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Erleada (apalutamide) has already been FDA-approved for use in non-metastatic castration-resistant prostate cancer (non-m CRPC), which affects relatively few men (remembering that metastatic was defined by bone scan/CT rather than PET scan). Now we have evidence that it increases overall survival in men with metastatic hormone-sensitive prostate cancer (mHSPC).

Chi et al. reported the early results of the TITAN randomized clinical trial at the ASCO meeting. The trial was conducted at 230 sites in the US and internationally. Patients received 240 mg/day of apalutamide (n=525) or placebo (n=527) plus ADT.

  • It was double blinded.
  • Prior treatments were allowed.
  • 8% had prior treatment for localized PC
  • 11% had prior docetaxel
  • 63% had high-volume metastases
  • 37% had low-volume metastases


After almost 2 years median follow-up, the outcomes were as follows:

  • Apalutamide reduced mortality by 33%
  • Apalutamide reduced radiographic progression or mortality by 52%
  • Benefit was seen in all subgroups (i.e, volume of metastases and prior treatments)
  • Time to docetaxel treatment was 61% longer in men getting apalutamide.
  • Because of the success, men getting placebo were allowed to get apalutamide
  • Grade 3 (serious) and grade 4 (life-threatening) toxicities were similar in both groups (41-42%)
  • Discontinuations due to adverse events were low in both groups (8% for apalutamide, 5% for placebo)

Xtandi (enzalutamide) has been FDA-approved since 2012 for mCRPC after docetaxel and since 2014 for mCRPC before docetaxel. Sweeney et al.  will report the results of the ENZAMET randomized clinical trial at the ASCO meeting. 1,125 patients at 82 sites in Australia, New Zealand, Ireland, Canada, and the UK received 160 mg/day of enzalutamide or placebo plus ADT. It was unblinded and will be reported earlier than expected.

  • It was double blinded.
  • ADT must have started within 12 weeks of trial entry. No other treatments were allowed.

Based on these successes, I'm sure the FDA will fast-track approval for both drugs for this new indication, joining Zytiga and Taxotere. Because they are already available for another indication, insurance may allow them off-label even sooner. The cost for either is about $12,000 for a 30-day supply. It is unknown if they are any more effective than abiraterone, which is now available as a lower cost generic called Yonsa for about $10,000 per month.
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The concept of an "oligometastatic state" is that there exists an early stage where metastases are few in number and are in some way different from metastases that develop later. It also means that there are no micrometastases in systemic circulation (in bone and lymph) and in reservoirs like bone, nerve cells, lymph nodes and other organs. If such a state exists, the cancer can be picked off, like dandelions in a lawn, and the person can be cured.

The alternative concept is that cancer spread is always polymetastatic. Thousands of cells are released from the primary tumor. They find their way to sites where they change the tissue they land in, making it amenable to future growth. This is called "seed and soil." A metaphor might be mushrooms growing at the base of an oak tree. The mycelium extends everywhere throughout the soil and into the roots of the tree. Occasionally, a mushroom crops up. You can pick all the mushrooms you want, but the fungus is never destroyed. There is no way to destroy the fungus short of destroying the roots of the oak tree and sterilizing the soil. This is what "systemic" means.

It is well known that tumor cells must undergo a genomic change called epithelial-to-mesenchymal transition (EMT) before they are capable of traveling and living outside of their original environment. Metastasized cells do not look like or behave like the original tumor in its original tissue; they are phenotypically different.

Are all cancers alike?

There are certain "hallmarks of cancer." To qualify as a cancer, it must be malignant, destroying healthy tissue. Most cancers multiply rapidly, losing the ability to self-destruct when its DNA goes awry (apoptosis). They are usually immortal and evade destruction by the immune system. They can travel from one place to another. Solid tumors change the structure of their host tissue and usually generate their own blood supply and nerve innervation (see cancer as a tissue-based disease).

But all cancers are different. Unlike most other solid tumors, prostate cancer is usually originally multifocal in the prostate. While some cancers can be cured by surgically removing the original tumor, the whole organ must be removed (or irradiated) for prostate cancer. Foci may be a centimeter or more apart, so it is known to have a strong signalling mechanism that changes host tissue. It has a predilection for lymph nodes and bone, where it usually creates osteoblastic lesions (bone overgrowth). It is activated by an androgen receptor, which eventually becomes impervious to androgen deprivation. Tumors tend to be hypoxic, and have low immune-cell infiltration. They are relatively radioresistant, and are not appreciably killed off by non-taxane chemotherapy. There are multiple growth pathways - block one and others predominate. It is also abnormally slow growing. It may take many years for EMT cells to originate. The time from the first detectable metastasis to the second may be years apart. Unlike other cancers, prostate cancer metastatic cells generate energy for reproduction from lipid metabolism at first. Many years later, glycolysis may come to predominate (as it does in most other cancers).

To determine if there is such a thing as an "oligometastatic state" it is therefore necessary to show that such a state exists for every kind of cancer. The first step is to show plausibility. With high throughput sequencing it may be able to distinguish the genomics of early metastases from later ones. However, because genetic breakdown is a characteristic of cancer, it is also necessary to show that the early clones are phenotypically different from later clones. If early clones lack the ability to disseminate and prepare the "soil" for metastatic progression, that would create a case for an oligometastatic state.

It is also necessary to show that such a state exists for every type of cancer, or at least to find the cancers in which such a state exists. One cannot just assume that all cancers are alike in this regard.

The SABR-COMET Phase 2 Trial

Palma et al. recruited 99 patients at 10 hospitals in Canada, Scotland, Australia and the Netherlands from 2012-2015. Patients had 1-5 metastases, and were randomly assigned to high-intensity metastasis-directed radiotherapy (SABR or SBRT) or systemic standard of care. After 2 years median follow-up, there were:

  • 66  patients in the SABR group
  • 33 patients in the control group
  • Most had 1-3 metastases: 94% in the control group, 93% in the SABR group
  • SABR dose was most commonly 35 Gy in 5 treatments,  60 Gy in  8 treatments, and 54 Gy in 3 treatments
  • 12% received additional SABR for disease progression


After a median follow-up of 25-26 months:

  • Overall mortality was 36% for SABR, 48% for control (Hazard Ratio = .75)
  • Overall survival (median) was 41 months for SABR, 29 months for control (Hazard Ratio = 0.57; p=0.09) Note: they prespecified that anything above 80% confidence would be sufficient to expand to a Phase 3 study.
  • 39% had metastatic progression in the SABR group, mostly new metastases
  • 61% had new metastases in the control group
  • Grade ≥2 adverse events: 9% in the control group, 29% in the SABR group
  • 5% of the SABR group died as a result of treatment: radiation pneumonitis, pulmonary abscess, and subdural hemorrhage from surgery to repair a perforated gastric ulcer


The authors are cautious about the toxicity, but optimistic that their study provides proof of an "oligometastatic state." They have already announced two Phase 3 randomized clinical trials for people with 1-3 metastases and 4-10 metastases.

Skewed Distribution of Cancers Accounts for the Purported Benefit

The distribution of cancer types was vastly different in the SABR and control groups. Metastatic colorectal cancer, which has an 70% 2-year mortality rate, is twice as likely to appear in the control group as the SABR group; while metastatic prostate cancer, which has a 10% 2-year mortality rate is more than 3 times as prevalent in the SABR group. This skewed distribution accounts for almost all of the difference that the authors attribute to a treatment effect.


Type of CancerControlSABR
expected 2-year survival (approx)
n% of totaln% of total
Breast515%1320%50% (1)
Colorectal927%914%30% (2)
Lung618%1218%10% (3)
Prostate26%1421%90% (4)
Other1133%1827%
TOTAL3366
(1) https://www.nature.com/articles/bjc2015127
(2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739317/
(3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096514/
(4) https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32486-3/fulltext


ControlSABR
Expected 2-year survival due to distribution35%48%
Expected 2-year mortality due to distribution65%52%
Hazard Ratio due to skewed distribution80%
Reported Hazard Ratio75%

I believe the authors of the study erred in accepting the results even with 80% confidence for forging ahead with a Phase 3 randomized trial. The treatment effect, if any, is so small that their Phase 3 trial as specified is insufficiently powered to detect a treatment effect. They do not propose to stratify by type of cancer. Also, much longer follow-up is needed for prostate cancer.

On top of that, they have not made the case for an oligometastatic state, which would have to be true for every cancer type and not just a weighted average sum of them. They would also have to include genomic and phenotypic analysis of biopsied tissue when there are both few metastases and many in order to demonstrate plausibility.

Patients should note the mortality rate attributable to SABR of metastases. There is little risk in irradiating metastases occurring in safe locations, like the pelvic bones. There may be unacceptable risk in irradiating metastases near the heart, lungs, or digestive tract. Since there is no evidence that metastasis-directed therapy for prostate cancer improves survival, patients should not avoid systemic therapy (for which there is convincing evidence). Patients who are interested in SABR of metastases should talk to experienced radiation oncologists in large tertiary-care facilities.
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Curcumin (a turmeric extract) is one of the most popular natural substances subjected to pre-clinical research. Based on mouse and lab studies, it has been touted as the cure to cancer and just about everything else, with reports of activity including anti-inflammatory, anti-HIV, antibacterial, antifungal, nematocidal, antiparasitic, antimutagenic, antidiabetic, antifibrinogenic, radioprotective, wound healing, lipid lowering, antispasmodic, antioxidant, immunomodulating, anticarcinogenic, and Alzheimer’s disease, among others. This "panacea" and the low level evidence behind it are satirized in this amusing video.

It is one of the most widely researched supplements - in mouse and lab studies. In spite of its spectacular success with mice, randomized clinical trials in humans have been lacking. Choi et al. reported on a double-blinded randomized clinical trial of curcumin on 82 evaluable men who completed one treatment cycle of intermittent hormone therapy. They were then given 1440 mg/day of curcumin or a placebo for 6 months. The goal of the study was to see whether curcumin could extend their time off of hormone treatment.
  • Those taking curcumin were able to avoid hormone therapy for 16.3 months
  • Those taking the placebo were able to avoid hormone therapy for 18.5 months
  • The difference was not statistically significant
  • 10% of patients taking curcumin had PSA progression during the curcumin treatment period vs 30% of those taking the placebo.
The fact that those taking the placebo had an insignificantly longer break from hormone therapy in spite of the fact that their PSA progression was greater than those who were taking curcumin in the first 6 months, indicates that curcumin may have interfered with the PSA tests while they were taking it. Clearly, circumin did not delay clinical progression.

Ide et al. found in a small (n=85) double-blind randomized clinical trial that a mixture of soy isoflavones and curcumin suppressed the serum PSA readings of men with high PSA (>10 ng/ml) who were confirmed by biopsy to not have prostate cancer. The curcumin mixture suppresses the PSA reading independent of prostate cancer.

Fabiani et al. reported on 50 consecutive patients with PSA over 4.0 ng/ml or PSA velocity > .75 ng/ml/year. They were given curcumin for 30 days.
  • Baseline % free PSA was 17%
  • After 30 days of curcumin, % free PSA was 20%
  • The changes in PSA and % free PSA were statistically significant
It seems that curcumin suppressed PSA. Although it is possible that 30 days of curcumin reversed the prostate cancer, that is unlikely. It is more plausible that curcumin affected the PSA assay.

This effect has been noted in the literature. The authors of this analysis and this one label curcumin as a Pan-Assay Interference Compound (PAINS), which means that it is known to interfere with assay readouts. Curcumin particularly confounds tests of molecules, like prostate specific antigen, that penetrate the cell wall. According to this analysis, other common supplements that may interfere with the integrity of the cell wall without actually binding to a site on the proteins (which would be a real drug effect) include genistein (a soy isoflavone), EGCG (green tea), resveratrol (grapes),  and capsaicin (chili peppers). Some of these compounds, including curcumin, are capable of forming stable metal ion complexes and should be scrupulously avoided by patients taking Ga-68-PSMA-11, Lu-177-PSMA-617, technetium bone scan, or gadolinium MRI contrast agent.

There are other supplements that may mask PSA readings without affecting progression. These include  saw palmetto, pygeum, and beta-sitosterol. 5-alpha-reductase inhibitors (Proscar and Avodart) affect PSA in men with BPH and prevent the occurrence of prostate cancer. Because they affect PSA in a known way in men with BPH, we are able to correct for the PSA aberration (by doubling the PSA reading). The FDA has warned that biotin, in many multivitamin preparations, may interfere with many laboratory blood tests.

In designing future clinical trials on curcumin, like this one or this one that tests its benefit as an adjuvant therapy to active surveillance, it is important that the measured endpoint not be dependent on PSA. PSA doubling time, biochemical recurrence-free survival, and time before ADT is initiated (which is usually given as a result of increasing PSA) are artificially increased by curcumin. Only endpoints like radiographic progression-free survival and metastasis-free survival are useful. Incidentally, this is also why those endpoints must be chosen when evaluating the effectiveness of metastasis-directed therapy, which will lower PSA arising out of macroscopic metastases but may or may not slow the cancer's progression.

I spent a very short career as a chemist developing radioimmunoassays for biological substances, like PSA, that were only detected in serum in nanomolar and picomolar amounts. I can attest that even small amounts of impurities that adsorb, quench fluorescence, or react with the protein or its antibody can completely invalidate a test. Curcumin seems to do this.

The biggest problem with curcumin as a medication is its oral bioavailability, which is less than 1% and its elimination half-life, which is about a half hour in rats. It is doubtful that enough is bioavailable to have any therapeutic effect. This is true in spite of substances like piperine that aid passage through the gut wall. It is metabolized very quickly by the liver. Moreover, what is actually in a pill labeled as curcumin is highly variable, and curcumin is chemically unstable.

Many men rely on PSA to monitor prostate cancer progression. It may be misleading to use a supplement that may invalidate this important test. If there were any valid clinical studies indicating a true benefit, the corruption of a biomarker might be forgivable. But curcumin has only shown a benefit to mice so far. Patients must be wary of any supplement whose benefit is only supported by mouse/lab studies, and which only seems to affect PSA measurements. It is entirely possible to treat PSA without actually treating the cancer.
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Last year, the American Society of Radiation Oncologists (ASTRO) looked at the available evidence comparing hypofractionated radiotherapy (either 60 Gy in 20 treatments or 70 Gy in 28 treatments) to standard fractionation (78-82 Gy in 40-44 treatments), and found it was at least as good in terms of oncological outcomes and toxicity. They found strong evidence for this recommendation (see this link). There are obvious benefits for the patient in terms of convenience and cost. They stopped short of strongly endorsing ultrahypofractionated radiation therapy (usually called SBRT), which is usually completed in only 4-5 treatments. There wasn't enough published data at the time.

Since then, there have been several published clinical trials, some with randomized comparisons. Jackson et al. have now compiled the data from 38 prospective clinical trials comprising 6,116 patients treated with SBRT for localized prostate cancer. Their meta-analysis found that 5-year biochemical recurrence-free survival (bRFS) was:

  • 97% among low-risk patients
  • 92% among intermediate-risk patients
  • more studies included intermediate risk than low risk
  • not enough high-risk patients to reliably report yet
  • 95% among all patients
  • 7-year bRFS was 94%
  • bRFS increased with higher doses
  • bRFS was not affected by the use of adjuvant ADT


In terms of physician-reported toxicity, they found:

  • Acute Grade ≥3 (serious) urinary toxicity occurred in 0.5% of patients
  • Acute Grade ≥3 (serious) rectal toxicity occurred in 0.1% of patients
  • Late-term Grade ≥3 (serious) urinary toxicity occurred in 2% of patients
  • Late-term Grade ≥3 (serious) rectal toxicity occurred in 1% of patients
  • Late urinary toxicity increased with dose, rectal toxicity did not


In terms of patient-reported adverse effects of treatment:

  • Urinary and Bowel scores returned to baseline within 2 years of treatment
  • They remained at those levels with 5 years of follow up
  • Sexual scores declined gradually over time


While the authors believe that their analysis provides enough evidence that SBRT should be considered a standard of care for low and intermediate risk patients, they stop short of recommending that SBRT be considered the standard of care for patients who choose radiotherapy.  (Active Surveillance is appropriate for most low risk patients.) There is an ongoing randomized clinical trial designed to prove whether SBRT or moderately hypofractionated radiation is superior. First results are expected in 2025. The PACE trials in the UK, will compare outcomes of SBRT vs surgery (PACE A) and SBRT vs IMRT (PACE B). Early toxicity results of PACE B have been presented. Results are expected in 2021.
Thanks to Amar Kishan for allowing me to see the full text of the analysis
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In October 2018, the American Society of Radiation Oncologists (ASTRO) strongly endorsed moderately hypofractionated IMRT (20/28 treatments) for primary radiation treatment (see this link). Since then, there has been another publication of a randomized clinical trial with ten years of follow-up (see this link).

The advantages for the patient are large: fewer visits than the conventional 38-44 treatments with a concomitant reduction in costs. Because there is now convincing proof that this can be accomplished without an increase in side effects and without loss of oncological effectiveness, there is no reason why any patient would suffer through the conventional regimen. The remaining question is whether the number of treatments (or fractions) can be reduced even further to only about 4 or 5. This kind of extreme hypofractionation is called stereotactic body radiation therapy or SBRT. This requires proof.

We have seen the results of a Scandinavian randomized clinical trial (RCT) that found that urinary, rectal, and sexual side effects were not inferior with extreme hypofractionation (see this link), and the oncological outcomes were about the same too (see this link).

Now two more RCTs have shown that the toxicity of SBRT is no worse than and possibly better than moderately hypofractionated or conventionally fractionated IMRT.

Van As et al. reported the acute toxicity results of the PACE-B RCT in the UK at the Genitourinary Conference of ASCO. 844 men with favorable risk prostate cancer were randomized to get SBRT (414 men) or conventionally fractionated/moderately hypofractionated  IMRT - "CFMHRT" (430 men). The qualifications were:

  • localized, favorable risk prostate cancer (Gleason score ≤ 3+4, Stage T1 or T2, PSA ≤ 20 ng/ml)
  • unsuitable for surgery or preferring radiation

The two groups were similar. The treatments were:

  • SBRT: 36.25 Gy in 5 fractions over 1-2 weeks
  • CFMHRT: 78 Gy in 39 fractions (conventional) or 62 Gy in 20 fractions (moderately hypofractionated)
  • ADT was not permitted

At 12 weeks post treatment, acute grade 2 or higher toxicity was:

  • rectal: 10% for SBRT vs 12% for CFMHRT - difference was not statistically significant
  • urinary: 23% for SBRT vs 27% for CFMRT - difference was not statistically significant

Poon et al. reported the one year late-term toxicity results of a RCT in Hong Kong. 64 low- and intermediate-risk patients were randomized to get SBRT (31 patients) or conventionally fractionated IMRT - "CFIMRT" (33 patients). The qualifications were: Stage T1 or T2, Gleason score ≤ 7, and PSA < 20 ng/ml.

The treatments were:

  • SBRT: 36.25 Gy in 5 fractions over 2 weeks
  • IMRT: 76 Gy in 38 fractions
  • Intermediate risk patients could optionally have ADT before their radiation.

at 1 year post treatment:

  • one grade 3 (serious) urinary side effect was reported in each arm
  • rectal grade 1 (mild) or higher: 64% for SBRT vs 84% for CFIMRT - significantly different
  • urinary grade 1 (mild) or higher: 93% for SBRT vs 100% for CFIMRT - not significantly different


It is too early to assess if there are any differences in oncological outcomes in these two RCTs.
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The conventional wisdom with cancer is that "earlier is better." As cancers progress, they mutate: there are many more genetic errors in older cancers than in younger ones. Because of this, a therapy that may work well against a cancer in one stage of its development, may not work at all in an earlier or a later stage.

Prostate cancer is one of the most slow-growing of cancers in its early stages. This is why we can take so much time to decide on initial treatment, even in high-risk cases (see this link). It is also why low-risk men may safely choose active surveillance over immediate radical therapy. Progression is only weakly correlated with time since diagnosis, even for recurrences (see this link).

Early Use of Docetaxel

We have already seen that docetaxel is of limited (if any) use when combined with radiation therapy and ADT for high risk cancer patients (see this link).

Oudard et al. conducted a randomized clinical trial of docetaxel+ADT vs ADT-alone in non-metastatic men with a recurrence after primary treatment. All 250 patients were "high risk," which was defined as at least one of the following:
  • Gleason score ≥ 8
  • PSA velocity > 0.75 ng/ml/year
  • PSADT ≤ 6 months
  • time to recurrence ≤ 12 months
Previous treatments were:
  • 73% had prior prostatectomy
  • 27% had prior primary radiotherapy ± ADT
  • 60% of men who had a prostatectomy also had salvage EBRT
The outcomes were as follows:
  • Median PSA progression-free survival was no different:19 months if they got docetaxel, 20 months if they didn't
  • Median time to radiographic progression was no different: 9 years in each group
  • There was no difference in 12-year overall survival rates: 60% in the docetaxel group, 55% in the no-docetaxel group. (The docetaxel group was 2 years younger)
  • Adverse hematological events from docetaxel included neutropenia (48%), febrile neutropenia (8%) and thrombocytopenia (3%)
CHAARTED showed that the survival increase attributable to docetaxel in newly-diagnosed, metastatic men was only observed among men with a high volume of metastases, but not among men with a low volume of metastases. "High volume" was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae.

One small observational study suggested that docetaxel may benefit men who are castration-resistant but are not yet detectably metastatic.

At the other end of the progression spectrum, in men who are both metastatic and castration-resistant, docetaxel added a median survival of 3 months (see this link), compared to a median of 17 additional months among men with high volume metastases in the CHAARTED trial.

Docetaxel remains effective even after second line hormonals (e.g., Zytiga, Xtandi) have stopped working. In fact, there have been cases where use of docetaxel has reversed resistance to them caused by the AR-V7 splice variant.

The "sweet spot" for docetaxel seems to be after there are multiple metastases but before castration resistance is fully established. Used earlier, it seems to have no effect in most men; used later, it is still effective, but less so.


Early Use of Hormone Therapy

It is well established that hormone therapy alone adds nothing to the survival of localized prostate cancer (see this link and this one). We also know that hormone therapy adds nothing to the effectiveness of radiation therapy for favorable risk prostate cancer (see this link and this one and this one). Even with recurrent prostate cancer post-prostatectomy, a major randomized clinical trial (RTOG 9601)  found that adding long-term antiandrogen therapy to radiation did not increase outcomes as much in men who had Gleason score ≤ 7, PSA ≤ 0.7 ng/ml or negative surgical margins.

However, an early analysis of the TOAD randomized clinical trial suggests that using androgen ablation on men who are recurrent after prostatectomy but not yet detectably metastatic may have a net survival benefit over the selective pressure it exerts towards castration resistance. In fact, men who started on ADT earlier developed castration resistance significantly later. This effect was also noted in the TROG 03.04 RADAR trial. The authors wrote, "The cumulative incidence of transition to castration resistance was significantly lower in men receiving [longer term ADT with their EBRT]."


Early Use of Second-line Hormone Therapy

We have learned that the use of abiraterone (Zytiga) in newly-diagnosed metastatic men increases survival markedly over waiting. Zytiga adds 4 months to survival among men who are castration-resistant and have had chemo (see this link). Median (50%) survival has not been reached with the limited follow-up of the two clinical trials (STAMPEDE and LATITUDE), but we can look at 60% survival and  note that the curves are diverging, so the survival improvement is at least this large. In STAMPEDE, early Zytiga increased median survival by at least 18 months; In LATITUDE, early Zytiga increased median survival by at least 12 months. Abiraterone was equally effective regardless of the number of metastases or whether they were classified as higher or lower risk (see this link).

Enzalutamide (Xtandi) is probably also beneficial if used earlier. A non-randomized clinical trial of early use of Xtandi showed it is very effective if used earlier (see this link), and a Phase 3 trial for its use in hormone-sensitive prostate cancer has had good results, according to a press release.

The FDA has approved apalutamide (Erleada) and enzalutamide (Xtandi) for use in non-metastatic castration-resistant prostate cancer. Darolutamide and abiraterone (Zytiga) will probably also be approved for this indication. Non-metastatic castration-resistant prostate cancer is probably an early version of metastatic castration-resistant prostate cancer, where micrometastases have not yet grown large enough to become detectable on a bone scan/CT.

Clinical trials suggest or are in process to determine if there is a role for advanced hormonal agents even earlier; for example in any of the following early settings:

• as part of an active surveillance protocol for men with favorable risk prostate cancer (see this link)
• adjuvant to radiation in high-risk localized prostate cancer (see this link)
• when it as advanced to only as far as pelvic lymph nodes (Stage N1 M0) (see this link)
• when it is recurrent but not yet detectably metastatic (see this link)

Early Use of Immunotherapy

Although Provenge is more effective when the patient's disease is less progressed (see this link), it was not any more effective when used for mHSPC in one small study (see this link). There are several clinical trials to help determine whether immunotherapy can play a role in extending the time that a man can stay on active surveillance (see this link and this one and this one).

At some point, cancer cells start displaying antigens that can be recognized by the immune system as "non-self," but it is not clear when that occurs in prostate cancer progression. Perhaps the fragments generated by chemo or radiation may make the cancer more susceptible to immune attack (see this link). It is also unclear when immune infiltration into tumors can occur, when checkpoint inhibitors (like PD-L1) begin to appear, and when regulatory T cells are overwhelmed by killer T-cells. Pro- and anti-inflammatory cytokines undoubtedly play a role in immune signaling and may occur at different stages.

Early Use of Radiopharmaceuticals

The ideal candidate for Xofigo will get all 6 treatments, preferably earlier, while bone health is still good (see this link). It has been found to work better on smaller tumors, so it is best used earlier rather than later (see this link). Because the combination of Xofigo and Zytiga caused excessive fractures and deaths (see this link), they can't be given simultaneously, at least not without a bone-preserving agent (like Zometa or Xgeva). Since a full cycle is completed in 24 weeks, taking Xofigo before Zytiga allows one to get the benefit of both in less time.

We do not know enough about the natural history of PSMA yet. We don't know when the PSMA protein first appears on the tumor surface. It has been detected in "high risk" patients, and is more often associated with higher grade cancer and in men with higher PSAs (see this link and this one). It as been detected in up to 95% of metastases. PSMA-based PET scans (Ga-68-PSMA-11 or DCFPyL) are used to check for PSMA-avidity before treatment. Without significant PSMA, the radiopharmaceutical would have nothing to latch onto, and might cause toxicity with no cancer-killing benefit.

A pilot test in South Africa suggests that Ac-225-PSMA-617 had good efficacy in patients who were not heavily pretreated, but their cancer was more progressed when treated. A trial with Lu-177-PSMA found that overall survival was 11 months in patients who had already had chemo (and were more progressed) and was 27 months in chemo-naive patients (who were also less progressed). Earlier seems to be better.


Although it is generally true that earlier treatment is better, we have learned that there are exceptions. There is tremendous individual variation, and it is likely that the window of opportunity varies.
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While excellent outcomes of stereotactic body radiation therapy (SBRT) have been reported since it was first used for prostate cancer in 2003, the delivered doses have ranged from 35 Gy in 5 treatments to 40 Gy in 5 treatments. We saw in a University of Texas Southwest (UTSW) study (see this link) that toxicity escalates when doses are greater than 45 Gy.

Memorial Sloan Kettering designed a clinical trial (described here) among low and intermediate-risk men. They started with about 35 men treated at 32.5 Gy and checked for dose-limiting toxicity. When most reached 6 months of follow-up, and fewer than 10% had dose-limiting toxicity, they increased the dose to the next group of 35 men by 2.5 Gy in 5 treatments. In all, they had 136 patients who were followed up for 5.9 yrs, 5.4 yrs, 4.1 yrs and 3.5 yrs with doses of 32.5 Gy, 35 Gy, and 37.5 Gy and 40 Gy, respectively.

Their toxicity and oncological outcomes are shown in the table below:



Dose delivered in 5 treatments

32.5 Gy
35.0 Gy
37.5 Gy
40.0 Gy
Acute toxicity




Urinary – grade 2
16.7%
22.9%
8.3%
17.1%
Rectal – grade 2
0%
2.9%
2.8%
11.4%
Late-term toxicity




Urinary – grade 2
23.3%
25.7%
27.8%
31.4% (1 grade 3 stricture)
Rectal – grade 2
0%
0%
0%
0%
Oncological outcomes




5-year PSA failure
15%
6%
0%
0%
2-year positive biopsy
47.6%
19.2%
16.7%
7.7%

Other than the one urinary stricture, there were no acute or late-term grade 3 (serious) toxicities.

Because follow-up decreased with increasing dose, it is unclear whether the zero biochemical failure rates for doses of 37.5 Gy and 40 Gy will be sustained, but in other studies, almost all SBRT failures had occurred within 5 years. The positive biopsy rates will probably continue to decline with longer follow-up because the non-viable cancer cells can take up to 5 years to clear out. Clearly, 32.5 Gy is too low because of its unacceptable oncological results.

A dose of 40 Gy in 5 treatments has very acceptable toxicity and excellent cancer control. It would be reasonable to use doses as low as 37.5 Gy in patients with insignificant amounts of low grade cancer (who would usually be excellent candidates for active surveillance). Based on the UTSW study, it would be reasonable to escalate the dose as high as 45 Gy in patients judged to have radioresistant cancers.
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As we saw (see this link) among men with Gleason 9 or 10, brachy boost therapy (BBT: external beam radiation with a brachytherapy boost to the prostate) was shown to provide better oncological outcomes (10 year metastasis-free survival and 10 year prostate cancer specific survival (PCSM)) compared to surgery (RP) or external beam radiation (EBRT) alone. Some researchers argue that the comparison was unfair. In that study, 43% of the RP patients received adjuvant or salvage radiation, and virtually all of the BBT patients received 1 year of adjuvant ADT. What if ALL of the RP patients were to receive radiation and ADT?

Tilki et al. did a retrospective study to answer that question. They looked at two groups of Gleason 9/10 patients treated at two institutions between 1992 and 2013:

  • 559 men received RP+pelvic lymph node dissection (PLND) at the Martini-Klinik Cancer Center in Hamburg
    • 88 received adjuvant EBRT
    • 49 received adjuvant ADT
    • 50 received both (called MaxRP)
    • Median ADT duration - 8.6 months in 49 men with negative lymph nodes
    • Median ADT duration - 14.5 months in 39 men with positive lymph nodes
  • 80 men received BBT+ADT (called MaxRT) at the Chicago Prostate Center
    • Median ADT duration - 6 months
After 5.5 years of median follow-up for MaxRT and 4.8 years of median
follow-up for those receiving RP, they found that the risk of PCSM compared to MaxRT was:
  • 2.8 times greater for any RP (statistically significant)
  • 0.5 times less for RP+adjuvant EBRT (not statistically significant)
  • 3.2 times greater for RP+adjuvant ADT (statistically significant)
  • 1.3 times greater for MaxRP (not statistically significant)
The 5-year PCSM was:
  • 2% for MaxRT
  • 22% for any RP (significantly higher than MaxRT)
  • 4% for RP+adjuvant EBRT (not significantly different from MaxRT)
  • 27% for RP+adjuvant ADT (significantly higher than MaxRT)
  • 10% for MaxRP (not significantly different from MaxRT)
They computed a 76% chance ("plausibility index") that the PCSM was plausibly the same for MaxRT vs. MaxRP.

Kishan et al. supplied numbers from his study that are more directly comparable. They are shown in the table below.

Study
Tilki
Kishan
Sample size
BBT: 80
RP+EBRT: 88
RP+ADT: 49
RP+EBRT+ADT: 50
BBT: 436
RP+EBRT: 272
RP+ADT: 175
ADT duration (median)
BBT: 6 months
RP (N1): 14.5 mos.
RP (N0): 8.6 mos.
BBT: 12 months
RP (% N1)
44%
17%
5-year % PCSM
RP (any): 22%
BBT: 2%
RP (any): 12%
BBT: 3%
Adjusted PCSM Hazard Ratio compared to BBT:
RP+ADT: 3.2
RP+EBRT: 0.5 (not sig.)
RP+ADT: 3.2
RP+EBRT: 2.0


We see that the two studies are really not comparable in some respects. The Kishan study was much larger, and was done among many of the top institutions. The Hamburg patients had a much higher percent of positive lymph nodes, and their mortality was twice as high as in the Kishan study. The Chicago patients only got half as much ADT vs. the Kishan study. Importantly, the Kishan study found that RP+EBRT had PCSM that was twice as high as BBT, while the Tilki study showed no statistically significant difference.

Another important aspect was not reported in either study - the toxicity of treatment. We know that surgery plus radiation has worse urinary and sexual side effects compared to surgery alone.BBT carries risk of higher late-term urinary side effects compared to EBRT alone.

Until we have a randomized clinical trial of BBT vs MaxRP, we will never have certainty, but for now, the Kishan study better reflects expected outcomes of these therapies at top institutions.

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Bayer has announced a new clinical trial of the latest entry in the race for radiopharmaceuticals to treat prostate cancer, joining Lu-177-PSMA-617, Ac-225-PSMA-617, and I-131-MIP-1095. They are trying Thorium-227 attached to a PSMA antibody.

Thorium-227, like Ac-225, is an alpha-particle emitter. Alpha emitters are very powerful, but very short range, only killing cells that are 2 to 10 cells away from the cancer cell it attaches to. This may limit its toxicity, but may require higher doses for larger, more widespread tumors.  Beta emitters, like Lu-177, are less powerful, but the beta particle penetrates to a much greater depth, affecting about 125 cells. Researchers at the University of Heidelberg are experimenting with mixtures of the two.

The other part of the equation is the ligand that the radioactive atom is attached to and that attaches to the PSMA protein on the prostate cancer cell. Ligands include PSMA-617, PSMA-I&T, MIP-1095, and J591. Ligands may be small molecules, antibodies, or "minibodies." Bayer is using a proprietary antibody-type ligand that they developed for the purpose. Ligands that are more specific for PSMA have less toxicity.

On the other side of the ligand molecule, it must bind very tightly to the radioactive element. If it doesn't, the radioactive element might be released into systemic circulation where it can damage healthy cells. Heavy metals, like thorium, are attached relatively weakly by a process called "chelation," but some chelators are stronger than others. Researchers have so far been unsuccessful in developing a stable chelate for Ra-223 (the main ingredient in Xofigo, which is also manufactured by Bayer) to a PSMA ligand. However, Th-227 decays into Ra-223, so it is unknown if the thorium chelate will continue to hold as it decays. However, Bayer has already begun two clinical trials for Th-227 chelated to an antibody for non-Hodgkin's lymphoma since 2015, and for ovarian cancer and mesothelioma since April, which have not been terminated for excess toxicity. There is every reason to hope that the chelation complex they devised for the PSMA-antibody ligand holds up in biological systems.

This is a dose-finding (Phase 1) clinical trial among 108 patients with metastatic castration-resistant prostate cancer. They list 4 locations that will be recruiting: Memorial Sloan Kettering in NYC, as well as locations in the UK, Finland, and Sweden.
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Stereotactic Body Radiation Therapy (SBRT, or sometimes SABR or SHARP or CyberKnife) has had excellent 7-year outcomes in an update of the consortium study. Amar Kishan presented the results of his analysis at the ASTRO meeting today.

The consortium consisted of

1 Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA
2 Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA
3 Flushing Radiation Oncology Services, Flushing, NY, USA
4 21st Century Oncology, Fort Myers, FL, USA
5 Department of Radiation Oncology, Georgetown University, Washington, DC., USA
6 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
7 Division of Genesis Healthcare Partners Inc., CyberKnife Centers of San Diego Inc., San Diego, CA, USA
8 Swedish Radiosurgery Center, Seattle, WA, USA.
9 Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON,
Canada.
10 Section of Radiation Oncology, Virginia Mason Medical Center, Seattle, WA, USA
11 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
12 Department of Radiation Oncology, University of Michigan
13 Scripps Health, 11025 North Torrey Pines Road, La Jolla, CA, USA
14 Virginia Hospital Center, 1701 N. George Mason Dr, Arlington, VA, USA

The meta-analysis covers 2,142 low (n=1,185) and intermediate-risk men treated with SBRT between 2003 and 2012. Intermediate risk men were further subdivided into "favorable intermediate risk" (n=692) and "unfavorable intermediate risk" (n=265) per the NCCN definition.

After a median follow-up of 6.9 years, the 7-year biochemical recurrence-free survival was:

  • low risk: 95.5%
  • favorable intermediate risk: 91.4%
  • unfavorable intermediate risk: 85.1%
  • all intermediate risk: 89.8%

Low risk patients and some of the favorable intermediate risk patients would probably be diverted to active surveillance today. The 7-year intermediate risk biochemical recurrence-free survival compares favorably with (note: this is not a randomized comparison, which is the only valid way of comparing):

  • Surgery: favorable intermediate risk (PSA=6.0, T1c, GS 3+4, 33% cancerous cores): 81% (mean of 5 and 10-yr Progression-free survival) (1)
  • Surgery: unfavorable intermediate risk (PSA=6.0, T1c, GS 4+3, 67% cancerous cores): 53% (mean of 5 and 10-yr Progression-free survival) (1)
  • Hypofractionated IMRT (5 year):  85% (2)
  • Conventional IMRT (5 year): 85% (2)
  • Low dose rate brachytherapy: favorable intermediate risk (avg of 5 and 10-yr): 85% (3)
  • Low dose rate brachytherapy: unfavorable intermediate risk (5-year): 81% (3)
  • Brachy boost therapy: unfavorable intermediate risk (10 year): 92% (4)

7-year metastasis-free survival was:

  • low risk: 99.9%
  • favorable intermediate risk: 98.3%
  • unfavorable intermediate risk: 97.0%
  • all intermediate risk: 98.0%

There were no prostate cancer-related deaths.

Use of ADT and higher doses (doses ranged from 33 Gy to 40 Gy in 4 or 5 treatments) did not affect recurrence.

Acute (within 3 months of treatment) toxicity was low:

  • Urinary toxicity Grade 2: 8.8% Grade 3: 0.6%
  • Rectal toxicity Grade 2: 3.2% Grade 3: 0.1%

Late-term cumulative toxicity was low:

  • Urinary toxicity Grade 2: 9.4% Grade 3+: 2.1%
  • Rectal toxicity Grade 2: 3.9% Grade 3+: 0.4%


Late-term grade 3 or greater urinary toxicity of 2.1% compares favorably to other radiation monotherapies reported in other studies. For example:

  • Low dose rate brachytherapy: 7.6% (5)
  • High dose rate brachytherapy (3 fractions):11% (6)
  • Hypofractionated IMRT (70 Gy/28 fx): 3.5% (7)
  • Conventionally fractionated IMRT: 2.3% (7)
  • Brachy boost therapy: 19% (8)


Late-term grade 3 or greater rectal toxicity of 0.4% compares favorably to other radiation monotherapies reported in other studies. For example:

  • Low dose rate brachytherapy: 0.8% (5)
  • High dose rate brachytherapy (3 fractions):1% (6)
  • Hypofractionated IMRT (70 Gy/28 fx): 4.1% (7)
  • Conventionally IMRT: 2.6% (7)
  • Brachy boost therapy: 9% (8)

This 7-year analysis on a large group of patients from multiple sites, should make intermediate risk patients comfortable in choosing SBRT, especially if they are favorable intermediate risk. For patients who are unfavorable intermediate risk, brachy boost therapy affords incomparable oncological control, but at the risk of much higher late term urinary and rectal toxicity.


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