Whole-pelvic radiation therapy for high-risk patients

The decision about whether or not to treat the entire pelvic lymph node area along with the prostate (called whole pelvic radiation therapy (WPRT)) or to treat just the prostate with a margin around it (called prostate-only radiation therapy (PORT)) has long been a matter of judgment. Now we have proof of its benefit in most high-risk patients.

Murthy et al. reported the results of "POP-RT," a randomized clinical trial conducted among 224 high-risk and very high-risk patients treated at the Tata Memorial Hospital in Mumbai, India between 2011 to 2017. What sets this trial apart from previous trials that had equivocal results (like RTOG 9413 and GETUG-01) are the rigorous patient selection criteria and the now-proven treatments they received.

80% of patients were screened using PSMA PET/CT to rule out those with already-detectable lymph node or distant metastases. The rest were staged using bone scan/CT. Local staging (T1-4) was done with CT, MRI, and physical examination. Patients had to have a probability of microscopic lymph node metastases of greater than 20% using the Roach formula:

Probability of cancer in pelvic lymph nodes = (⅔ x PSA) + (10 x (Gleason score - 6))

This meant that high-risk patients had to have the following risk characteristics:

• If Gleason Score 8-10: Any PSA, T1- T3a N0 M0 
• If Gleason Score 7: PSA > 15, T1-T3a N0 M0 
• If Gleason Score 6: PSA > 30, T1-T3a N0 M0
• Also, any other "Very High Risk" including T3b-T4 N0 M0, with any Gleason Score, any PSA, if their Roach probability was > 20%
• In this group of patients, the median Roach probability was about 40% and the median PSA was 28 ng/ml.

Treatment consisted of dose-escalated IMRT and 2 years of adjuvant androgen deprivation therapy (ADT):

• Prostate dose= 68 Gy in 25 fractions or treatments (equivalent to about 81 Gy in 40 treatments)
• Pelvic lymph node dose = 50 Gy in 25 treatments (note: this is somewhat higher than the 45 Gy in 25 treatments that is usually given)
• Pelvic lymph nodes up to the aortic bifurcation were treated, which conforms to current RTOG specs.
• ADT was started 2 months before IMRT and continued for a total of 2 years
• Note: this trial began before ASCENDE-RT proved the superiority of brachy boost therapy, but used a higher IMRT dose and longer ADT. This high-dose IMRT/long-term ADT treatment was proven effective by the DART 01/03 GICOR trial.

After median follow-up of 68 months, the oncological results were:

• 5-year biochemical failure-free survival was 95% for the WPRT group vs. 81% for the PORT group.
• 5-year disease-free survival, which means they had no PSA progression and no radiographic progression, was 90% for WPRT (15 recurrences) vs 77% for PORT (36 recurrences).
• 5-year metastasis-free survival, which is a good surrogate endpoint for overall survival, was 95% for WPRT vs 88% for PORT
• Younger patients (< 66) derived more benefit from WPRT
• Among those with recurrences, most (52%) of the recurrences in the PORT arm were in pelvic lymph nodes, whereas few (12.5%) were nodal recurrences in the WPRT arm.

Murthy et al. also reported on toxicity and patient-reported quality of life outcomes comparing the two treatments.

• Acute grade 2 or greater GI toxicity was 33% for WPRT vs 25% for  PORT (not statistically different)
• Acute grade 2 or greater GU toxicity was 33% for WPRT vs 24% for PORT (not statistically different)
• Late-term grade 2 or greater GI toxicity was 8.2% for WPRT vs 4.5% for  PORT (not statistically different)
• Late-term grade 2 or greater GU toxicity was 20.0% for WPRT vs 8.9% for PORT (statistically different)
• Very few patients in either arm suffered serious (grade 3) toxicity. There was no grade 4 toxicity.
• While higher rectal radiation doses were not associated with higher bowel toxicity, higher bladder doses were associated with higher urinary toxicity.
• Patient-reported outcomes were not significantly different for urinary, bowel or sexual adverse effects.
• (update 3/24) no significant changes at 75 months.

It is worth noting that cancer in the Indian population is generally more progressed than in the US population at the time of diagnosis. Those with Stage T3b/T4 (seminal vesicle invasion and invasion into surrounding organs) accounted for 47% of this group, whereas it's a rare finding in the US because of more prevalent earlier PSA testing. Another difference is that 27% of patients had a previous TURP, which is high compared to the US. It is possible that the high TURP rate may have contributed to extra urinary toxicity seen in men getting WPRT.

Given the relatively mild side effect profile with no clinically significant difference to patients, WPRT should be the standard of care for high-risk patients at high risk of pelvic lymph node involvement. In 2027, we will have the results of a much larger, multi-institutional randomized trial (RTOG 0924) of WPRT vs PORT. Also, there was no increase in second malignancies due to the expanded coverage in this study.

Is whole pelvic radiation needed for primary treatment of Gleason 9/10?

Whether whole pelvic radiation therapy (WPRT) is beneficial for men newly diagnosed with Gleason 9/10 (Grade Group 5) is controversial. There is an ongoing randomized clinical trial (RTOG 0924) that will have results by 2027 at the earliest, but it includes intermediate and high-risk patients, very few of whom will have Gleason 9/10. Two previous randomized clinical trials (RCTs) gave conflicting results: RTOG 9413 showed a benefit to WPRT combined with ADT started before and continued through radiation treatment, while GETUG 01 found no benefit. However, neither RCT delivered doses of radiation that would be considered adequate by today's standards (70 Gy vs 80 Gy).

Sandler et al. analyzed the databases of 12 major institutions that treated 1170 Gleason 9/10 patients between 2000 and 2013.

• 299 received external beam radiation therapy (EBRT) boost to the prostate + WPRT
• 435 received EBRT only to the prostate + a small margin around it
• 320  received a brachytherapy boost (BBT) to the prostate + WPRT
• 116 received BBT only to the prostate + a small margin around it
• Patients were matched on age, T stage, PSA, Gleason score, and analyzed by ADT duration

After median follow-up of 5.6 years, 5-year biochemical recurrence-free survival (bRFS) was:

• 88% for BBT+WPRT
• 78% for BBT alone
• 66% for EBRT+WPRT
• 58% for EBRT alone
• WPRT was significantly improved by BBT (Hazard Ratio = 0.5, p=0.02) but not by EBRT (HR=0.8, p=0.4))
• Neither distant metastasis-free survival nor prostate cancer-specific survival were significantly improved by WPRT

In interpreting these findings, patients should discuss the following considerations with their radiation oncologists.

Lack of long-term follow-up

As we have observed before (see this link), it can take 15 or more years until over half of high risk patients have detectable metastases (by bone scan/CT) or have succumbed to prostate cancer. In this study, only 35% of those getting EBRT alone had been diagnosed with distant metastases, and only 23% had died of prostate cancer. The rates for all other groups were smaller. As the data mature, we expect that the now-evident and statistically significant differences in biochemical failure will eventually result in higher rates of metastases and mortality.

Lack of local control with EBRT only

ASCENDE-RT proved that prostate cancer is better controlled in high-risk patients by a brachytherapy boost than by EBRT alone. Local control (of cancer in the prostate) is obviously required because the high grade cancer easily progresses and metastasizes from the prostate.

Lack of regional control with surgery

As we have seen, prostatectomy, even when followed by radiation (see this link) seems to provide inferior cancer control compared to BBT with WPRT. This may be because the salvage radiation dose to the prostate bed (usually only 66-70 Gy) is inadequate compared to the primary radiation dose (see this link).

Inadequate coverage/detection of pelvic lymph nodes

In the present study, patients received WPRT to the standard pelvic lymph nodes. We have seen that this is inadequate to reach  the cancerous pelvic lymph nodes in over 40% of patients (see this link). Current methods do not allow us to find most of the cancerous lymph nodes (see this link). While PET scans are not yet FDA-approved for high-risk patients (as they are for recurrent patients), there are a few available in clinical trials.

Inadequate dose to pelvic lymph nodes

The dose to pelvic lymph nodes is often about 45-50 Gy given in 1.8 Gy increments. If it's true that perfect cancer control is achieved only with doses around 80 Gy, this treatment may be inadequate to control some of the larger lymph node metastases. This may be especially true because lymph node metastases are not well-oxygenated (hypoxic). As PET/CTs and PET/MRIs become available for high-risk patients, it may become possible to target known lymph node metastases with higher doses. Another fertile area for investigative research is radiosensitization with hyperthermia (see this link).

Toxicity

In RTOG 0534, late Grade 2 or worse gastrointestinal toxicity occurred in 7% of those receiving WPRT. While this is higher than the 2% experiencing this degree of toxicity with prostate-only EBRT treatment, it is nevertheless at a low level. In a large non-randomized, retrospective study comparing WPRT to prostate-only radiation, Parry et al. found no difference in the 3-year cumulative incidence of gastrointestinal and urinary toxicity among high risk and locally advanced patients.

Because we may never have more reliable data, patients and their radiation oncologists must make this decision based on this study and judgement for the foreseeable future.

note: Thanks to Amar Kishan for allowing me to see the full text.

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?

ADT and radiation for first-line treatment of node-positive (N1) prostate cancer

It’s now a rare occurrence (12%) to be newly diagnosed with pelvic lymph node positive (N1) prostate cancer. Traditionally, this had been treated with ADT only because radiation therapy (RT) was thought to be of no benefit in extending survival. A new study seems to show that adding RT to ADT can extend survival.

There are a couple of reasons why this kind of diagnosis is rare. First, since PSA-screening became widespread in the US, patients are usually diagnosed before the cancer has spread to the lymph nodes (LNs). Secondly, while detection tools have improved, detection of positive nodes remains challenging. CT scans can only detect lymph nodes that have been seriously enlarged by cancer invasion, and enlargement doesn’t necessarily mean it’s cancerous. For that, a confirming biopsy is necessary yet very difficult because of huge anatomic variation and the near-invisibility of LNs. Multiparametric MRIs and C11-Choline PET/CT may improve diagnostic accuracy over CT alone, but they lack the sensitivity we would ideally want. There is hope that the new generation of PSMA antibody-linked PET-indicators, especially when tied to the new PET/MRI machines, may improve diagnostic accuracy. USPIO MRIs have been used to find cancerous LNs, but not in the first-line therapy setting. Cost of screening may be prohibitive for any of these to be used routinely.

Let’s distinguish between several settings in which radiation might be used on lymph nodes. All of these settings assume there are no distant metastases (M0):

a. First-line RT to the whole pelvis when cancerous nodes have been identified. I will be addressing setting “a” in this article.

b. First-line RT to the whole pelvis when cancerous nodes are suspected but not identified. This was the subject of the clinical trial RTOG 94-13, and the ongoing clinical trial RTOG 0924.

c. Adjuvant or salvage RT to the pelvic LNs when cancerous nodes have been identified. This was the subject of two retrospective studies published last year by Abdollah et al.  and by Rusthoven et al. that showed a benefit to salvage RT, and one by Kaplan et al. that showed no benefit. Update (10/2017) analyses by Zareba et al. of the National Cancer Database and by Touijer et al. of retrospective data from MSK, Mayo and San Raffaele Hospital (Milan) also suggest a benefit to salvage RT.

d. Adjuvant or salvage RT to the pelvic LNs when cancerous nodes are suspected but not identified. This is the subject of the ongoing clinical trial RTOG0534.

e. Spot radiation to one or several LNs upon recurrence after radical prostate treatment. This was the subject of some small studies by Picchio et al., Bonomo et al., and Jereczek-Fossa et al.

(Update 4/2019) Sargos et al. reported the results of a multi-institutional randomized trial comparing whole pelvic radiation+ADT to ADT alone in 263 men with locally advanced prostate cancer.

• all men received 3 years of Lupron
• half the men also received 66-74Gy to the prostate and 46 Gy to the whole pelvis
• 8-year progression-free survival was 48% for RT+ADT vs 7% for ADT alone
• 8-year prostate cancer mortality was reduced by 48% by adding RT
• 8-year overall survival was 65% for RT+ADT vs 57% for ADT alone (similar at 8 years)
• 8-year metastasis-free survival was similar at 8 years, but loco-regional progression was lower in the RT+ADT arm

In a 2001 study from MD Anderson, Zagars et al. retrospectively looked at patients who had a prostatectomy between 1984 and 1998, but where the surgery was not completed after positive LNs were detected. Traditionally, if frozen sections of pelvic nodes revealed cancer, the prostatectomy was discontinued and ADT only was immediately begun. Such patients fared much better in terms of disease progression if they were treated with both ADT and RT than if they were treated with ADT alone. After 10 years, the overall survival among those who received RT and ADT was 67%, but only 46% if they only received ADT.

In a 2013 retrospective analysis of the SEER database, Tward et al. found 1,100 patients who were diagnosed with node-positive prostate cancer between 1988 and 2006. The 10-year prostate cancer specific survival was 63% among those who received definitive RT, but was significantly lower, 50%, among those who did not.

In a similar analysis of the SEER database last year, Rusthoven et al. found 796 patients who were clinically diagnosed with positive lymph nodes between 1995 and 2005. 43% had RT and the rest had no local therapy. The 10-year prostate cancer specific survival was 67% if they received definitive RT, but was 53% if they did not.

In an early subgroup analysis of the STAMPEDE trial, those who were N1 and received ADT and RT (at least RT was planned) had a 2-year failure-free survival of 85%. This compared to only 55% among those who were N1 and received only ADT.

In an analysis of the National Cancer Database, Lin et al. identified 3,682 patients who were clinically diagnosed with positive lymph nodes between from 2004 to 2011. A third were treated with ADT only, and a half had both RT and ADT. The 5-year overall survival was 86% for those who received both RT and ADT, but was 71% if they received ADT only. They found 331 matched pairs of patients who had similar risk factors, and found that adding RT to ADT decreased 5-year mortality by 58%. The authors conclude:

"These data, if appropriately validated, suggest that a significant proportion of such patients at high risk for prostate cancer death may indeed be undertreated warranting a re-evaluation of current practice guidelines.”

Further evidence that whole-pelvic RT may be beneficial for all node-positive patients comes from retrospective analyses of its use in the salvage setting. As mentioned in setting “c” above, several previous studies have looked at adjuvant or salvage RT after positive lymph nodes have been detected during prostatectomy using  pelvic lymph node dissection (PLND). Extended PLND (ePLND) is gaining in popularity, especially in Europe, in which 30 or more pelvic lymph nodes are extracted in hope of a providing a cure without adding RT. Alternatively, the surgeon may remove the prostate, and refer the patient for adjuvant RT. While the two most recent retrospective studies have shown a survival benefit to adjuvant/salvage radiation, one did not, and we do not yet have a randomized clinical trial to provide definitive answers.

While most of these recent studies suggest a benefit to whole pelvic RT treatment of node positive newly diagnosed prostate cancer, we cannot be sure of that until randomized clinical trials are conducted. To my knowledge, there are none so far.

The other side of the equation is the effect of pelvic radiation on quality of life. The data are equivocal. In RTOG 94-13, Grade 3 lymphopenia, and Grade 3 GI toxicity was a problem for 8% and 5%, respectively,  among those receiving neoadjuvant ADT and whole pelvic RT.  DeVille et al. noted a higher rate of acute GI toxicity, but not late GI toxicity. At escalated doses, Johnson et al. noted that late term GI toxicity was much higher in men who received whole pelvic RT, while Patel et al. noted no significant difference in toxicity.

There are many outstanding questions, with few clear answers, for the doctor and patient to discuss with respect to RT for N1 prostate cancer:

• What is the most appropriate radiation dose?
• Is there a limit to the number of infected nodes beyond which it is fruitless to use RT? 
• Should simultaneous integrated boost RT be used on infected nodes? 
• Can SBRT equal or improve the risk/benefit profile over IMRT? 
• What is the best timing for neoadjuvant/concurrent/adjuvant ADT? 
• Can outcomes be improved with docetaxel? 
• Can outcomes be improved with immunotherapy? 
• Is whole pelvic RT or ePLND more effective? 
• Can staging be improved with new imaging techniques? 
• Can RT toxicity be reduced with improved image guidance or advanced delivery devices? 
• Should rectal spacers be used to reduce GI toxicity? 
• What are the patient risk factors that affect oncological control and toxicity? 
• How much of the improved survival is a delay due to cytoreduction, and how much is actual cure?