low PSA (<0.2), even our best PET scans may not find the cancer. Also, it may be that long-term ADT may improve results even further, and that dose escalation may improve results. While this changes the standard of care for many men with persistent PSA and recurrences after prostatectomy, the patient and his radiation oncologist still must rely on judgment.



Wednesday, January 3, 2018

When can ADT be safely avoided with salvage radiation therapy?

Two randomized clinical trials (GETUG-AFU-16 and RTOG 9601) proved that adding at least some ADT to salvage radiation (SRT) improved outcomes. "Some ADT" was 6 months of goserelin in the GETUG-AFU-16 trial, and two years of bicalutamide in the RTOG 9601 trial. Retrospective studies suggest improved outcomes as well (see this link and this one). On the whole, adjuvant ADT improves SRT outcomes. But is there a subgroup of patients, especially those treated early enough, in whom adjuvant ADT can be safely avoided?

This was the subject of a retrospective analysis by Gandaglia et al. They examined the records of 525 post-prostatectomy patients treated with SRT at six international institutions between 1996 and 2009. Inclusion criteria were:
  • Undetectable PSA (<0.1 ng/ml) after prostatectomy
  • Biochemical recurrence - two consecutive PSA rises above 0.1 ng/ml
  • PSA mostly ranged from 0.2 to 0.9 ng/ml (median 0.4) at the time of SRT
  • No detected lymph node metastases
There were 178 patients who received adjuvant ADT (median 15 months) and 347 who had SRT without ADT. Compared to those who received no ADT, those that did were:
  • Similar in age, initial (pre-op) PSA, and Gleason score
  • More likely to be stage T3b/4
  • Less likely to have positive margins
  • Received higher SRT dose (70 Gy vs 66 Gy)
There were 8 years median follow-up for those who had no ADT, and 12 years median follow-up for those who had adjuvant ADT. The authors compared the actual 10-yr metastasis rate to the predicted 10-yr metastasis rate based on PSA at SRT, Gleason score, stage, positive margins, SRT dose, and whether lymph nodes were treated. They found that:
  • Only those with a 10-year probability of distant metastases greater than 1 in 3 benefited from the addition of ADT
  • The benefit grew exponentially with increasing risk
  • Adjuvant ADT only benefited those with higher PSA (≥0.4 ng/ml), Gleason score 8-10, stage T3b/4. 
  • Higher SRT dose and whole pelvic SRT improved outcomes independently of whether adjuvant ADT was used.
It should be noted that high-dose SRT and whole pelvic treatment were used in a minority of cases, and there is a significant risk of selection bias in this study.

The authors conclude that a higher radiation dose alone may be sufficient to treat many patients with a recurrence detected early enough, but for those with aggressive tumor characteristics, adjuvant ADT will improve outcomes measurably. While this was not proved with a randomized trial, it does suggest that adjuvant ADT will not be necessary in all cases of SRT. Patients who are undecided may wish to have a Decipher genomic classifier done on their prostate tissue to determine their 10-year risk of metastases.

Wednesday, December 27, 2017

Is ADT still needed for high risk patients receiving brachy boost therapy?

Brachy boost therapy (external beam plus a brachytherapy boost to the prostate) is the gold standard for high risk patients, reporting the best oncological outcomes of any therapy. While long-term adjuvant ADT has proven to be beneficial in prolonging survival in high risk patients when used in conjunction with dose-escalated external beam radiation (DART 01/05 GICOR), there has never been a randomized trial to determine if there is any benefit to ADT when used with brachy boost therapy.

All we have to go by are several single or multi-institutional studies and one large database analysis. Almost all of the studies so far show no effect to short-term (4 months, starting 2 months prior and running concurrent with the radiation therapy) adjuvant ADT.

Two of the studies used a boost of low dose rate brachytherapy, predominantly using Pd-103 seeds. Dattoli et al.  found there was no significant difference in 16-year PSA progression-free survival (PSA-PFS) whether 4 months of ADT were added or not. D'Amico et al. also found no significant difference in 8-year prostate cancer specific mortality (PCSM) with the addition of ADT. However, they felt that it was "approaching significance" (p=.08) and might become statistically significant with longer follow-up. In contrast to the Dattoli study, the D'Amico study did not treat the pelvic lymph nodes.

A recent analysis of the large National Cancer Database by Yang et al. did not detect any benefit to adding ADT on 8-year overall survival (OS). The database lacks specific information about type of brachytherapy, radiation doses, duration of ADT, and whole-pelvic treatment,

Several studies that used high dose rate brachytherapy as a boost also looked at this issue retrospectively. Demanes et al. was the earliest of those studies. They found no difference in 10-year PSA-PFS in their 113 high risk patients treated between 1991-1998. Several subsequent studies confirmed those findings. Galalae et al. concatenated the databases from 3 institutions: Kiel University, University of Washington Seattle and William Beaumont Hospital. Short-term adjuvant ADT failed to demonstrate improved 10-year PSA-PFS in the 359 high risk patients treated between 1986 and 2000. And the lack of effect was demonstrated at all three institutions. Kotecha et al. also failed to find any differential improvement in 5-year PSA-PFS among 61 high risk patients treated with HDR brachy boost at Memorial Sloan Kettering between 1998 and 2009.

There has been one "outlier" study. Schiffmann et al. reported on 211 consecutive high-risk patients treated at the University Medical Center Hamburg-Eppendorf from 1999 to 2009. After 10 years, the biochemical recurrence-free survival was 50% with the adjuvant ADT but only 39% without it - a very statistically significant and meaningful difference. However, even the "improved" outcome seems low compared to the ASCENDE-RT trial where everyone got early neoadjuvant and adjuvant ADT. In that trial, the 9-year PSA-RFS for high risk patients receiving the trimodality therapy was 83%. Another multi-institutional study of HDR-brachy boost therapy reported 10-year PSA PFS of 85% with ADT and 81% without ADT in high risk patients. It is plausible that the patients in the Hamburg study had more advanced disease and had more undetected micrometastases compared to the other studies.

The following table summarizes the treatments given in the aforementioned studies, and whether there was a statistically significant improvement (p<.05).




Relative BED is the biologically effective radiation dose as a percent of the BED of 79.4 Gy of IMRT in 44 fractions.


Short-term vs. Long-term Adjuvant ADT

ADT is believed to have two effects when used in conjunction with radiation. Used before radiation begins (neoadjuvant use) and during radiation treatments (concurrent use), it radio-sensitizes the cancer. Lab findings suggest that it interferes with cancer cell repair of the induced DNA double-strand breaks. Used after radiation (adjuvant use), ADT is believed to "clean up" any remaining local micrometastases that survived. The death of cancer cells from both the radiation and the ADT dumps antigens into the serum that may activate T-cells. Those T-cells may hunt out and destroy small amounts of cancer cells nearby (the bystander effect) or systemically (the abscopal effect).

The bulk of the above retrospective studies suggest that the radiosensitizing effect is unnecessary with the very high radiation doses given with brachy boost therapy. However, what remains to be shown is whether long-term ADT might confer any additional benefit. The DART 01/05 GICOR trial proved that there was a significant benefit to 28 months of ADT compared to 4 months in high risk patients treated with dose-escalated EBRT. It is possible that while short-term ADT may have no benefit, long-term ADT combined with brachy boost therapy might.

TROG 03.04 RADAR was an Australian randomized trial that was designed to detect whether Zometa and longer duration of ADT (18 months vs 6 months) could provide better cures when combined with varying doses of radiation (radiation dose received was stratified but not randomized). Some of the patients received brachy boost therapy. In general, it found that higher radiation doses combined with longer duration of ADT provided the best outcomes. However, among those patients who received HDR brachy boost therapy, there was no significant difference in local progression (fig.2 - showing overlapping standard error bars) whether they received 18 months or 6 months of ADT. Future follow-up may reveal whether long-term ADT prevents distant progression.

The very high rates of cancer control (around 80%-85%) using brachy boost therapy may be as high as we can reasonably hope for, given that there will always be some patients with undetected occult micrometastases.

Better patient selection

High-risk patients are usually given a bone scan and CT to help rule out distant metastases. Bone scans are non-specific to prostate cancer and are not very sensitive when the PSA is below 20 ng/ml. CT scans detect metastases larger than about 1.2 cm, but most metastases are smaller than that. The newly-approved Axumin PET scan, and the experimental PSMA-based PET scans now in clinical trials may be able to detect those distant metastases earlier. However, there are currently no PET scans approved for high-risk patients outside of clinical trials (they are only approved for recurrent and advanced cancer patients). In the future, those high-risk men in whom metastases have been detected via PET scans may be better candidates for systemic therapies, while those in whom no metastases have been detected may be better candidates for brachy boost therapy. It may be economically justifiable to use PET scans for this purpose. Perhaps we will see another 5-10% increase in cancer control rates, even without ADT, with better patient selection. A recent analysis of recurrent patients after prostatectomy diagnosed using the Ga-68-PSMA PET/CT found that 12% had previously undetected metastases outside of the radiation treatment field.

Dose Escalation

At the high biologically effective doses (BEDs) used in all the brachy boost studies, there does not seem to be a significant interaction between dose used and whether ADT was effective. The Dattoli study had the lowest BED, but no benefit to added ADT, while the Galalae study had the highest BED, but also no benefit to added ADT. The Hamburg study had high BED but did demonstrate a benefit to added ADT. All of the brachy boost studies seem to have adequate radiation doses.

Whole Pelvic Radiation

It is possible that pelvic lymph nodes are best treated with a combination of radiation and ADT.  Bittner et al. looked at 186 high risk patients treated with the brachy boost  therapy. The 10-year PSA-PFS was:

  • 94% if they received both whole pelvic radiation and ADT
  • 82% if the received whole pelvic radiation without ADT
  • 90% if they received ADT without whole pelvic radiation
  • 75% if they received neither ADT nor whole pelvic radiation


ADT seemed to have a bigger effect than whole pelvic radiation. This may be because the whole pelvic radiation dose is inadequate. The doses given to the pelvic lymph nodes are quite a bit lower (about 50 Gy in 28 fractions) than the dose to the prostate. If Dr. King is right that prostate cancer is inherently radioresistant and requires a higher lethal dose (about 79.2 Gy/44 fx) to be effective, even when the cancer is only in the prostate bed (see this link), it is possible that pelvic lymph nodes require a higher dose as well. Because of the potential bowel toxicity of escalated pelvic doses, adjuvant ADT may be necessary to achieve effective cell kill rates without dose-limiting toxicity. We saw in a recent analysis that, in the salvage situation among patients with GS 8-10, whole pelvic radiation and ADT both had significant benefits. Whether whole pelvic radiation is effective in high risk patients treated with brachy boost therapy and ADT is the subject of a major ongoing randomized clinical trial (RTOG 0924).

Retrospective vs Prospective Trials

All of the published studies so far have been retrospective and are therefore subject to selection bias: those who received the ADT had more progressed disease than those who received the brachy boost without ADT. Therefore, it will always be impossible to convincingly resolve this issue without a prospective randomized clinical trial.

Patient decisions

Until we have definitive results from randomized clinical trials, the decision over whether to add ADT to brachy boost therapy will be challenging. Many patients are persuaded by the extra insurance ADT provides, and that only a short course seems to be necessary. Others are so ADT-averse that even a short course is unthinkable, especially with no concrete evidence of efficacy.

The decision over whether to include the whole pelvic area in the external beam radiation field may be an easier decision. High risk patients have a significant probability that there are small metastases harbored in pelvic lymph nodes. Recent studies have shown the treatment field must be wider than  was previously thought. For some patients with anatomical abnormalities, low visceral fat, and a history of bowel disease, this too may present a challenging decision.



Sunday, December 24, 2017

Salvage whole pelvic radiation after cancerous pelvic lymph nodes have been found

Is it still worthwhile to attempt salvage radiation (SRT) after positive pelvic lymph nodes (stage pN1) have been pathologically detected? Traditionally, patients with PLND-diagnosed pN1 prostate cancer have been considered to have incurable systemic disease. Therefore, they were either observed until distant metastases were identified or started on lifelong androgen deprivation. Retrospective studies of the benefit of salvage whole pelvic SRT for pN1 patients have been equivocal: Abdollah et al. and Rusthoven et al. showed a benefit to salvage RT, but Kaplan et al.showed no benefit.

In an analysis of the National Cancer Database of 7,791 prostatectomy patients (treated from 2003-2010) who were staged pN1 after PLND, Zareba et al. found that most (63%) were initially observed without treatment, and an additional 20% received androgen deprivation (ADT)-only within a year of diagnosis. Only 18% received SRT, most of those (72%) with adjuvant ADT. Those treated with whole pelvic SRT+ADT had worse disease characteristics than those who were observed only: higher Gleason score, higher stage, higher positive surgical margin rate, and greater number of positive lymph nodes.

After 5.9 years median follow-up on 3,680 patients:
  • Treatment with whole pelvic SRT+ADT decreased 10-yr mortality by 31% compared to observation only, and by 35% compared to ADT-only.
  • Treatment with ADT-only or SRT-only was not associated with an increase in survival

Touijer et al. reported on 1,388 pN1 patients treated at three top institutions: Memorial Sloan Kettering (MSK), the Mayo Clinic, and San Raffaele Hospital in Milan. The MSK cohort was primarily only observed, the Mayo cohort primarily received lifelong ADT-only, and the Milan cohort was primarily treated with whole pelvic SRT+ADT As in the Zareba study, SRT+ADT patients had worse disease characteristics.

After 5.8 years median follow-up:
  • Treatment with whole pelvic SRT+ADT decreased 10-yr mortality by 59% compared to observation only, and by 54% compared to ADT-only.
  • Those with worse disease characteristics benefited the most.
  • Treatment with ADT-only was not associated with an increase in survival compared to observation, although prostate cancer-specific survival was increased.

None of these studies reported the toxicity of the salvage treatment, but with improved external beam radiation techniques and scrupulous image guidance, toxicity has been improving.

These two studies had very similar outcomes. Although they were both retrospective studies rather than prospective randomized trials, it should be noted that the selection bias that typically plagues retrospective studies favored those who did not receive SRT+ADT. In spite of their worse disease characteristics, the patients who received pelvic SRT+ADT survived longer.

Recently we saw a similar advantage to pelvic SRT+ADT even in men who were not diagnosed as stage pN1 with a PLND (see this link). Taken together, these studies indicate a marked survival advantage to treating the whole pelvic area in men with pathologically diagnosed high-risk prostate cancer post-prostatectomy. A previous study found that among men with pN1, the ten-year incidence of distant metastases was 35%, suggesting that spread may be confined to pelvic lymph nodes for some time. This creates a unique window of opportunity during which salvage treatment may still be curative.

We have also seen evidence that high risk patients with imaging-detected positive lymph nodes benefited from whole pelvic radiation as primary therapy (see this link).

These studies also constitute better evidence than we currently have that whole pelvic radiation with ADT is a better idea than picking off lymph nodes one at a time (for which we have no evidence of survival benefit). As we have seen (see this link), our ability to detect all cancer-infected lymph nodes is poor.

There are several variables that the patient and doctor must decide upon, and for which there is no clear evidence: duration of adjuvant ADT, amount of radiation, and the pelvic lymph node field. Clinical trials show that at least 6 months of adjuvant ADT with SRT even without lymph node involvement increases oncological effectiveness, the optimal duration is unknown and may vary with disease characteristics (see this link). The amount of radiation to the pelvic lymph node field seems to be about 50 Gy in most cases, and the amount given simultaneously to the prostate bed will ideally be at least 70 Gy (see this link). The extent of the treated area has been questioned recently. Studies show that infected lymph nodes are often missed in the common iliac area (see this link). There will be variations due to individual anatomy and known bowel sensitivity.

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


PBRT
WPRT
TOTAL
With ADT
51%
66%
55%
Without ADT
48%
60%
50%
TOTAL
49%
62%
51%




Among GS 7:



With ADT
56%
70%
59%
Without ADT
52%
66%
54%
TOTAL
53%
67%
56%




Among GS 8-10:



With ADT
45%
64%
49%
Without ADT
34%
44%
35%
TOTAL
37%
53%
44%


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, March 27, 2017

Conflicting messages after surgery for high-risk patients from radiation oncologists and urologists

In spite of the data suggesting that brachy boost has better outcomes for high risk patients, it is being utilized less often and surgery is being utilized more often. After surgery, the high-risk patient is monitored by his urologist (Uro). If the urologist fears a recurrence, he may (1) refer his patient to a radiation oncologist (RO) for adjuvant or salvage radiation therapy (A/SRT), (2) refer his patient to a medical oncologist if he believes the recurrence is metastatic and incurable, or (3) he may continue to monitor the patient. The rate of utilization of A/SRT has been dwindling in spite of three major randomized clinical trials that proved that ART has better outcomes than waiting. If the patient does get to see a radiation oncologist, he may be advised to be treated soon, in conflict with the urologist advising him to wait. This puts the patient in a difficult situation.

Kishan et al. report the results of a survey among 846 ROs and 407 Uros. The researchers sought their opinions about under which conditions they would offer a high-risk post-prostatectomy patient A/SRT. For the purposes of their survey, they defined "adjuvant RT" as radiation given before PSA has become detectable, and "salvage RT" as radiation given after PSA has become detectable. "Early salvage RT" means PSA is detectable but lower than 0.2 ng/ml.

The following table shows the percent of ROs and Uros who agreed with each survey question:



RO
Uro
ART underutilized
75%
38%
ART overutilized
4%
19%
SRT underutilized
65%
43%
SRT overutilized
1%
5%



SRT when first PSA is detectable
93%
86%
ART when first PSA is undetectable
43%
16%
Early SRT when first PSA is undetectable
42%
43%
SRT when first PSA is undetectable
16%
41%



Recommend SRT if PSA is:


Detectable
15%
7%
2+ consecutive rises
30%
20%
>0.03-0.1
8%
8%
>0.1-0.2
13%
11%
>0.2-0.4
29%
35%
>0.4
5%
19%



Recommend ART if pathology report is adverse:


Positive margin
80%
47%
Extraprostatic Extension (pT3a)
60%
32%
Seminal Vesicle Invasion(pT3b)
68%
47%
Local organ spread (pT4)
66%
46%
Pelvic lymph node (pN1)
59%
29%
Gleason score 8-10
20%
20%
Prefer SRT
12%
25%



Recommend adjuvant ADT with ART if:


Positive margin
14%
12%
Extraprostatic Extension (pT3a)
15%
11%
Seminal Vesicle Invasion(pT3b)
29%
25%
Local organ spread (pT4)
36%
37%
Pelvic lymph node (pN1)
65%
46%
Gleason score 8-10
46%
28%
No ADT
22%
31%



Recommend whole pelvic A/SRT if:


Positive margin
6%
9%
EPE
12%
9%
SVI
25%
22%
pT4
30%
30%
pN1
82%
64%
GS 8-10
36%
24%
No role
12%
24%
Other
13%
3%

In contrast to Uros, ROs are more likely to believe that both ART and SRT are underutilized. Uros believe that are used about right. ROs often see patients too late if they see them at all.

When the first PSA is detectable, both kinds of doctors would recommend SRT. When the first PSA is undetectable, 43% of ROs would recommend ART nonetheless, while only 16% of Uros would recommend ART.

Most of the ROs would treat when they see 2 consecutive rises in PSA, or if the PSA was detectable and under 0.2. Most (54%) Uros would wait until PSA was over 0.2.

Over half the ROs would recommend ART to high risk patients demonstrating any of several adverse pathological features: positive margins, stage T3/4, or positive pelvic lymph nodes. The majority of Uros would not recommend ART to high risk patients with those adverse pathologies.

The majority (65%) of ROs would include adjuvant ADT if there were positive lymph nodes. Uros were less likely to recommend adjuvant ADT based on lymph node involvement and Gleason score.

While most of both groups would have added whole pelvic radiation for patients with positive lymph nodes, 82% of ROs would, but only 64% of Uros.

ROs, knowing that a locally advanced cancer can suddenly become metastatic, and therefore incurable, would like to give A/SRT as soon as possible. Uros, who treat patients for the combined effect of surgery and radiation on urinary and sexual function, would like to wait as long as possible. The patient is caught in the middle of this difficult decision. Some have recommended beginning neoadjuvant ADT at the lowest detectable PSA and extending that time for as long as needed  to give urinary tissues maximum time to heal. Whatever the high-risk patient may eventually decide is in his best interest, he should meet with an RO immediately after surgery to hear both sides of the issue. Uros are blocking access to information that the patient needs.