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)


Wednesday, December 16, 2020

Best Evidence So Far: Metformin Has No Benefit for Prostate Cancer

In studies of men with diabetes, men taking metformin seemed to have low incidence of prostate cancer and fewer deaths from prostate cancer. I stress the word "seemed" because all of the evidence for it came from observational studies rather than randomized clinical trials (RCTs). The problem with observational studies is "selection bias." Selection bias means that those taking the drug did so for a reason, and the reason may have affected prostate cancer incidence or progression because of some other reason, Observational studies can only show association. Only a randomized trial can prove causality. For example, we can easily observe that people who weigh less are more likely to get breast cancer (an association), but that does not mean that if one loses weight, one will get breast cancer (a causal factor). It is merely because almost all the people who get breast cancer are women and women, on the average, weigh less than men, that there is an association. In spite of this problem of "selection bias," some patients and doctors jumped to the conclusion that metformin can prevent progression. Others (like me) argued that because side effects are mild, there is probably little risk. Let's examine the evidence for causation instead of association.


124 patients were randomly assigned to receive ADT+bicalutamide or metformin+ADT+bicalutamide. Newly diagnosed patients may have been diagnosed with either:
  • High-risk localized prostate cancer
  • Prostate cancer in distant sites (stage M1)
  • Prostate cancer in pelvic lymph nodes only (stage N1)

After short follow-up (18 months, median), 23% of the patients had died. The effects of metformin were:
  • Time to castration resistance was delayed in the high-risk group and in those with stage N1
  • Time to castration resistance was not slowed significantly in men staged M1, especially no effect in those with a high volume of metastases.
  • There was no effect on PSA
  • There was no effect on survival
So metformin may slow progression among men who may be cured by radical therapy (removing or irradiating the prostate with or without pelvic lymph nodes) anyway. It is possible that with larger sample size and longer follow-up there may be an effect on survival among metastatic men, but the lack of a PSA response suggests that won't happen.


28 patients with recurrent prostate cancer were given either metformin or observation for 8 weeks. All patients had a short PSA doubling time and a high body mass index. As metformin or placebo continued for 24 more weeks, bicalutamide (50 mg/day) was given to both groups.
  • After the initial 8 weeks, PSA dropped in the metformin group
  • By 32 weeks, however, there was no difference in PSA
  • The trial was ended early for futility


100 patients with metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned to get docetaxel chemotherapy with or without metformin. By the end of chemotherapy (up to 10 infusions, every 3 weeks):
  • There was no difference in PSA response between the 2 groups
  • There was no difference in objective response
  • There was no difference in clinical progression-free response
  • There was no difference in overall survival
  • There was a higher incidence of diarrhea with metformin


36 patients were randomized to receive metformin+ADT or ADT-alone (+ placebo). Patients were either recurrent (n=15) or newly diagnosed with metastatic prostate cancer (n=21). All were beginning lifelong ADT for the first time. After 28 weeks:
  • There was no difference in PSA response between the 2 groups
  • There was no difference in metabolic syndrome (see "PRIME RCT" below) between the 2 groups
The researchers conclude that drugs that reduce metabolic syndrome in diabetics do not reduce metabolic syndrome among ADT users.



This RCT was conducted to detect any particular tissue effects metformin might cause. 20 patients were randomized to receive metformin or placebo for 4-12 weeks prior to surgery. Analysis of post-prostatectomy tissue revealed:
  • There were no differences in any of the biomarkers of hypothetical biochemical benefit for prostate cancer (see below)

METAb-Pro - prospective trial (not randomized)

25 patients with metastatic castration-resistant prostate cancer (mCRPC) who were already taking abiraterone received metformin. After 12 weeks:
  • Only 12% were free of progression (35% progression-free survival was the benchmark for an effect)
  • Most had PSA progression; almost half had radiographic progression
  • There was higher-than-expected gastrointestinal toxicity (nausea, diarrhea, loss of appetite)

Purported Anti-Carcinogenic Biochemical Mechanisms

Metformin has been used for many years in diabetic people to reduce blood sugar (it blocks glucose production by the liver), counteract the effects of metabolic syndrome, maintain insulin sensitivity, and diminish appetite. Its effects are mediated through its ability to activate an enzyme called AMPK. 

There are several hypotheses about how metformin might exert an anti-carcinogenic effect in prostate cancer. All of the hypotheses are based on lab tests rather than clinical data. Some of its purported effects might arise because metformin activates an enzyme called AMPK.
  • AMPK in turn activates an enzyme called Acetyl Coenzyme A Carboxylase (ACC) which regulates fatty acid oxidation - the chief source of energy for the prostate cancer cell. 
  • AMPK also activates a protein (p53) that is an important tumor suppressor. 
  • AMPK inhibits an enzyme called mTOR. mTOR inhibitors prevent cancer protein synthesis and reduce Cyclin D1 activity. This leads to cell-cycle arrest.
Other proposed anticarcinogenic mechanisms are that metformin: 
  • increases Cleaved Caspase 3 (CC3), which is needed for apoptosis of mutated cells
  • decreases Insulinlike Growth Factor (IGF-1) that allows energy utilization by the cancer. However, because more specific IGF-1 inhibitors have been found to have no effect on prostate cancer: lisitinib, figitumumab, and cixitumumab, this is an unlikely mechanism.
  • decreases testosterone formation (it is known to slightly decrease testosterone in women with polycystic ovary syndrome)
  • decreases free testosterone formation by increasing sex hormone binding globulin - SHBG.
Nguyen et al. showed that men taking metformin had no differences in serum or tissue levels of  CC3, Cyclin D1, IGF-1, testosterone, SHBG, or mTOR inhibition.  This leaves metformin without a plausible mechanism by which it could slow prostate cancer progression.

Lower detection among diabetic men using metformin is a confounder

So why have so many observational studies of metformin in diabetic men found an association with reduced prostate cancer progression? And why has the association failed to be observed in non-diabetic men? A Stockholm study provides a plausible explanation: Beckmann et al. reported that diabetic men using metformin were less likely to get a biopsy for elevated PSA compared to a matched sample of men who did not use metformin. This suggests that the lower incidence of prostate cancer among men taking metformin is simply that their prostate cancer was less likely to be detected.

Contradictory Evidence from Observational Studies

Because so many patients have relied on observational studies to make a metformin treatment decision, it's worth seeing just what those studies say. All observational studies have been conducted among diabetic men.

This meta-analysis is large. It encompasses 30 cohort studies, covering 1.7 million diabetic men. While there was no association with incidence of prostate cancer (no protective effect),  there were positive associations with overall survival, prostate cancer-specific survival, and recurrence-free survival. No correction for risk factors or patient matching was possible.

This UK database analysis of over 55,000 diabetic men, using inverse probability weighting to account for selection bias, found there was no association between metformin use and the detection of any kind of cancer.

This secondary analysis of the REDUCE RCT compared 194  metformin users to 205 non-users of diabetic medications and 141 who used some other diabetic medication. All were diabetic and had at least one biopsy. After correction for all risk factors, there were no associations for incidence of prostate cancer, neither high grade nor low grade.

Merrick et al. reported on 65 diabetic men at Wheeling Hospital treated with metformin (median, 6 years), compared to 88 diabetic men treated with another antidiabetic medication, and 881 non-diabetic men who were biopsied. There were no significant differences in prostate cancer diagnosis, Gleason score, number of positive cores, or risk group based on metformin usage. Nor did diabetes make a difference.

A study at Mayo looked at recurrences among men following prostatectomy. There were 323 diabetic metformin users and 562 diabetic non-users. After 5 years of follow-up, and after correction for known confounders, there were no differences in biochemical recurrence, progression, or all-cause mortality. Neither were there any differences in postprostatectomy pathological findings: Gleason score, stage, positive surgical margin rate, or tumor volume.

Taira et al, reported on 126 diabetic men at Wheeling Hospital treated with metformin (median, 6 years), compared to 144 diabetic men treated with another antidiabetic medication, and to 2,028 non-diabetic men. All received brachytherapy. There were no 15-year differences in biochemical failures, prostate cancer-specific mortality. 

A 1:5 case-control study of diabetic men diagnosed with prostate cancer was conducted in Ontario. There were 1,104 men who had high-grade and 1,117 men who had low-grade PCa after prostatectomy. In addition, there 3,524 men diagnosed with a biopsy only. Metformin use made no difference in prostate cancer incidence, detection of high-grade PCa, low-grade PCa, or biopsy-detected PCa.

A SEARCH database study looked at diabetic men who underwent prostatectomies, 156 used metformin, 215 didn't. There was no association found between metformin use, dose or duration of use and time to biochemical recurrence, High metformin dose was associated with earlier castration resistance, metastases, and PC-specific mortality.

A 1:10 case-control UK Database study looked at 536 diabetic men who had used metformin and 203 diabetic men who hadn't. Metformin use was not associated with prostate cancer incidence. In fact, prostate cancer risk increased in proportion to the number of metformin prescriptions.

Tan et al. used the SEER database to see if there was an association between metformin, statins, or the combination of the two on prostate cancer mortality in high-risk men. They found that metformin alone had no association. However, statins alone and the combination did have an association. The association disappeared in men with advanced (Stage IV) prostate cancer.

Possible Metformin Danger

In a secondary analysis of two randomized clinical trial databases, there were 486 patients treated with prostatectomy and/or radiation. Follow-up was over 10 years. 10-year biochemical recurrence-free survival was:
  • 73% if they used metformin
  • 85% if they did not use metformin
Metformin was associated with inferior biochemical outcomes.

Should I take metformin?

All of the higher-level evidence so far is consistently showing that there is no benefit in taking metformin for prostate cancer. Also, a plausible mechanism for a beneficial effect is so far lacking. However, all the RCTs so far have been small and short-term, so it is possible that a very large trial with long follow-up, like STAMPEDE, might yet prove there is a small effect, or metformin might prove useful if used early enough, as in men on active surveillance, or in combination with other substances (e.g., statins). There are several ongoing randomized clinical trials (see below).

While metformin does not have serious side effects in most men, it does have gastrointestinal side effects (diarrhea, cramps, nausea, vomiting, and flatulence). It should be avoided in men with known contraindications: lactic acidosis, metabolic acidosis, poor liver or kidney function, and hypoglycemia. There are many drug/supplement interactions that should be carefully checked.

Metformin has been recalled repeatedly by the FDA because of carcinogenic (NDMA) impurities.


Ongoing RCTs:

STAMPEDE - ARM K: Metformin+SOC vs SOC for locally advanced and newly-diagnosed metastatic patients. Results expected: 2024
IMPROVE:  Enzalutamide vs Metformin+Enzalutamide for mCRPC. Results expected 2022
MAST: Metformin vs Placebo for Active Surveillance. Results expected 2023
LIGAND: Metformin+atorvastatin vs placebo for recurrent men: Results expected 2021
PRIME: Metformin vs placebo to prevent metabolic syndrome in men starting ADT: Results expected 2022
SAKK 08/15 - PROMET Metformin vs placebo with salvage radiation. Results expected: 2022









Thursday, December 10, 2020

Targeting Bone Metastases with Radiation in Oligorecurrent Men has No Survival Benefit in Mayo Study

Oligometastases in bones

Metastasis-directed therapy (MDT) when there are only a few bone metastases (called "oligometastatic") is controversial. It can certainly relieve pain, and prevent fractures and spinal compression. It can also provide good "local control" (cancer in the irradiated metastasis is permanently destroyed) and reduce the PSA that those metastases put out. But is there any survival benefit?

Patients often ask radiation oncologists (ROs) for radiation of those metastases using targeted radiation (which I'll call "zapping"), and they ask their ROs to treat new metastases as they are detected. This is called "metachronous treatment," but I'll call it "whack-a-mole" Sometimes metastases appear in places where radiation treatment may be problematic, such as near vital organs or deep in the spine. The nagging question is whether such treatment really does the patient any good. With the approval of ever more sensitive PET scans, like the PSMA PET scan approved last week, patients will undoubtedly detect more metastases.

The Mayo Clinic has been one of the cheerleaders for MDT. They have posted a deceptive youtube video featuring their C-11 Choline PET scans showing only how good the local control is. What the video can't show is how those patients would have done without MDT - there was no control group ever used or shown in their video.

Perhaps to partially correct for the misleading video, Boeri et al. at Mayo retrospectively looked at 115 patients who had an oligometastatic recurrence to the bones (1-5 metastases):

  • 115 patients were treated with SBRT. They had a median of 1 bone metastasis.
  • 47 patients were treated with ADT-only. They had a median of 2 bone metastases.

This was not a randomized study, so it is entirely likely that there was "selection bias" -- those who received ADT-only may be because it was felt they would not be able to benefit from SBRT or that it might be unsafe. Patients who received ADT-only had a higher number of bone metastases and a higher PSA. All of those receiving MDT for bone metastases were also receiving ADT.

  • The 5-year prostate cancer mortality was no different between the two groups
  • The 5-year radiographic recurrence-free survival was no different between the two groups
  • Among those with 5 years of follow-up, the time remaining free of the next significant systemic therapy (e.g., chemo, Zytiga, etc.) was longer for those getting zapped. However, it should be noted that the decision to give an additional significant therapy is a physician decision based on many factors, including patient status, number of metastases, and PSA. Because number of metastases and PSA are changed by MDT, and those receiving MDT started with one less metastasis, the physician may feel pressured to start a new therapy sooner in patients receiving ADT-only.
Pending confirmation from long-term randomized clinical trials of MDT to oligometastases in bones, there is no evidence of oncological benefit.

Oligometastases in Pelvic Lymph Nodes (PLNs)

MDT of oligorecurrent metastases that are only in pelvic lymph nodes (PLNs) is less controversial. Lymph is a slow-moving fluid, and metastatic cancer cells emerging from the prostate might get trapped in the lymph nodes that drain the prostate. So it has been hypothesized that treatment of the PLNs when a few are found to be cancerous may still provide a cure. This has not yet been proven in a randomized clinical trial, but there is observational evidence of a significant benefit to salvage whole-pelvic radiation (see this link).

What is controversial about the way they are treated at the Mayo Clinic is that only those cancerous PLNs and a small margin around them were surgically removed, and whole pelvic salvage radiation wasn't routinely given. They were treated in any of three ways:

  1. Salvage Pelvic Lymph Node Dissection (sPLND). Jeffrey Karnes at Mayo is one of the few top surgeons in the US who does this difficult surgery. It is difficult because PLNs detected on a PET scan can be very small. They are invisible, can be hidden in fat deposits, and are very difficult to find. There are innovative techniques like fluorescent or gamma-ray PSMA indicators that can facilitate detection. Patients treated with sPLND also received 6 weeks of bicalutamide.
  2. External Beam Radiotherapy (EBRT) to PLNs as part of salvage radiation treatment (SRT). At Mayo, 72% received salvage IMRT to the identified PLNs plus a large margin around them, while 28% received SBRT to just the identified PLNs plus a small margin around them. This was typically done along with 12-18 months of ADT.
  3. ADT-only, Patients treated with either of these two forms of MDT were compared to patients who received ADT-only, which is the current standard-of-care. Again, this was not part of a randomized clinical trial, so it is likely that the ADT-only patients were not offered MDT for a reason. Most importantly, about half had cancerous LNs in the retroperitoneum or abdomen (Stage M1a) - already outside of the prostate drainage area (Stage N1), and they had more positive LNs. In contrast, only 9% of the sLND group  and 19% of the EBRT group had cancerous LNs outside the pelvis. The ADT-only group had much further progression at the time of treatment.

After a median follow-up of 47 months:

  • Prostate Cancer-specific mortality was 13.5% for ADT-only, 9.5% for EBRT, and 6.3% for sLND (the difference between ADT-only and sLND was statistically significant)
  • Radiographic recurrence was 65% for ADT-only, 40% for EBRT, and 61% for sLND.
  • Castration-resistance was 39% for ADT-only, 19% for EBRT, and 21% for sLND.
    • The median time until castration-resistance set in was 59 months for ADT-only, 73 months for EBRT, and 98 months for sLND.
  • Second-line systemic therapies were offered to 43% for ADT-only, 29% for EBRT, and 24% for sLND.
    • The median time until the therapies were offered was 28 months for ADT-only, 32 months for EBRT, and 44 months for sLND.
  • Inexplicably, the percent of cancerous lymph nodes outside of the pelvis (% M1a) was not included as a variable to correct for in their multivariable analysis, and was largely ignored.

The authors found an association between MDT and radiographic progression in their retrospective sample of patients. However, it leaves unanalyzed how much of that association is due to the extraordinarily high rate of out-of-pelvis progression already present in the ADT-only treated patients. In fact, it seems likely that that is the reason they didn't receive MDT. 

They also make the same error with respect to castration-resistance and use of second-line therapies that they made in their bone MDT analysis; i.e., they "treated PSA" with their MDT, so they can't use castration-resistance and time to second-line therapy as useful endpoints. Tellingly, radiographic recurrence is similar for ADT-only and sLND, while EBRT is lower, possibly only because of the longer use of adjuvant ADT with EBRT.

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.

(Update 12/30/2020) Farolfi et al. reported on 16 patients who received sLND based on PSMA PET scan detection, and still had persistently detectable PSA 6 weeks later. They were given a second PSMA PET scan. Additional cancerous PLNs were found in 56% (in an additional 31%, cancer was found in non-pelvic LNs). In 63% of patients, the PLN cancers were in at least one of the same sites. This shows how poor surgical dissection is for PLN metastases, even with PSMA PET guidance.

Other articles about studies of oligometastatic prostate cancer:

Treating PSA

ORIOLE RCT

STOMP RCT

SABR-COMET RCT

Unwarranted Claims

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

Debulking the prostate in newly diagnosed oligometastatic men