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 (PLN) have been pathologically detected (stage pN1)? Traditionally, patients with PLN dissection (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.

(Update 9/25/2022) Fonteyn et al. reported the results of the first randomized clinical trial, the PROPER RCT. Unfortunately, the trial did not reach its recruitment targets (n=64) and follow-up was shorter than planned.

• All patients had 1-4 positive PLNs found via PLND, most had 1 positive PLN
• Most (75%) also had prostatectomy, 64% had positive surgical margins

Patients were randomized to 2 years of ADT and either:

• Whole pelvic RT (as high as common iliac LNs) (WPRT), or
• Prostate bed-only RT (boost dose was allowed for known sites of recurrence) (PORT)

After 3-years of follow-up:

• Biochemical recurrence-free survival was 92% for WPRT vs 79% for PORT
• Acute grade 2+ gastrointestinal (GI) toxicity was 45% for WPRT vs 15% for PORT
• Late-term grade 2+ gastrointestinal toxicity was 21% for WPRT vs 3% for PORT
• Acute grade 2+ urinary toxicity was 52% for WPRT vs 48% for PORT (no diff.)
• Late-term grade 2+ urinary toxicity was 41% for WPRT vs 42% for PORT (no diff)

GI toxicity was probably increased by the wide margins used (5 mm) and by the fact that radiation was given on top of surgically dissected tissue. Such extended PLND is rarely done outside of Europe. The SPPORT and POP-RT trials, which did not include previous PLND, found no increase in GI toxicity. Now that PSMA PET/CT is available for recurrent patients, toxicity will probably be lower. The new MRI-targeting linacs (Viewray MRIdian and Elekta Unity) can control for intestinal motion that causes toxicity. Also, there may be an opportunity for better oncological results if para-aortic lymph nodes are also treated (see this link). A STAMPEDE trial found that 2 years of abiraterone increased oncological results.There may also be an opportunity to enhance results with apalutamide.

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.

Zareba and Touijer did not report the toxicity of the salvage treatment, but with improved external beam radiation techniques and scrupulous image guidance, toxicity has been improving.

Zareba and Touijer 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.

(Update 4/25/21) A major Phase 3 randomized clinical trial (INNOVATE) in 141 locations will determine whether intensifying the hormonal side of the treatment with 2 years of Zytiga+Erleada+ADT has better outcomes than 2 years of ADT. They prefer detection with an Axumin scan but allow PSMA and C-11 Choline too. The whole pelvic radiation dose will be determined by the treating radiation oncologist.

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?

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.