"If all you have is a hammer, everything looks like a nail"

It was called "instrument bias" by Abraham Maslow and Abraham Kaplan, but for present purposes, we'll call it "specialty bias" - over-reliance on the tool one is most familiar with. Kishan et al. conducted a survey among urologists ("Uros") and radiation oncologists ("ROs") concerning their opinions about how best to treat high-risk patients in various situations from initial treatment to recurrence after initial treatment. They tabulated responses from:

• 846 ROs and 407 Uros
• 63% of ROs and 96% of Uros practiced in the US; the rest mainly in Australia and NZ
• They had a median of over 10 years of experience
• 41% of ROs and 51% of Uros were in private practice

Initial Treatment of High Risk Patients

ROs were 5 times more likely to believe that initial treatment with radiotherapy (RT) with androgen deprivation therapy (ADT) and with local salvage therapy, if needed, was preferred. They were also twice as likely to believe that it offered the patient equivalent outcomes as radical prostatectomy (RP) and salvage radiation (SRT), if needed. Uros were 4 times more likely to believe that RP ± SRT was the preferred treatment. Only 29% believed that RT had a place in initial treatment.

Preferred Initial Treatment	RO	Uro
RP±SRT	18%	71%
RT+ADT±local salvage	30%	6%
No preference	52%	23%

The "right" answer is...

Currently, the American Urological Association (AUA) and the American Society of Radiation Oncologists guidelines state:

"Clinicians should recommend radical prostatectomy or radiotherapy plus ADT as standard treatment options for patients with high-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)"

NCCN guidelines also list both as options. They note, however:

"A large, multicenter, retrospective cohort analysis that included 1809 men with Gleason score 9–10 prostate cancer found that multimodality therapy with EBRT, brachytherapy, and ADT was associated with improved prostate cancer-specific mortality and longer time to distant metastasis than either radical prostatectomy or EBRT with ADT. In addition, an analysis of outcomes of almost 43,000 men with high-risk prostate cancer in the National Cancer Database found that mortality was similar in men treated with EBRT, brachytherapy, and ADT versus those treated with radical prostatectomy, but was worse in those treated with EBRT and ADT . (MS25)

This can only be decided definitively by a randomized clinical trial, but given the difficulties of recruiting for such a trial, patients must make the decision based on lower level evidence.

Adjuvant RT (ART) and SRT for High-Risk Patients after RP

ROs were 2.7 times as likely to advocate for ART with undetectable PSA, and were twice as likely to believe that ART is underutilized. Conversely, Uros were 2.5 times more likely to approve of waiting until PSA has risen to 0.2 ng/ml. Most believed it is utilized appropriately (it is seldom utilized in this situation) or overutilized. About 2 in 5 ROs and Uros were OK with early SRT.

Two-thirds of ROs thought SRT was appropriate with 2 consecutive rises, or at any detectable level or any level under or equal to 0.1. Less than half of Uros held that belief. ROs were more likely than Uros to believe that SRT is underutilized.

ART Appropriate	RO	Uro
With undetectable PSA	43%	16%
Early SRT with detectable PSA < 0.2 ng/ml	42%	43%
Delayed SRT with PSA ≥ 0.2 ng/ml	16%	41%

ART Under/Over-Utilized	RO	Uro
Underutilized	75%	38%
Appropriately utilized	21%	43%
Overutilized	4%	19%

Lowest PSA at which SRT is Appropriate	RO	Uro
Detectable	15%	7%
≤ 0.1	21%	19%
At least 0.2	29%	35%
At least 0.4	4%	12%
At least 1.0	1%	7%
At least 2 consecutive rises	30%	20%

SRT Under/Over-Utilized	RO	Uro
Underutilized	65%	43%
Appropriately utilized	34%	52%
Overutilized	1%	5%

The "right" answer is...

The 2019 AUA/ASTRO guidelines state:

Guideline Statement 2. Patients with adverse pathologic findings including seminal vesicle invasion, positive surgical margins, and extraprostatic extension should be informed that adjuvant radiotherapy, compared to radical prostatectomy only, reduces the risk of biochemical recurrence, local recurrence, and clinical progression of cancer. They should also be informed that the impact of adjuvant radiotherapy on subsequent metastases and overall survival is less clear; one of three randomized controlled trials that addressed these outcomes indicated a benefit but the other two trials did not demonstrate a benefit. However, these two trials were not designed to identify a significant reduction in metastasis or death with adjuvant radiotherapy. (Clinical Principle)

 Guideline Statement 3. Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy including seminal vesicle invasion, positive surgical margins, or extraprostatic extension because of demonstrated reductions in biochemical recurrence, local recurrence, and clinical progression. (Standard; Evidence Strength: Grade A)

Guideline Statement 8. Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA.  (Clinical Principle) 

"...patients should be advised that if recurrence is detected without evidence of distant metastases, then RT should be administered at the earliest sign of PSA recurrence ..."

The 2019 NCCN guidelines state:

Indications for salvage RT include an undetectable PSA that becomes subsequently detectable and increases on 2 measurements or a PSA that remains persistently detectable after RP. Treatment is more effective when pre-treatment PSA is low and PSADT is long.

Salvage for High-Risk Patients after RT

About 2/3 of Uros believed that RP and Cryo are appropriate salvage therapies after biochemical recurrence following primary RT (when imaging was negative for distant metastases). Very few thought salvage radiation or other ablation therapies were appropriate. Among ROs, most approved of salvage RP, but sizeable minorities felt that salvage brachytherapy and salvage cryo was appropriate. About 1 in 5 thought salvage SBRT or salvage HIFU was appropriate.

Salvage therapies after RT failure	RO	Uro
RP	56%	66%
LDR brachytherapy	34%	6%
HDR brachytherapy	42%	10%
SBRT	20%	5%
Cryoablation	40%	69%
HIFU	21%	13%

However, 2/3 of both ROs and Uros and agreed that salvage after RT was not as effective as salvage after RP.

Is salvage after RT as effective as SRT after RP?	RO	Uro
No	64%	66%
Yes	36%	34%

And most of both groups believe that focal salvage is inferior to whole gland salvage after RT failure. But Uros were much more likely to hold this belief vs ROs.

Focal salvage=whole gland salvage?	RO	Uro
No	56%	75%
Yes	44%	25%

The "right" answer is...

NCCN guidelines state:

Salvage RP is an option for highly selected patients with local recurrence after EBRT, brachytherapy, or cryotherapy in the absence of metastases, but the morbidity (ie, incontinence, loss of erection, anastomotic stricture) is high and the operation should be performed by surgeons who are experienced with salvage RP. 

Brachytherapy can be considered in men with biochemical recurrence after EBRT. In a retrospective study of 24 men who had EBRT as primary therapy and permanent brachytherapy after biochemical recurrence, the cancer-free and biochemical relapse-free survival rates were 96% and 88%, respectively, after a median follow-up of 30 months.Results of a phase 2 study of salvage HDR brachytherapy after EBRT included relapse-free survival, distant metastases-free survival, and cause-specific survival rates of 68.5%, 81.5%, and 90.3%, respectively, at 5 years.

HIFU also has been studied for treatment of radiation recurrence. Analysis of a prospective registry of men treated with HIFU for radiation recurrence revealed median biochemical recurrence-free survival at 63 months, 5-year OS of 88%, and cancer-specific survival of 94%.

For a discussion of salvage therapies after RT, see this link. Salvage after RT is generally as effective or better than SRT after RP. Focal salvage is as effective as whole gland salvage in many cases.

What to do about specialty bias

It is not surprising that specialists are more knowledgeable about, and more favorably disposed to their own field (otherwise, they're in the wrong job). However, there are knowledge gaps even within their own field. Many patients expect their doctors to be knowledgeable about their own field, and to be able to compare it to other therapies. We have seen that this is an unrealistic expectation. Here are some recommendations for patients:

• Don't expect a specialist to be knowledgeable outside his own field. Consult with a variety of specialists, if possible.
• Remember that it is radiation oncologists, not urologists, who treat and follow-up on SRT for surgical recurrences. ROs are more experienced than Uros at SRT.
• Salvage brachytherapy after RT recurrence is highly specialized - there aren't many practitioners with expertise. Salvage ablation and salvage SBRT specialists are even more rare. Patients should avoid salvage surgery due to its high morbidity.
• Second opinions are critical. Finding specialists may involve travel, which may be precluded by cost/insurance limitations.
• For patients who are inclined to research these topics themselves, they must be aware that the quality of research on all of these topics is low to moderate. There have been very few randomized clinical trials focussed on high risk patients, so we have to make informed judgments based on observational studies or single-arm, single-institution clinical trials in most situations. AUA, ASTRO and NCCN guidelines are updated and may be their best source of information (other than this blog 😉).

Focussing on physicians, the authors recommend interdisciplinary clinics, which might work well in academic centers. However, a substantial proportion of both ROs and Uros were in private practice. They also suggest continuing medical education, and cross-specialty training. Professional organizations typically do not currently require this. Uros do not typically attend ASTRO meetings, nor do ROs attend AUA meetings.

- with thanks to Dr. King for allowing me to see the full text and questionnaire.

Is whole pelvic radiation needed for primary treatment of Gleason 9/10?

Whether whole pelvic radiation therapy (WPRT) is beneficial for men newly diagnosed with Gleason 9/10 (Grade Group 5) is controversial. There is an ongoing randomized clinical trial (RTOG 0924) that will have results by 2027 at the earliest, but it includes intermediate and high-risk patients, very few of whom will have Gleason 9/10. Two previous randomized clinical trials (RCTs) gave conflicting results: RTOG 9413 showed a benefit to WPRT combined with ADT started before and continued through radiation treatment, while GETUG 01 found no benefit. However, neither RCT delivered doses of radiation that would be considered adequate by today's standards (70 Gy vs 80 Gy).

Sandler et al. analyzed the databases of 12 major institutions that treated 1170 Gleason 9/10 patients between 2000 and 2013.

• 299 received external beam radiation therapy (EBRT) boost to the prostate + WPRT
• 435 received EBRT only to the prostate + a small margin around it
• 320  received a brachytherapy boost (BBT) to the prostate + WPRT
• 116 received BBT only to the prostate + a small margin around it
• Patients were matched on age, T stage, PSA, Gleason score, and analyzed by ADT duration

After median follow-up of 5.6 years, 5-year biochemical recurrence-free survival (bRFS) was:

• 88% for BBT+WPRT
• 78% for BBT alone
• 66% for EBRT+WPRT
• 58% for EBRT alone
• WPRT was significantly improved by BBT (Hazard Ratio = 0.5, p=0.02) but not by EBRT (HR=0.8, p=0.4))
• Neither distant metastasis-free survival nor prostate cancer-specific survival were significantly improved by WPRT

In interpreting these findings, patients should discuss the following considerations with their radiation oncologists.

Lack of long-term follow-up

As we have observed before (see this link), it can take 15 or more years until over half of high risk patients have detectable metastases (by bone scan/CT) or have succumbed to prostate cancer. In this study, only 35% of those getting EBRT alone had been diagnosed with distant metastases, and only 23% had died of prostate cancer. The rates for all other groups were smaller. As the data mature, we expect that the now-evident and statistically significant differences in biochemical failure will eventually result in higher rates of metastases and mortality.

Lack of local control with EBRT only

ASCENDE-RT proved that prostate cancer is better controlled in high-risk patients by a brachytherapy boost than by EBRT alone. Local control (of cancer in the prostate) is obviously required because the high grade cancer easily progresses and metastasizes from the prostate.

Lack of regional control with surgery

As we have seen, prostatectomy, even when followed by radiation (see this link) seems to provide inferior cancer control compared to BBT with WPRT. This may be because the salvage radiation dose to the prostate bed (usually only 66-70 Gy) is inadequate compared to the primary radiation dose (see this link).

Inadequate coverage/detection of pelvic lymph nodes

In the present study, patients received WPRT to the standard pelvic lymph nodes. We have seen that this is inadequate to reach  the cancerous pelvic lymph nodes in over 40% of patients (see this link). Current methods do not allow us to find most of the cancerous lymph nodes (see this link). While PET scans are not yet FDA-approved for high-risk patients (as they are for recurrent patients), there are a few available in clinical trials.

Inadequate dose to pelvic lymph nodes

The dose to pelvic lymph nodes is often about 45-50 Gy given in 1.8 Gy increments. If it's true that perfect cancer control is achieved only with doses around 80 Gy, this treatment may be inadequate to control some of the larger lymph node metastases. This may be especially true because lymph node metastases are not well-oxygenated (hypoxic). As PET/CTs and PET/MRIs become available for high-risk patients, it may become possible to target known lymph node metastases with higher doses. Another fertile area for investigative research is radiosensitization with hyperthermia (see this link).

Toxicity

In RTOG 0534, late Grade 2 or worse gastrointestinal toxicity occurred in 7% of those receiving WPRT. While this is higher than the 2% experiencing this degree of toxicity with prostate-only EBRT treatment, it is nevertheless at a low level. In a large non-randomized, retrospective study comparing WPRT to prostate-only radiation, Parry et al. found no difference in the 3-year cumulative incidence of gastrointestinal and urinary toxicity among high risk and locally advanced patients.

Because we may never have more reliable data, patients and their radiation oncologists must make this decision based on this study and judgement for the foreseeable future.

note: Thanks to Amar Kishan for allowing me to see the full text.

Two new advanced hormonal agents (apalutamide and enzalutamide) increase survival in metastatic hormone sensitive prostate cancer (mHSPC)

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)

(Update 9/18/19 It has been FDA approved for this indication).

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

• 3-year overall survival (3yrOS) was 79% for enzalutamide vs 72% for AA (Hazard Ratio = 0.66 - statistically significant)
• For men with high volume metastases, 3yrOS was 71% for enzalutamide vs 63% for AA (Hazard Ratio = 0.74 - not statistically significant)
• For men with low volume metastases, 3yrOS was 89% for enzalutamide vs 82% for AA (Hazard Ratio = 0.48 -  statistically significant)
• For men who also planned to receive early docetaxel, 3yrOS was 73% for enzalutamide vs 74% for AA (Hazard Ratio = 0.91 - not statistically significant)
• For men who did not plan to receive early docetaxel, 3yrOS was 83% for enzalutamide vs 70% for AA (Hazard Ratio = 0.51 - statistically significant)

Toxicity was higher for enzalutamide:

• Serious adverse events occurred in 42% of those taking enzalutamide vs 34% for AA
• Treatment discontinuation due to adverse events occurred in 33 patients taking enzalutamide vs 14 patients for AA
• Adverse events were higher in those who had taken docetaxel
• Fatigue was more common for men taking enzalutamide
• Seizures occurred in 7 patients taking enzalutamide and no patients for AA

(update 12/16/2019: It has been FDA approved for this indication)

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 new formulation called Yonsa for about $10,000 per month.

Is there an oligometastatic state for prostate cancer?

(Updated)

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 pilot 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. Based on this, the larger phase II/III NRG Lu002 trial was instituted.

(update 5/29/24) Iyengar et al. reported the results of the NRG Lu002 trial. There were 215 patients at 68 sites with oligometastatic (≤3 mets) lung cancer. All were given systemic therapy (90% had both immunotherapy + chemotherapy). 81 were treated with "consolidative therapy" radiation/surgery to the lung and all metastatic sites followed by systemic therapy. After 2 years of follow-up:

• Overall survival was the same in both groups (HR=1.05, 95% CI= 0.70-1.56))
• Progression-free survival was the same for both groups (HR=0.93, 95% CI=0.66-1.31)
• Grade 3 toxicity (pneumonitis) was higher in the consolidative therapy group (10% vs 1%)

(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.

(Update 8/6/24) Liver injury has been associated with curcumin and green tea supplements (see links below). Australia has issued an alert. Patients who take any supplements should tell their doctors and have liver panels taken. There can be a delay of over 4 months between the start of consumption and evidence of liver injury.

Estimated Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults

Liver Injury Associated with Turmeric - A Growing Problem 

Catechins in Dietary Supplements and Hepatotoxicity

Clinical Features and Outcomes of Complementary and Alternative Medicine Induced Liver Failure and Injury 

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