Showing posts with label N1. Show all posts
Showing posts with label N1. Show all posts

Monday, December 21, 2020

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)

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 (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.

Tuesday, December 19, 2017

Metastasis-Directed Therapy for Oligometastatic Recurrence - the STOMP trial

Metastasis-directed therapy (MDT) for recurrent oligometastatic prostate cancer is a very controversial topic. Researchers who should know better have made unjustified claims (see this link) and have even posted YouTube videos replete with "gee whiz" cases.

Now we have the first randomized clinical trial on the subject. It's a small Phase 2 trial (62 patients randomized to MDT or Surveillance) called STOMP and it only ran for three years (not long enough to detect survival differences in early metastatic patients). The objective of the study was not to see if MDT extended survival (which is what we really want to know), but to determine whether it extended the period before salvage ADT was required. The authors believe that if that more modest claim is realized, then a larger, longer Phase 3 randomized trial to detect any survival improvement would be justified.

"Oligometastatic" was defined as 1 to 3 detected metastases. Metastases were detected using a Choline PET/CT scan. Metastases could be in the pelvic lymph nodes (stage N1) or in distant locations (stage M1). Due to the small sample size in this study, there was a serious disparity in the number of metastases: the MDT group had fewer detected metastases (58% had only one) than the Surveillance group (29% had only one). From the start, the median number of detected metastases was 2 in the Surveillance group vs. only 1 in the MDT -- the Surveillance group started with a significant disadvantage.

"Recurrent" means after primary prostatectomy or radiation therapy has failed, and in some cases, salvage therapies have failed as well. Primary therapy may have included extended pelvic lymph node dissection (ePLND) with prostatectomy or whole-pelvic radiation along with prostate radiation. In this study, most (76%) had prostatectomy and many of them (85%) had failed salvage radiation.

"Metastasis directed therapy" included spot radiation (SBRT) to detected metastases, or surgical removal of lymph nodes or soft-tissue metastases. In this study, 55% of patients had lymph node metastases. If the patient had already had whole pelvic radiation or ePLND and any cancerous pelvic lymph nodes were detected, only those lymph nodes were removed. Otherwise a salvage ePLND was performed. Some patients were treated with SBRT to individual lymph node metastases, but none were treated with radiation to the whole pelvic lymph node field. Bone metastases were treated with SBRT (in 45% of patients), and one lung met was surgically removed. If metastases were detected on follow up in the MDT group, they were treated if there were 3 or fewer (i.e., whack-a-mole).

"ADT-free survival" is the time from randomization to the time ADT was required for any of three reasons: symptomatic progression, progression to more than 3 metastases (called "polymetastatic progression"), or local progression of baseline-detected metastases. PSA progression was not an adequate reason to start ADT. It is well known that MDT will result in a temporary reduction of PSA that is not sustainable. The goal of any therapy is to treat the disease, not to treat the PSA.

After a median follow up of 3 years, Ost et al. reported that:
  • Median ADT-free survival was 8 months longer in the MDT group
    • 21 months  in the MDT group vs. 13 months in the Surveillance group
    • The difference was not statistically significant with 95% confidence, but was within the pre-specified 80% confidence range*
  • 39% had not started ADT in the MDT group vs. 19% in the Surveillance group
  • 61% started ADT for polymetastatic progression (half of them within one year of treatment) in the MDT group vs 55% in the Surveillance group
  • Location of metastases did not affect ADT-free survival
  • 58% had only 1 metastasis (median=1) at baseline in the MDT group vs 28% in the Surveillance group (median=2).
  • There was no significant difference in ADT-free survival (even at 80% confidence) among those who had a PSA doubling time (PSADT) at baseline of >3 months (only 10 men in each group had a PSADT ≤ 3months)
  • Treatment toxicity was mild
* The authors pre-specified an 80% confidence interval for this pilot study. This is unusual. Ostensibly, this was because they knew they would be implementing an expanded Phase 3 study and only wanted to check for gross differences in this Phase 2 pilot study.  In a more conventional statistical analysis, the hypothesis that MDT affected ADT-free survival would have been rejected. Also, at 80% confidence, they should have accepted the hypothesis that the higher number of metastases in the Surveillance group made a difference - but the authors seem to ignore the inconsistency. Because of this, patients and clinicians are cautioned to not make changes in treatment decisions based on this.

Because "polymetastatic progression" was the endpoint used to determine whether ADT was indicated for treatment, and 39% of the Surveillance group were already starting with 3 metastases at baseline, it is surprising that it took 13 months for a single new metastasis to become detectable in that group, and that for 19% of the Surveillance group, a fourth metastasis never became detectable throughout the 3 years of follow up. In the MDT group, four new metastases had to become detectable after the first ones were eradicated by treatment. 31% (11 of 31) had a second round of treatments, and 6% had a third round of treatments before the sudden appearance of four or more detectable metastases all at once. By setting "ADT-free survival" as the endpoint and making it conditional upon the simultaneous detection of four metastases, they guaranteed that the endpoint would be reached earlier in the Surveillance group. What is surprising is that even with that built-in bias, the difference was not significant with 95% confidence. It is also worth noting that in a pre-planned subgroup analysis, there was no significant difference in ADT-free survival (even at 80% confidence) among those who had a PSA doubling time at baseline of >3 months. Patients with "indolent" metastases did not benefit from MDT. This study does not show that metastatic progression was slowed by MDT. Only an improvement in overall survival time can show that.

This study used a Choline PET (F18, I presume) scan to detect metastases. We recently saw that there is a clinical trial at Johns Hopkins to detect and treat oligometastases using the more accurate PSMA PET scan. While outcomes may be improved with a more accurate scan, it will undoubtedly eliminate many patients from the oligometastatic pool of patients.

This study did not investigate whether salvage radiation to the entire pelvic lymph node field would have had better outcomes than spot SBRT treatment. We are still not very good at finding cancerous lymph nodes (see this link) and the treatment field is inadequate most of the time (see this link).

Importantly, this study does not address whether it is beneficial or detrimental to delay start of ADT. The 8-month delay in the start of ADT may result in 8 months that the cancer is systemically multiplying and evolving. The TOAD trial suggested that early amelioration of the micrometastatic burden in recurrent patients may have a greater influence on survival than any selective evolutionary pressure that starting earlier may exert. It furthermore showed that overall quality of life was unaffected by the earlier ADT start. ADT is the standard of care when metastases have been discovered. Clinical trials of oligometastatic MDT should include ADT use in both arms to give a realistic appraisal and to be ethical.

While this trial was done among recurrent patients, the STAMPEDE trials (see this link and this link), the CHAARTED trial, and the LATITUDE trial among newly-diagnosed patients proved that aggressive systemic therapy, as early as possible after metastases are discovered, provides a significant survival advantage.

It is important that patients understand the very real risk of avoiding systemic treatment when there are known metastases. While it risks little to treat those oligometastases that can be safely treated, we must understand that there is no known survival benefit to doing so. There is a known risk to delaying systemic therapy. Dr. Ost wrote to me, "MDT does not replace ADT and our results should not be interpreted in that way."

Saturday, January 21, 2017

We're still not very good at finding cancerous pelvic lymph nodes


Pelvic lymph node (PLN) detection is important because it is one of the first places prostate cancer travels to after leaving the prostate or prostate bed. Cancer cells in the interstitial fluid of the prostate drain out into sentinel LNs and then into many other LNs. The LNs act like filters, catching the errant cancer cells. Sometimes the white blood cells surround and destroy the cancer cells, but sometimes the cancer changes the white blood cells and lymph node tissue, creating a microenvironment that is more hospitable to cancer cells implanting themselves there and growing. It can take years for enough cancer cells to create such a hospitable habitat and grow to a size that can be detected with a scan. When it is detected there, it is called stage N1, and is called "locally advanced." In some cases, prostate cancer may still be cured if it is locally advanced. The standard ways of detecting cancerous pelvic lymph nodes (PLN) are via surgical removal or radiographic detection. Neither is very good.

CT Scan

The standard of care for detecting positive LNs is a pelvic CT scan with contrast. (Sometimes MRIs are used for this with no advantage other than billing for the hospital.) This is often done the same day as a bone scan for high risk patients. The CT detects the size of LNs, and suspicion of cancer is as follows:
  • < 8 mm: not suspicious
  • 8-11 mm: gray area
  • ≥ 12 mm: suspicious
The problem with detection by size is that many small LNs may harbor cancer, and enlarged LNs may be enlarged due to infection or due to inflammatory processes in nearby cells. The problem with CT detection is that it's possible for a LN with cancer to be small, and the cytokines released by it to enlarge a nearby LN that does not bear any cancer. While a biopsy of an enlarged node may be difficult to perform, enlarged nodes that shrink with androgen deprivation is a sure sign that cancer was causing the enlargement.

Patients with fewer and smaller positive LNs have longer survival, so if the patient wants treatment for N1 prostate cancer, whether local or systemic therapy, it is best to use an alternative method of detection.


Ultra-small paramagnetic iron oxide (USPIO) particles accumulate in healthy LNs more than in cancerous LNs. The particles and their lack can be detected in LNs using MRI. Combidex (ferumoxtran) is a brand of USPIO that is now available for this purpose, but only at Radboud University in Nijmegen, The Netherlands. It can detect positive LNs with a diameter as small as 2 mm in some cases (see this link). It is better than a C-11 Choline PET scan, which has a size limit of 6 mm. (Update 2/7/23) Fortuin at al. reported on a new trial there comparing PSMA PET/CT to USPIO with MRI.  In the same 45 patients, all with high risk of cancerous LNs (before primary therapy or recurrent):
  • PSMA PET/CT found 71 suspicious LNs in 25/45 (55%) patients -2.8 per patient
  • USPIO w/ 3T MRI found 160 suspicious LNs in 33/45 (73%) patients - 4.8 per patient
  • MRI only missed 19 of the PSMA-detected LNs, but found over twice as many, and upstaged ⅓ more patients
In 20 patients, they used a 7T MRI and found:
  • 115 suspicious LNs in 17/20 (85%) patients - 6.8 per patient
  • 91% were smaller than 5 mm (the PSMA PET/CT size limit)
  • 63% were smaller than 3 mm (the 3T MRI size limit)
Most of the suspicious LNs were outside of the surgical pelvic LN dissection area.
The outstanding question is: what is the value of detecting every last cancerous LN?


As we've seen, the currently best PET scan is the DCFPyL PET/CT, which has been approved in the US for high-risk and recurrent patients. Tumor to background ratios may be especially better than the Ga-68-PSMA PET/CT scans. DCFPyL detected 30% more positive LNs in the same patients. It has high specificity (95%) but low sensitivity (~ 40%). The Axumin (fluciclovine) PET/CT is less accurate (see this link). PET/MRIs, now available at a handful of US institutions will provide greater accuracy. Detection of small metastases (< 5 mm) is unproven even in the best of these scans.

Meredith et al. reported on 532 patients diagnosed with the Ga-68-PSMA  PET/CT after PSA recurrence following initial treatment with prostatectomy (425 patients) or RT (107 patients).

  • Among those treated with primary prostatectomy, positive lymph nodes were detected in 68%.  
  • Among those treated with primary RT, positive lymph nodes were detected in 40%.

(Update 11/14/17) Schmidt-Hegemann et al. reported on 129 patients diagnosed with the Ga-68-PSMA PET/CT:

  • 20 patients were scanned before initial RT treatment
  • 49 patients were scanned after PSA recurrence after prostatectomy
  • 60 patients were scanned after PSA persistence after prostatectomy (PSA never became undetectable)

Positive pelvic lymph nodes were detected in:

  • None in the pre-initial treatment group
  • 16% in the PSA-recurrent group
  • 33% in the PSA-persistent group
  • Detection rates were about the same in patients with PSA< 0.05 ng/ml

Multiparametric MRI (mpMRI)

Multiparametric MRI is more specific than CT, but is no more sensitive at detecting positive LNs. In one study, only 57% were correctly staged with a DW-MRI.

Surgical pelvic lymph node dissection (PLND)

Surgical removal, or PLND, is usually performed at the same time as a prostatectomy. The surgeon looks for about 5-10 PLNs and removes them for pathological analysis. In the US, this isn't done routinely by most surgeons because it is usually negative (only about 5% of prostate cancer patients have PLN invasion when first diagnosed), there are often false negatives, and there are risks of lymphocele and lymphedema from it. There are two indicators that it may be advisable to perform a PLND:
  1. Risk of PLN invasion is greater than 2% (or 2.6%) on a validated nomogram like this one based on PSA, Gleason score and stage, or,
  2. Enlarged PLNs have been detected with CT or MRI
(Note: This recent nomogram based on European patients recommends ePLND when the risk of PLN invasion is at least 7%)
When cancer is found, sometimes wider removal of as many as 30 PLNs is performed, called extended PLND or ePLND. The hope is to find more infected LNs and remove them, all of them if one is lucky, but the ability to control cancer using ePLND is controversial and the subject of clinical trials. ePLND is difficult because LNs are nearly invisible, small, and difficult to find, obscured by more colorful tissue and sometimes hidden in the visceral fat. Unlike blood vessels, which branch out, lymph vessels are networked. ePLND yield may be increased by injecting a fluorescent liquid, called indocyanine green, into the prostate and letting it drain through the lymph vessels. Even so, this missed 24% of sentinel PLNs in one study. A magnetometer that finds iron oxide particles that accumulate in lymph nodes has been tried intraoperatively (see this link). Radiotracers that consist of a gamma emitter (Indium 111 or Technetium 99m) attached to a PSMA ligand have also been used intraoperatively for this purpose in some recurrent cases (see this link) . PET scans may be used to detect some of the larger nodes to be removed. ePLND is a more common practice in Europe than in the US.

Even the most thorough ePLND misses positive PLNs. In one recent study, almost a quarter of positive LNs would have been missed even if ePLND had been used. Metastases don't just stick in sentinel LNs (the first ones that drain from the prostate). This is unlike breast cancer, for example. Cancer may accumulate in a LN without being detectable in all the LNs upstream from it.

The definition of the PLN field  of whole pelvic radiation as defined by a consensus of radiation oncologists missed 44% of the positive LNs, in this study. A study of LN failures after whole pelvic radiation therapy found that more than half had a failure above the treated area.

Clearly, there is no imaging modality that will find all metastatic cells in the PLN area. Failure of either ePLND or whole pelvic radiation to adequately treat the pelvic LNs that are most likely to be positive is problematic. As the coverage/dissection area expands, so does the risk of side effects. Lymphedema and lymphocele may result from ePLND. Late-term damage to the upper bowel is a risk of increasing the radiation field (see this link).

Such risks must be balanced against the evidence for benefits of treatment. The success of pelvic radiation in various settings was discussed here, and early results from the STAMPEDE clinical trial among N1 patients are encouraging.

Monday, September 12, 2016

Most of the recurrences after primary radiation failure are salvageable

Salvage therapy is curative in about half of men who have a biochemical failure after primary therapy. That's true whether the primary therapy was surgery or radiation. It's true when the salvage therapy was radiation after surgery. And it's true whether the salvage therapy was surgery, cryotherapy, or brachytherapy after radiation. Salvage success rates can be as high as 3 in 4, in certain well-selected patients treated with appropriate therapies (see this link, for example), but it can be a lot lower too. Salvage therapy always increases the complications over what they were for the primary therapy, so we would avoid it if we knew it was likely to be futile. Thanks to the new generation of PET scans, we are beginning to understand why, and what we may be able to do to improve those odds.

For any salvage therapy to be effective, two conditions must be met:
  1.  The recurrence must be local. Local means in the prostate, seminal vesicles, the prostate bed, nearby organs (e.g., bladder, rectum, etc.), and/or in the pelvic lymph nodes.
  2.  The recurrence must not be distant. Distant means metastases in the bones; remote organs like the lungs, liver, or remote lymph nodes; or in systemic circulation in the bloodstream.
In the past, it has been difficult to ascertain that both conditions were met. Bone scans are not very reliable when the PSA is below 20 ng/ml, and they are not specific for metastases. Moreover, by the time the PSA increases that much, the cancer is almost certainly distant and incurable. The NaF18 PET/CT scan can detect metastases sometimes at a PSA as low as 4 ng/ml, but it only detects bone metastases, and it is not specific for metastases. An Ultra-Small Superparamagnetic Iron Oxide (USPIO) MRI may sometimes detect metastases, but only in lymph nodes.  A multiparametric MRI may sometimes detect local recurrences, and may be used to target areas for biopsy in the prostate and prostate bed. It may be reliable after primary radiation (see this link). However, it tells us nothing about distant metastases.  CT scans only detect the larger lesions that may be suspect. A transperineal template mapping biopsy may detect prostate cancer in the prostate, but tells us nothing about distant metastases. It should be noted that biopsied prostate tissue looks very different after radiation, and it should be analyzed by highly experienced pathologists.

Clinical trials have proved that adjuvant radiation after prostatectomy has better outcomes than waiting, and recent studies suggest that overtreatment may be avoided by using early salvage radiation rather than adjuvant radiation therapy. Perhaps early salvage therapy after primary radiation therapy may have improved outcomes too. That is, it may be more successful if started before the patient's PSA reaches the nadir+2 level, which is the official definition of biochemical recurrence after primary radiation therapy.

The FDA-approved C-11 Choline PET/CT (or the similar C-11 Acetate PET/CT) fills some of the critical information gaps. It can detect prostate cancer in the radiation-treated prostate, the local area, and throughout the entire body at a PSA as low as 2 ng/ml, especially if the PSA has been rapidly rising. However, its sensitivity is not very good for small sites of cancer (they must be larger than 5mm), or cancer in lymph nodes. And when used to detect cancer within the prostate, prostatitis and BPH may generate false positives. Some of the new experimental PET scans (e.g., DCFPyL) may be more sensitive. Now that we have an adequate tool for detecting both of the above-mentioned conditions (local and not distant), we are beginning to be able to select which recurrences can be cured with salvage therapy, and which can only be managed with lifelong hormone therapy.

Parker et al. report on the Mayo Clinic experience with 184 patients with rising PSAs after primary radiation therapy on whom the C-11 Choline PET/CT was used to detect local and/or distant prostate cancer progression.

  • 87% of patients were PET-positive.
  • The C-11 Choline PET/CT correctly identified 98% of patients who were later found to have residual prostate cancer on subsequent histological analysis. 
  • However, 42% of patients that were identified as negative by the C-11 Choline PET scan later suffered from cancer progression - they were false negatives.
  • Patients were especially likely to be PET-positive if they had higher pretreatment PSA, were high risk, had higher PSA level at the time of the PET scan, had a greater increase from nadir PSA, had a shorter PSA doubling time, and had a higher PSA velocity. All of those with PSA≥ 10 ng/ml were PET-positive.
  • Risk category, PSA increase from nadir, and time since primary radiation therapy were independently associated with PET-positivity, and can help predict when recurrences are salvageable.
  • 59% of PET-positive patients were confirmed by histological analysis (either biopsy or salvage prostatectomy). 76% were confirmed by a multiparametric MRI.
  • 46% of those who were PET-positive had cancer only in the prostate and seminal vesicles. These patients were potentially salvageable with any of the salvage therapies mentioned above.
  • An additional 16% (62% in total) had cancer in the soft tissue pelvic region. These may be salvageable with extended pelvic lymph node dissection (ePLND) or radiation in select areas of the pelvis that were not treated originally.
  • While only a few patients (21) had a PET scan before their PSA reached nadir+2, half of them had a local recurrence only, and are potentially salvageable. This suggests that the  patient does not have to wait for nadir+2. However on this small sample, the salvageability does not seem to be very different for those who detect it earlier.
This study confirms the findings of the larger study at Memorial Sloan Kettering (MSKCC) (reviewed at this link).  In that study, 55% had a recurrence in the prostate and/or seminal vesicles only, compared to 46% at Mayo. At MSKCC, an additional 8% had recurrences in the pelvic lymph nodes only, compared to 16% at Mayo. There were important differences between the studies. At Mayo, unlike MSKCC, patients may have had brachytherapy as all or part of their primary therapy, they may have had enlarged lymph nodes from the start, they had significantly lower doses of radiation (76 Gy vs ~80 Gy), they were younger (65 vs 69), fewer had adjuvant hormone therapy (30% vs 54%), they all had rising PSA but not necessarily nadir+2, and they all received a C-11 Choline PET/CT, there was less histological confirmation (59% vs 71%), and the median follow-up time was shorter (68 months vs 83 months).

As noted in the commentary of the MSKCC study, these findings may not apply when the primary therapy used a very high biologically effective radiation dose, such as with brachy boost therapy, SBRT, or high dose rate brachytherapy.

It makes sense to rule out the possibility of distant metastases using an advanced PET scan. Even at a cost of $2,500 or so, it may save the patient much more than that for the cost of salvage therapy. However, unless the PET scan is done at Mayo using C-11 Choline, is done as part of the clinical trial using the newly FDA-approved PET indicator fluciclovine, or is one of the free ones at NIH, the out-of-pocket cost may be formidable. Hopefully, the FDA will approve more of them, and availability will expand. Unfortunately for those considering early salvage after a prostatectomy failure, none of them are accurate for PSAs that low (≤0.2 ng/ml).

The authors constructed a nomogram to help the prospective patient predict whether his recurrence, detected with a C-11 Choline PET/CT, is likely to be a salvageable recurrence or unsalvageable recurrence. In the first table, fill in the number of points that comes closest to your situation, and add them up. In the second table, look up the probability of a distant recurrence (unsalvageable) that comes closest to your total number of points.

Risk Factor
Points to assign
My Points
PSA increase from nadir
2 ng/ml: 13
5 ng/ml: 32
10 ng/ml: 63
15 ng/ml: 95

Years since RT
1 yr: 100
2 yrs: 95
3 yrs: 90
5 yrs: 80
10 yrs: 52
20 yrs: 0

Risk Group
Low: 0
Intermediate: 8
High: 45


My Total
Probability of recurrence outside of the pelvic area

This nomogram outperformed using a PSA threshold alone in its predictive power, and may help the patient decide whether potentially-curative salvage therapy or lifelong hormone therapy is the better course of action.

I'm not sure why radiation dose was not significantly correlated with the site of recurrence at Mayo (p = 0.1) as it was in the MSKCC study. In fact at MSKCC, those who received doses of at least 79.2 Gy had half the rate of recurrence compared to those who only received 75.6 Gy (which seemed to be the norm at Mayo). It may be that those who were treated at Mayo only received higher doses when their cancer was already systemic. We know that this is on the steep part of the dose/response curve where even a small increase in dose can increase its effectiveness greatly. Whatever the reason for the data discrepancy, higher doses do prevent local recurrences.

(update 11/18/2018) Hayman et al. reported on 49 men who had a biochemical recurrence after whole pelvic primary radiation therapy and long-term ADT who were clinically staged as node positive (N1) via MRI. Using imaging (probably a PET/CT scan) they found the site(s) of recurrence in 46 of the men:

  • 25 (54%) had a recurrence in the prostate only
  • None had a recurrence in lymph nodes only
  • 21 (46%) had a recurrence that included a distant metastasis

This is very similar to Mayo and MSK.

note: Thanks to Dr. Will Parker for letting me review the full text of his published study.

Monday, August 29, 2016

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

In a previous commentary, we mentioned the early top-line results of the STAMPEDE trial, which demonstrated a benefit to whole-pelvic radiation and ADT for treatment of high risk prostate cancer when positive pelvic lymph nodes have been detected. We now have some additional details.

James et al. analyzed data from the control arm of the STAMPEDE trial. The control arm excluded patients with distant metastases and those who had previous treatment. All patients were high risk and were treated between 2005 and 2014 with a minimum of two years of ADT. At physician’s discretion, some were also treated with RT 6-9 months after the start of ADT. Patients with lymph nodes larger than 10 mm were typically staged as “node positive” (N1). Patient counts for this analysis were as follows:
  • ·      N0 and RT – 121 patients – 43% received whole pelvic radiation
  • ·      N0 and no RT – 46 patients
  • ·      N1 and RT -  71 patients - 82% received whole pelvic radiation
  • ·      N1 and no RT -  86 patients

Age, Gleason scores, and performance status were similar in all groups. Pre-treatment PSA was higher in patients who had RT, although the differences were not statistically significant. The planned radiation dose to the prostate and seminal vesicles was 74 Gy in 37 fractions or the equivalent hypofractionated dose. The planned dose to the pelvic lymph nodes was 46-50 Gy in 23-25 fractions or 55 Gy in 37 fractions. Increased doses were allowed if the physician was experienced in delivering nodal doses.

Although overall survival was measured, there was too little mortality as of this interim analysis to be worth reporting. Instead, the authors focused on 2-year Failure-Free Survival (FFS), defined as no biochemical recurrence, and no radiographically-detected progression among survivors. Patients would have been ADT-free for 12-15 months by that point, unless they showed early evidence of progressing.

Among the men with no detected nodal involvement( N0):
  • ·      The 2-yr FFS was:

o   96% among men who received RT
o   73% among men who did not receive RT
  • ·      Late GI toxicity was:

o   Proctitis: Grade 2: 7%, Grade 3: 2%
o   Diarrhea: Grade 2: 3%, Grade 3: 1%
o   Rectal ulcer: Grade 3: 1%
  • ·      Late GU toxicity was:

o   Cystitis: Grade 2: 2%, Grade 3: 1%
o   Hematuria: Grade 2: 3%, Grade 3: 1%

Among the men with detected nodal involvement (N1):
  • ·      The 2-yr FFS was:

o   89% among men who received RT
o   64% among men who did not receive RT
  • ·      Late GI toxicity was:

o   Proctitis: Grade 2: 8%
o   Diarrhea: Grade 2: 6%
  • ·      Late GU toxicity was:

o   Cystitis: Grade 2: 5%
o   Hematuria: Grade 2: 2%, Grade 3: 2%

Although this was a prospective study, patients were not randomized to receive RT or not, so there may be selection bias at work. The higher pretreatment PSA in the patients who did not get RT suggests that they may have been considered to be too far progressed to benefit from radiation. However, the benefit of RT was maintained even after adjustment for pretreatment PSA, age and Gleason score.

The planned radiation dose, 74 Gy, is lower than the 80 Gy now considered to be curative. The dose delivered to the pelvic lymph nodes is still within the standard of care. Although almost half of those with no nodal involvement were treated with whole pelvic RT, there was no analysis of benefit in that subgroup.

RT clearly delayed the time to relapse among high-risk patients, regardless of nodal status. The FFS curves continued to diverge after 2 years, indicating a lasting effect of treatment, at least out to 5 years post-treatment. Long-term toxicity was low among all patients who received RT.

Subject to the above caveat on selection bias, this early analysis indicates that men with high risk prostate cancer, whether they had detected nodal involvement or not, benefited from long-term ADT+RT. As there was little long-term toxicity attached to this decision, there seems little reason to withhold such treatment.

The questions mentioned in our earlier commentary continue to be important:

  • 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?
  • 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?

Sunday, August 28, 2016

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?