Thursday, February 18, 2021

Xofigo 2.0

Xofigo (Radium 223 dichloride) is a systemic radiopharmaceutical. Radium is chemically similar to calcium and is taken up by bones in places where bone is actively growing, as in prostate cancer bone metastases. Radium 223 emits powerful alpha radiation that kills the cancer cells in the bone metastases. It has been found to double 2-year survival (see this link), extending survival time and reduce the skeletal-related events by almost a third. It often will not reduce PSA or show bone metastases shrinking in imaging, which some patients find disappointing.

It is FDA-approved for castration-resistant men with painful bone metastases, who do not show evidence of visceral metastases on a CT or MRI  (lymph node metastases are allowed). So far, it is only FDA-approved as a monotherapy, but researchers have wondered whether it may be more effective in combination with other medicines, or used in other situations.

Second-line hormonal therapies

It has long been known that androgen deprivation therapy (ADT) sensitizes prostate cancer cells to radiation therapy. Could a more powerful type of hormonal therapy work even better?

The combination of Zytiga and Xofigo was tried in the ERA 223 trial. The trial was stopped early because there were about 3 times more fractures in the group receiving the combination than in the group receiving a placebo and Zytiga. The combination now carries a black-box warning against the combined use.

It appears that the problem may be at least partly resolved by using a bone-strengthening agent (like Xgeva or Zometa). When they looked at the subgroup who had taken bone-strengthening agents, 15% of those taking Xofigo+Zytiga vs 7% of those taking Zytiga-only experienced a fracture. So, even though Zometa or Xgeva reduced the fracture rates by about half in both arms, the fracture rate was still twice as high among those taking the combination. 

The combination of Xtandi and Xofigo is being tried in the EORTC1333/PEACE 3 trial, which is still recruiting. Because of the problems with the ERA 223 trial, they sent out a safety alert to assure that everyone in both arms was also getting a bone-strengthening agent. Bertrand Tombal reported that skeletal events so far occurred in:
  • 33% of men taking Xofigo and Xtandi without a bone-strengthening agent
  • 3% of men taking Xofigo and Xtandi with a bone-strengthening agent
  • 13% of men taking Xtandi and a bone-strengthening agent
It is too early to ascertain whether the combination increases radiographic progression-free survival.

Agarwal et al. reported on a small Phase 2 trial where 39 metastatic castration-resistant men were randomized to Xofigo+Xtandi or Xtandi alone. Bone metabolic markers were reduced significantly by the combination, suggesting increased efficacy. A safety analysis found few serious cytopenias and no skeletal events in either arm. A new post-hoc analysis found:
  • PSA progression-free survival was 9 months for Xofigo+Xtandi vs 3 months for Xtand-alone (not significantly different on this small sample size)
  • Time to PSA progression after the next therapy was 19 months for Xofigo+Xtandi vs 8 months for Xtandi-alone (significantly different)
  • Time to next therapy was 16 months for Xofigo+Xtandi vs 3 months .for Xtandi-alone (not significantly different)
  • Overall Survival  was 31 months for Xofigo+Xtandi vs 21 months for Xtandi-alone (not significantly different)
  • There were 3 asymptomatic fractures found in the Xofigo+Xtandi arm.
Presumably, the combination has a deleterious effect on the bone microenvironment or structural integrity. While Zometa has been proven to have no effect on survival as a monotherapy, in a subset of the STAMPEDE trial the combination of Zometa and Celebrex increased survival by 22%. Patients should not combine Xofigo with a second-line hormonal therapy without a bone-strengthening agent, and preferably only in a carefully watched clinical trial. Using them sequentially may be safer. Patients may wish to discuss adding Celebrex as well.

Clinical trials combining Xofigo with second-line hormonals include these:


Morris et al. reported the results of a small trial comparing Xofigo + docetaxel to docetaxel alone in 53 castration-resistant men who had ≥ 2 bone metastases. They were given either:
  • Xofigo (55 KBq/kg) every 6 weeks for 5 injections and lower dose docetaxel (60 mg/m2) every 3 weeks for 10 infusions
  • Standard dose docetaxel (75 mg/m2) every 3 weeks for up to 10 infusions
  • The normal schedule for Xofigo is 55 KBq/kg once every 4 weeks for 6 injections
  • The normal schedule for docetaxel is 75 mg/m2 once every 3 weeks for 6 infusions
  • The timing adjustments were made for patient convenience
  • Almost all had tried a second-line hormonal therapy
  • Most were taking a bone-strengthening agent
With 52 weeks of follow-up:
  • Median PSA progression occurred after 6.6 months in the combination arm vs 4.8 months in the docetaxel-only arm
  • PSA declined by ≥ 50% in 61% of the combination arm vs 54% of the docetaxel-only arm
  • Median radiographic or clinical progression occurred after 12 months for the combination vs 9 months for docetaxel only
  • All 10 treatments were given for the combination, whereas there was a median of 9 of 10 treatments in the docetaxel-only arm
  • 12% discontinued treatment in the combination arm vs 23% in the docetaxel-only arm
  • Serious adverse events were suffered by 48% in the combination arm vs 62% in the docetaxel arm
  • Serious blood disorders were noted more often for docetaxel-only
It seems that the more toxic docetaxel dose could be reduced by the combination without any loss of efficacy.

Xofigo was also found to work well after docetaxel. Docetaxel's effectiveness was not diminished by previous Xofigo.

These clinical trials combine docetaxel and Xofigo:

There is a synergy between radiation and immunotherapy (see this link). Radiation kills cancer cells and their proteins (antigens) are detected by immune cells that form antibodies to them. 

Marshall et al. reported the results of a small trial that randomized 32 mCRPC patients to Provenge + Xofigo or Provenge alone. After median follow-up of 5.3 months:
  • Median progression-free survival (PFS) was 10.7 months for the combination vs 3.1 months for Provenge alone.
  • The % who had a PSA reduction by more than half was 33% for the combination vs 0% for Provenge alone
  • The % who had an alkaline phosphatase reduction of more than 30% was 60% for the combination vs 7% for Provenge alone
  • There were no increases in side effects for the combination
Increases in PFS and reductions in PSA and bone ALP are usually not seen for either medication alone, so it is noteworthy that the combination had an enhanced effect.

But immune stimulation will never be long-lasting. Eventually, the immune system will regard the cancer cell as if it were a normal healthy cell of one's own and will stop attacking it. To continue the attack, a different sort of immune encouragement is required. These "checkpoint blockers" are currently represented by drugs that have been FDA-approved for use in other cancers, like Yervoy (ipilimumab) and Keytruda (PD 1 inhibitor).  This trial did not find any clinical benefit in combining Xofigo and Tecentriq. (atezolizumab). Hopefully, future Xofigo clinical trials will include a checkpoint blocker as well as an immune stimulant. There are two ongoing clinical trials at UCSF and in Melbourne of Lu-177-PSMA-617 combined with Keytruda.

This clinical trial includes an arm where patients receive Xofigo + external beam radiation + Bavencio (avelumab):
PARP inhibitors

PARP inhibitors (e.g., olaparib, rucaparib, etc.) have known activity in men who have certain DNA-repair defects, particularly BRCA mutations (either germline or somatic). They boost the deficiency in self-repair, causing the cancer cells to die. They may also be useful in conjunction with radiation. When radiation creates sublethal DNA damage, preventing the DNA-repair machinery from operating, a PARP inhibitor may put the cell over the edge.

van der Doolen et al. reported the results of an exploratory retrospective analysis of 93 castration-resistant patients at Johns Hopkins treated with Xofigo for bone metastases:
  • 28 had DNA-repair defects (DRD+)
  • 65 had no DNA-repair defects (DRD-)
Compared to the men who were DRD-, the DRD+ men had:
  • Twice as high alkaline phosphatase (ALP) response: 80% vs 39%
  • Longer time to ALP progression: 6.9 mos vs 5.8 mos. (not statistically significant)
  • Longer time to next systemic therapy: 8.9 mos. vs 7.3 mos. (not statistically significant)
  • Twice as long overall survival: 36.3 mos. vs 17.0 mos. 
  • Better Xofigo completion rates: 79% vs 47%
  • No difference in PSA response
Xofigo seems to work especially well in men who are DDR+. The combination of PARP inhibitors and Xofigo may be especially effective. There is a trial in Australia of a PARP inhibitor combined with Lu-177-PSMA-617.

These clinical trials examine the effect of DRD+ or PARP inhibitors on Xofigo effectiveness:
Earlier Treatment

A lab study at M.D. Anderson found that Xofigo was excellent at treating micro-metastases, but not as good at treating large bone metastases. This suggests that earlier Xofigo treatment may be preferable, and that larger tumors are optimally treated with a combination medical therapy or with a combination with external beam radiation (see below).

In a retrospective study, survival after Xofigo treatment was associated with better performance status, lower PSA at the time of treatment, lower pain scores, less use of advanced hormonals, lower bone scan index, and normal ALP levels.

Hematologic toxicity and bone marrow failure are potential adverse events associated with using Xofigo after extensive bone metastases are already present (see this link and this one). A clinical study showed that high tumor burden predicted skeletal-related events (SREs) and lower overall survival.

Xofigo has only been tested in men with bone-metastatic CRPC, who have bone pain and no visceral metastases. It's use in earlier states of progression have been unexplored.

This clinical trial includes Xofigo for biochemically recurrent patients before metastases are visible:
External Beam Radiation

Because Xofigo is especially good at targeting micrometastaic bone metastases, and not so good at targeting the macroscopic bone metastases, it may be optimal to target the visible ones (if there are very few) with SBRT, and the invisible ones with Xofigo.

These clinical trials include Xofigo as well as SBRT to oligometastases:

There are several known radiosensitizers (medicines that increase the cell-killing potential of ionizing radiation). The problem with many radiosensitizers is that they may sensitize healthy cells too, increasing toxicity. Ideally, we want a medicine that only radiosensitizes cancer cells, while not affecting or even being radioprotective of healthy cells. Among the types of medicines being explored for this affect are PARP inhibitors and other DNA-damage repair inhibitors (above), heat shock protein inhibitors, HDAC inhibitors, idronoxil, and a plethora of natural products. Veyonda (idronoxil) has had some promising results when combined with Lu-177-PSMA-617 (see this link). So far, there are no clinical trials pairing radiosensitizers with Xofigo.


While there was no benefit found in increasing the dose per treatment over 55 KBq/kg or extending the number of consecutive treatments beyond 6 (see this link), repeat treatment may be beneficial. Sartor et al. found that repeat cycles are effective and well-tolerated. Multiple treatments are commonly used for Lu-177-PSMA-617.


The RESTORE - Cohort C trial of bipolar androgen therapy (BAT) found that testosterone-loading among men who had not had Xtandi or Zytiga only had a benefit among men with lymph node-only metastases. This raises the possibility that Xofigo may be complementary to BAT in men with both lymph node and bone metastases.

This clinical trial will combine Xofigo and BAT in mCRPC patients:

Th-227 decays into Ra-223. While Th-227 readily chelates to the PSMA ligand, Ra-223 does not. So it is possible that as it decays, the Ra-223 detaches and may be picked up by bone tissue, just as Xofigo does. If so, there may be a double treatment effect.

This clinical trial uses Th-227-PSMA-antibody:
For those trying to decide between Lu-177-PSMA and Xofigo, here's a comparison (but not a randomized comparative trial) about the way the two radiopharmaceuticals work.

Saturday, January 30, 2021

Avoiding radiation damage to salivary glands with Ac-225-PSMA-617 therapy

As we await the results of the VISION trial of Lu-177-PSMA-617, research continues into improving radiopharmeuticals. Ac-177-PSMA-617, which is more lethal to cancer cells within a more limited range, is one of several promising alternatives (see this link).

One of the serious side effects of the experimental Ac-225-PSMA-617 therapy is radiation damage to salivary glands. "Xerostomia" (dry mouth) also occurs with Lu-177-PSMA-617 therapy, but it is usually transient and less severe, although it does increase with the number of treatments. Sathkegke et al. reported occurrence in 85% of South African patients treated with Ac-225-PSMA-617, but no one stopped treatment entirely because of it. Kratchowil et al. reported occurrence of xerostomia in Heidelberg, Germany so severe in 4 of 40 treated patients that treatment had to be discontinued. Feuerrecker at al reported that all their treated German patients suffered from xerostomia; it was so severe as to curtail treatment in 6 of 26 patients.

Acute, low-grade xerostomia is caused by the temporary irritative inflammatory effects of the radiopharmaceutical on salivary tissue. Lasting damage may result from radioablation of the saliva-producing cells and the nerves that innervate them, and their replacement with and obstruction of the ducts with mucus and scar tissue. Loss of saliva can make chewing and swallowing almost impossible, leading to choking and vomiting. Digestion is impaired, and the ability to taste food may be lost. Saliva has antimicrobial properties, so its loss can lead to tooth decay, gum disease, and oral thrush. Speaking can become difficult.  It can feel like burning, and interfere with sleep. Humans normally produce about a liter of saliva each day.

Some simple therapies (local cooling with ice, Vitamin C, lemon juice, and PMPA) have been found to be ineffective. Ta├»eb et al. report that treatment with botulinum toxin, Vitamin E and MnBuOE may be more successful, but that regeneration of salivary glands with stem cells or genetic modification may ultimately be necessary. Riley et al. found very low quality of evidence that amifostine, pilocarpine, palifermin, biperidine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin) may be useful. More benefit may be accomplished with some of the following strategies:


Rathke et al. reported the successful use of sialendoscopy in 11 patients. Sialendoscopy is a kind of endoscopic procedure involving the insertion of a thin probe into the salivary glands. It dilates the openings that have closed due to inflammation. They irrigated the glands with saline and prednisolone. It only worked when done immediately.

Pre-treatment with PSMA-11

PSMA-11 is the small molecule ligand used with Ga-68-PSMA-11. Taken without the radiotracer, it attaches to the salivary tissue, where it can block further uptake by the PSMA-617 ligand. Kalidindi et al. found that in mice, pretreatment with 1000 picomoles blocked uptake of Lu-177-PSMA-617 in the salivary glands and kidneys; but uptake, while reduced, was still at therapeutic levels in tumor tissue. This finding would have to be replicated in clinical trials.

Use only when there is significant PSMA-avidity

Damage to normal, healthy tissue increases when there is insufficient PSMA-avid tumor tissue to attach to. Gaertner et al. found that across 135 patients, uptake by normal tissues of the salivary glands, tear ducts, kidneys, and other vital organs was significantly reduced in men with high tumor load. While it is true for many pharmaceuticals that earlier use is more effective and less toxic, there is a balance to be struck between the tumor-killing effect and toxicity for the PSMA-targeted radiopharmaceuticals. We have seen that such treatment can be too late as well, when new metastases lose PSMA-avidity (see this link).

Mix Lu-177-PSMA-617 and Ac-225-PSMA-617

A cocktail of the two may increase the cancer-killing power of Lu-177-PSMA-617 while decreasing the toxicity of Ac-225-PSMA-617. Khreish et al. reported that only 5 of 20 patients given the cocktail reported mild xerostomia.

Use a PSMA antibody

PSMA-617 and PSMA-11 are small molecules that have been found to attach to the PSMA molecule on the surface of prostate cancer cells. They are not as specific as other ligands. Scott Tagawa is exploring the use of a PSMA antibody, called J591 in two clinical trials (this one and this one), that may be more specific than the small molecules. In a previous clinical trial, there were no reports of xerostomia.  The clinical trial of Th-227 targeting PSMA uses a highly specific antibody.

Use a non-PSMA-targeted ligand

Another strategy is to forgo the PSMA target entirely. Ac-225 has been attached to an antibody that very specifically targets hK2 (one of the 4 prostate cancer proteins detected by the 4KScore test). It has entered a clinical trial.

Beware of MSG and other supplements

Harsini et al. conducted a small clinical trial where patients were randomized to take tomato juice with and without monosodium glutamate (MSG). Glutamate is a known heavy-metal chelator. Each patient had two double-blinded PSMA PET scans -- one with MSG; the other without MSG. MSG did reduce the uptake of PSMA into the salivary glands and the kidneys. Unfortunately, it also blocked the uptake of PSMA into tumor tissue. Armstrong et al. reported a similar trial where patients could swish MSG in their mouths or ingest it. Each patient had Ga-68-PSMA-11 PET scans with and without MSG. Swishing had no effect. Oral ingestion reduced uptake in salivary glands and in tumors. Patients getting PSMA theranostics should avoid MSG and Chinese food.

Because the PSMA-targeted radiopharmaceuticals are very loosely held together (chelated) by a coordination complex, it is easily reversed by other heavy metals (like iron, cobalt, vanadium, etc. supplements) or other chelates or chelators (like those frequently found in multi-mineral tablets). Curcumin, a popular supplement, has been found to be a chelator. Use of such supplements may increase the toxicity of these radiopharmaceuticals, or render them ineffective. Antioxidants and free radical absorbers may interfere with the DNA damage that radiopharmaceuticals are trying to achieve. To be safe, and to maximize their effectiveness, patients should avoid all supplements during therapy.

Thursday, January 28, 2021

Dose Painting: simultaneous integrated boost (SIB) to the dominant intraprostatic lesion (DIL)

Two technologies have come together to allow for a new kind of radiation treatment known as simultaneous integrated boost (SIB), or, more informally, “dose painting.” The two technologies are: 
  1. improved imaging by multiparametric MRIs that can more precisely locate tumors within the prostate, and 
  2. improved external beam technology that can deliver doses with submillimeter accuracy. 
Dose painting can be achieved with brachytherapy as well. But just because it can be done, doesn’t mean it should be done. That is, the following two questions must be answered:
  1. Is there any benefit in terms of oncological outcomes?
  2. Is there any increase in treatment toxicity attributable to it?
The arguments for dose painting include:
  • There is often a dominant intraprostatic lesion (DIL) or index tumor. There is some evidence that cancer spreads via clones from it. Because such tumors are often large and high grade, some think that the index tumor may be relatively radioresistant, perhaps because of hypoxia or cancer stem cells. Therefore, a higher dose of radiation may be necessary to kill its cancer cells.
  • By concentrating the radiation’s killing power at the DIL, it may be possible to reduce the radiation dose where it is less needed, and thus spare organs at risk (e.g., bladder and rectum).
The arguments against dose painting include:
  • The index tumor hypothesis is far from proven. In fact, prostate cancer is multifocal in about 80% of men. Reducing the dose elsewhere is risky because cancer cells may survive and propagate.
  • If the dose needed to kill the cancer cells is inadequate, why not increase the dose throughout the prostate to a dose that is adequate? With today’s pinpoint technology, the clinical target volume (the prostate) can be defined with sub-millimeter accuracy and near-perfect shaping.
  • Using mpMRI to precisely delineate the DIL may miss much of it. In fact, a study at UCLA found that tumors delineated by mpMRI missed 80% of the tumor's actual volume.
  • While mpMRI is good at finding large high-grade tumors, sometimes the highest grade tumor is not large, and mpMRI cannot locate it.
  • Intense foci of radiation may increase the probability of normal tissue complications, including damage to the urethra, bladder neck, sphincter, rectum and bowel.
With all these pros and cons in mind, the FLAME randomized clinical trial was instituted to determine whether dose painting is effective and safe in real-world application. Kerkmeijer et al. reported the results of 571 patients treated at 4 institutions in Belgium and the Netherlands from 2009 to 2015. Patients were:
  • Predominantly (85%) high risk
  • Adjuvant ADT was given to 65% for a median of 18 months.
  • Received hypofractionated radiation to the prostate: 77 Gy in 35 treatments, which is biologically equivalent to 82 Gy in 41 treatments.
  • Half received a SIB to the DIL as well: 95 Gy in 35 treatments, which is biologically equivalent to 116 Gy in 58 treatments.
  • The boost dose was reduced sometimes to meet very tight dose constraints on organs at risk.
After 6 years of follow-up:
  • 5-year biochemical disease-free survival (bDFS) was 92% for those that received the SIB and 85% for those who didn't, a significant difference.
  • Both biochemical failures and clinical recurrences were cut in half by the SIB
  • In the limited follow-up period, there weren't enough distant metastases or deaths to detect a significant difference.
  • There were no significant differences in Grade 2 or Grade 3 urinary or rectal  toxicity,
  • As previously reported, late-term Grade 2 or greater toxicity was 10% for rectal, 27% for urinary with no significant differences.
  • There was no late-term Grade 3 rectal toxicity, and minimal late-term Grade 3 urinary toxicity in either arm.
  • There were no significant differences in patient-reported quality of life for urinary, rectal or sexual outcomes.
Because oncological results were as good as brachy boost therapy, the current gold standard for treating high-risk patients, and late-term urinary toxicity was minimal, hypofractionated IMRT with SIB is poised to become the new standard of care for high-risk patients. Longer follow-up will determine whether the results hold up.

There are some opportunities for improving results for patients even further.
  • SBRT with SIB: As we've seen extreme hypofractionation may provide more lasting results with equally good toxicity. Whole gland treatment with as high as 47.5 Gy in 5 fractions did not incur any excess toxicity in trials (see this link). 
  • Tumor detection and delineation with PSMA PET/CT scan: a small comparative study showed that PSMA PET/CT had superior sensitivity and positive predictive value compared to mpMRI. More importantly, it can eliminate patients who would not benefit from localized treatment because of occult metastases.
  • Genomics to detect radio-resistant tumors and radiation sensitivity
  • Imaging to detect hypoxic tumors (e.g., BOLD MRI, FAZA PET, or MISO PET)

Sunday, January 24, 2021

SBRT for High-Risk Patients

As we have seen, SBRT is a preferred therapy for low and intermediate-risk patients (see this link). It is effective, safe, convenient, and relatively inexpensive. However, its use for high-risk patients remains controversial.

Amar Kishan has accumulated data from 8 institutions that have used SBRT for 344 high-risk patients. They were treated as follows:

  • They received from 35 Gy-40 Gy in 5 treatments (7-8 Gy per treatment)
  • 72% received adjuvant ADT for a median of 9 months
  • 19% received elective nodal radiation

After a median follow-up of 49.5 months:

  • 4-year biochemical recurrence-free survival  (bRFS)was 82%
    • Higher dose, longer ADT, and nodal radiation were associated with better bRFS
  • 4-year metastasis-free survival was 89%
  • Late grade 3 GU toxicity was 2.3%
  • Late grade 3 GI toxicity was 0.9%
    • Toxicity was associated with dose and ADT use

Although the results of different prospective trials aren't comparable, the following table gives an idea of 4-6 year outcomes of prospective trials of high-risk patients using various therapies.





ADT (median)

Late GU Toxicity Grade ≥3

SBRT (1)

4 yrs


198-253 Gy

9 mos.


Surgery+SRT (2)

5 yrs


154 Gy

6 mos.

8% (3)

HDR-BT (4)

5 yrs


227-252 Gy

6.3 mos.


LDR- Brachy Boost (5)

5 yrs


227 Gy

12 mos.


HDR-Brachy Boost (6)

6 yrs


267 Gy

12 mos.


IMRT (7)

5 yrs


174 Gy

28 mos.


SBRT = stereotactic body radiation therapy,. External beam radiation (EBRT) concentrated in 5 treatments
bRFS= biochemical (PSA) recurrence-free survival
BED= biologically effective dose (comparable effectiveness)
ADT= androgen deprivation therapy used for a limited time to improve outcomes
late GU toxicity ≥3 = serious urinary side effects requiring intervention, occurring more than 3 months after therapy
HDR-BT = high dose rate brachytherapy (temporary implants)
LDR-BT = low dose rate brachytherapy (permanent implants/seeds)
Brachy Boost therapy - External beam radiotherapy (EBRT) with a boost of radiation to the prostate using brachytherapy 
IMRT = intensity-modulated radiation therapy, usually given in about 40 treatments

(2) with GS 8

As we've seen (see this link), brachy boost therapy is the gold standard for long-term recurrence-free survival. At about 5 years, however, all therapies seem to be about equally effective, with biochemical recurrence-free survival in the range of 78-91%. However, they differ markedly in the incidence of serious late-term urinary side effects. For LDR Brachy Boost therapy, the risk of urinary retention is high, while the risk of incontinence and urinary retention is elevated among patients having salvage radiation (SRT). External beam monotherapy, using either IMRT or SBRT, had a low risk of serious late-term urinary side effects (and almost no risk of serious rectal side effects).

IMRT, as a primary therapy for high-risk patients, requires long-term use of ADT to be effective. The DART RADAR trial showed that for high-risk patients, 6 months of adjuvant ADT wasn't nearly enough. Nabid suggests that 18 months of adjuvant ADT may be optimal when paired with IMRT. SBRT seems to be equally effective with less adjuvant ADT, but the optimal duration is yet to be determined.

The question that will only be resolved with longer follow-up is whether the recurrence rates are stable after 4 years, or whether they will deteriorate with longer follow-up. In the ASCENDE-RT trial of brachy boost therapy vs external beam radiation only, biochemical recurrence rates were similar after 5 years. Recurrence increased at a rate of 5% per year among those treated with EBRT alone, but only at a rate of 1% per year if they got the brachy boost. There was similar stability of outcomes when HDR brachytherapy was used. Recurrence after salvage radiation increased from 22% at 5 years to 30% at 10 years. There is every reason to believe that SBRT, which uses biologically effective doses (BED) of radiation similar to brachy boost therapy, will follow a stable recurrence pattern over time, but that remains to be shown.

Ensuring the safety of patients is critical, and high-risk patients are usually treated with wider margins that can affect toxicity. As we saw, SBRT there are many factors that must be considered when giving radiation this intense (see this link).

The first randomized trial (see this link) of radiation delivered in 6 treatments compared to 39 treatments to intermediate to high-risk patients proved that the cancer control and toxicity were similar. Another randomized trial (PACE-B) has already shown that the toxicity is lower with SBRT. An ongoing arm of that trial (PACE-C) is focusing on high-risk patients.

NCCN has included SBRT as a reasonable standard-of-care option for high-risk patients (Table 1 Principles of Radiation Therapy PROS-E 3 of 5 in NCCN Physicians Guidelines 3.2020). Due to the pandemic, an international panel of radiation oncologists is recommending that high-risk patients consider its use (see this link).

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.

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




Unwarranted Claims

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

Debulking the prostate in newly diagnosed oligometastatic men