Is there an oligometastatic state for prostate cancer?

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.

Iyengar et al. reported the results of a small trial where 14 patients with non-small cell lung cancer (NSCLC) with a small number of distant metastases were treated with SBRT to the lung and distant lesions ("consolidative therapy") and chemotherapy. 15 patients only received chemo. There was a significant increase in progression-free survival: 9.7 months vs 3.5 months. Larger trials (NRG LU002 and SARON) will investigate overall survival.

(update 12/6/23) NRG LU002 will not move to a Phase III trial because the Phase II Progression-Free Survival failed to meet its prespecified goal.

(update 6.2.22) Steven Chmura reported at the 2022 ASCO meeting (J Clin Oncol 40, 2022 (suppl 16; abstr 1007) that the randomized trial (NRG BR-002) of SBRT (+ standard of care (SOC)) to oligometastatic breast cancer failed to slow progression or increase survival over SOC alone. There were 125 patients (65 SBRT+SOC, 60 SOC). An expanded trial was canceled due to futility.  Clearly then, there is no oligometastatic "state" that applies to all cancers.

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 Cancer	Control		SABR		expected 2-year survival (approx)
	n	% of total	n	% of total
Breast	5	15%	13	20%	50% (1)
Colorectal	9	27%	9	14%	30% (2)
Lung	6	18%	12	18%	10% (3)
Prostate	2	6%	14	21%	90% (4)
Other	11	33%	18	27%
TOTAL	33		66

(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

	Control	SABR
Expected 2-year survival due to distribution	35%	48%
Expected 2-year mortality due to distribution	65%	52%
Hazard Ratio due to skewed distribution	80%
Reported Hazard Ratio	75%

Because of the uneven distributions in the treatment and control, the hazard ratio does not reach 80% confidence and the hypothesis should be rejected. The authors believe that just eliminating prostate cancer patients from both groups would correct the flaw, but they would have to eliminate colorectal cancer as well - I doubt the result would be significant with even 80% confidence. 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.

(update 05/25/2022) SABR-COMET was updated with 8-year results. They report:

• 8-yr overall survival was 26.2% in the SABR arm vs 13.2% in the control arm (HR=0.50)
• 8-yr progression-free survival was 21.6% in the SABR arm vs 0.0% in the control arm (HR=0.45)
• Rates of acute or late Grade 2+ toxicity were 30.3% in the SABR arm vs 9.1% in the control arm

The Kaplan-Meier survival curves showed a large drop-out of participants after 4 years in the control group. This is consistent with the relative lack of prostate cancer patients and the relatively large presence of colorectal cancer patients in the control group. 

There was no difference between arms in time to new metastases. So, the larger progression-free survival in the SABR arm is entirely due to local control. The cancer continued to seed new metastases at the same rate in both arms.

If you are using PSA to monitor your cancer, you may want to avoid curcumin (and some other supplements)

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, curcumin 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.

A multi-center, blinded randomized clinical trial in France of curcumin+docetaxel compared to docetaxel alone in men who were metastatic and castration-resistant was ended early because of futility. Although not statistically significant, combining docetaxel and curcumin consistently gave worse outcomes (progression, survival) than docetaxel plus placebo.

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 (PSA) and prostate-specific membrane antigen (PSMA), 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. Glutamate (MSG used in Chinese food) is also a powerful chelator. It has been found to markedly decrease the effectiveness of PSMA theranostics (see this link).

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. Men taking statins should also be aware that it may produce artificially low PSA readings (see this link and this one). Statins, which seem to be beneficial in some observational studies but not in others, may only have an apparent benefit because of masking of PSA, as in this study and this study.

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. There are also some safety concerns (see this link). 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.

Should SBRT be THE preferred treatment for intermediate risk prostate cancer?

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

SBRT has non-inferior acute and late-term toxicity vs IMRT in two randomized clinical trials

(updated)

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

(Update 9/14/22)

Tree et al. reported the late-term toxicity results of the PACE-B RCT.

At 24 months post-treatment, the worst late-term grade 2 or higher toxicity (RTOG* criteria) was:

• rectal: 2% for SBRT vs 3% for CFMHRT - difference was not statistically significant
• Using CTCAE 4.0* criteria, patients treated on the CyberKnife platform had less toxicity (1%) vs CFMRT (4%) and were better off than patients treated with other linacs (5%)
• urinary: 3% for SBRT vs 2% for CFMRT - difference was not statistically significant
• CTCAE 4.0* urinary toxicity was worse vs. RTOG* urinary toxicity: 12% for SBRT vs 7% for CFMRT
• Patients treated on the CyberKnife platform had no difference in toxicity (6%) vs CFMRT (7%) and were much better off than patients treated in 5 treatments with other linacs (17%)
• Patient-evaluated (EPIC*) moderate/severe urinary bother was worse for SBRT (10%) than for CFMRT (5%)
• Grade 3 toxicity was <1% in all groups
• There was no difference in erectile dysfunction

By 24 months post-treatment, the cumulative incidence of late-term grade 2 or higher toxicity (RTOG* criteria) was:

• rectal: 8% for SBRT vs 8% for CFMHRT - difference was not statistically significant
• CTCAE 4.0* rectal toxicity was worse vs. RTOG* rectal toxicity: 12% for SBRT vs 12% for CFMRT
• urinary: 18% for SBRT vs 11% for CFMRT - difference was statistically significant
• CTCAE 4.0* urinary toxicity was worse vs. RTOG* urinary toxicity: 32% for SBRT vs 20% for CFMRT
• Increased urinary frequency was the type of urinary toxicity most often reported: 10% for SBRT vs 5% for CFMRT

*RTOG and CTCAE 4.0 have different criteria for physicians to evaluate toxicity. EPIC-26 is a questionnaire that patients fill out.

Patients treated on appropriate platforms in high-volume centers had equal or better outcomes. Toxicity was low.

 

(updated 9/30/23) After a median follow-up of 6 years of 874 predominantly (91%) intermediate-risk patients across 38 centers in the UK and Canada, van As et al. reported:

• 95% and 96% were free of biochemical (PSA) failure for SBRT and conventionally fractionated radiotherapy, respectively.
• Grade 2 or worse urinary toxicity was 5.5% and 3.2% (not significantly different) for SBRT and conventionally fractionated radiotherapy, respectively.
• Only 1 patient in each cohort had Grade 2 or worse rectal toxicity.

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.

Timing is everything with docetaxel (and hormone therapy and probably with immunotherapy and radiopharmaceuticals too)

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 (see this link). 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). It is also ineffective when combined with prostatectomy and ADT for high-risk cancer patients (see this link). However, it can improve prognosis in men who have low PSA (<0.4ng/ml), high Gleason grade (8-10), and good performance status (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 recently-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. However, a STAMPEDE update showed no difference in overall survival or failure-free survival between the two subgroups. The STAMPEDE authors point to their larger trial and that their analysis applies more to newly diagnosed men, whereas the CHAARTED groups had more previously treated men.  They advocate early use of docetaxel regardless of metastatic burden.

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.

The "sweet spot" for docetaxel seems to be after there are detectable 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 Docetaxel + Second Line Hormonal Therapy

Triplet therapy means combining docetaxel with a second-generation hormonal medication and ADT. Triplets with abiraterone, darolutamide, and enzalutamide have been found to confer greater benefit than docetaxel+ADT in newly-diagnosed metastatic men (discussed here). The benefit held with darolutamide (in the ARASENS trial) even in men with low metastatic burden. Presumably, there will be a similar benefit with abiraterone when the PEACE1 trial matures.

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. However, when men are already castration-resistant, combining docetaxel and Xtandi slowed progression but did not result in a survival advantage over docetaxel alone in the Phase II CHEIRON trial. The Phase III PRESIDE trial proved that docetaxel could reverse Xtandi resistance, but did not increase survival.

Again, earlier use of docetaxel is better.

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.

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). In the STAMPEDE trial, median (50%) survival was 76.6 months with Zytiga vs 45.7 months with ADT alone.  So, early Zytiga increased median survival by 31 months, reducing mortality by 38%; In LATITUDE, early Zytiga increased median survival by16.8 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).

In the "CHECKMATE 650" clinical trial of a combination of the two checkpoint inhibitor-type immunotherapies, nivolumab (Opdivo) and ipilimumab (Yervoy), there was some response (in 25% of pre-chemo men and 10% of post-chemo men) from the combination, but no response from either drug alone in earlier trials. However, all of the responders  (60% of the pre-chemo group and 40% of the post-chemo group) had a high mutational burden and/or showed the presence of PD-L1 in the tumors (33% of the pre-chemo group and 19% of the post-chemo group). Conversely, none of the men who had low mutational burden or PD-L1 had any response to the combination therapy. Toxicity was unacceptably high. This indicates that the cancer must evolve to a high degree of genetic breakdown before such therapies become effective. Early use causes unacceptable toxicity without any survival benefit.

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 radiation may make the cancer more susceptible to immune attack (see this link). However, chemo, which also generates antigen fragments, has failed to stimulate an immunotherapy response from checkpoint inhibitors. The combination of docetaxel with a checkpoint inhibitor has proven to be ineffective in this trial and this one. 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. This is called the "tumor sink effect" and was noted in this study and this one.

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.

SBRT: Optimal Dose

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 reported here and 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.

Optimal prostate dose is also discussed:

SBRT dose escalation trial at Sunnybrook 

SBRT dose escalation trial at UTSW

Potters et al. trial

The multi-factorial nature of SBRT safety

Why we should care about standards of care

Escalated radiation dose doesn't improve 8-year overall survival in intermediate-risk men (but does it matter?)

Survival benefit of dose escalation for higher-risk patients