Whole pelvic salvage radiation may be better than precisely targeted lymph node salvage radiation

Last week, I looked at a retrospective study of metastasis-directed therapy (MDT) at the Mayo Clinic among oligorecurrent patients (see this link). Oligorecurrent means that they had already received primary therapy (mostly prostatectomy) and some had received salvage radiation as well, but there were only 1-5 metastases detected. They found there was no benefit if there were any bone metastases, but there may have been a benefit if the metastases were in the lymph nodes only. Lymph nodes were treated with either surgery (called pelvic lymph node dissection - PLND) or radiation to a small area around the detected (by C-11 Choline PET/CT) cancerous lymph nodes. I ended the analysis with this statement:

Another open question is whether whole pelvic salvage radiation might have been more effective than the limited margins they used at Mayo. With the more accurate PSMA PET scans, ROs are able to treat the entire PLN area with radiation boosts given to the detected ones. The RTOG-consensus treatment area has recently been expanded (see this link). It's important that patients understand the detection limits of even the best PSMA PET scan: metastases smaller than 4 mm, and those that put out only small amounts of PSA remain invisible.

De Bleser et al. reported the results of a retrospective study to examine precisely this question among 506 oligorecurrent patients conducted at 15 different institutions throughout Europe. Patients were selected and treated as follows:

• Detection of cancerous lymph nodes (LNs) was primarily (85%) with C-11 Choline PET/CT (a few with PSMA, FDG, or conventional imaging)
• 309 patients were treated with SBRT (at least 5 Gy per fraction, up to 10 fractions), A margin of 2-6 mm was treated also.
• 197 patients were treated with "Elective Nodal Radiation Therapy" (ENRT) of at least 45 Gy in 25 fractions to the entire pelvic lymph node area. Boost doses to detected lymph nodes were allowed. A margin of 5-7 mm was treated. 60 patients also had their prostate bed simultaneously treated.
• About half had already had salvage radiation to the prostate bed.
• About half had already had PLND at the time of prostatectomy. The SBRT group had a median of 1 positive LN at pathology, the ENRT group had 2.
• Patients with adjuvant ADT for more than a year were excluded. 77% of the SBRT had no ADT; 40% of the ENRT group had no ADT. Those who had ADT, had it for 6 months (median).
• 72% had pelvic LNs only; 28% had extrapelvic LNs (retroperitoneal) at imaging.
• 72% of the SBRT group had only one LN at imaging; 50% of the ENRT group had 2-5 LNs at imaging.
• Patients with bone or visceral metastases at relapse were excluded, as were patients already using ADT, and those with detected metastases before primary therapy.

After a median follow-up of 3 years:

•  3-year Metastasis-Free Survival (MFS) was 68%. (only distant metastases (M1) were counted)
• Among patients who were detected with only one positive LN at baseline, MFS was twice as long with ENRT compared to SBRT
• There was no difference among patients with more than one positive node at baseline.
• 57% of patients were detected with metastases (N1 and M1) in the SBRT group- 55% in pelvic LNs, 19% in extrapelvic LNs only, 20% in bone, and 6% in visceral organs.
• 38% of patients were detected with metastases (N1 and M1) in the ENRT group - 11% in pelvic LNs, 43% in extrapelvic LNs only, 35% in bone, and 8% in visceral organs.
• ENRT provided longer-lasting N1 control, but did not delay M1 control any more than SBRT.
• Castration-free survival did not differ between the two types of treatments.
• There was no acute toxicity reported for 99% of men receiving SBRT  and 94% of men receiving ENRT. Grade 3 (serious) toxicity was reported for 5 men receiving ENRT and none receiving SBRT.
• Similarly, there was no serious late-term toxicity reported for SBRT, and 2.5% for ENRT.

We conclude that ENRT provided better local (pelvic lymph node) control than SBRT, but neither seemed to delay distant metastases better. MFS was only improved by ENRT if there was just one LN metastasis detected at baseline. Reported toxicity, acute and late-term was low, but was lower with SBRT.

Of course, this retrospective study leaves many questions unanswered:

• Does either treatment improve MFS over ADT alone?
• What would have happened if long-term ADT were allowed rather than just 6 months? (see this link) 
• What if all patients received the same radiation dose, the same treatment margins, and a standard treatment area (up through the aortic bifurcation) were used?
• What would have happened if LN metastases were detected with PSMA PET/CTs rather than C-11 Choline PET/CT?
• What were the patient-reported quality of life outcomes?

These questions will be addressed in two randomized clinical trials:

• OLIGOPELVIS2 (FRANCE) is randomizing oligorecurrent patients to intermittent ADT with or without whole-pelvic IG/IMRT with a boost to PSMA-identified LNs. (Completion mid-2026)
• PEACE V (STORM) in Europe and Australia is randomizing oligorecurrent patients to MDT by either SBRT/salvage PLND or ENRT. C-11 Choline, PSMA or Axumin PET scans will be used for detection. (Completion end of 2023)

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.

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.

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.