Thursday, July 26, 2018

F18-PSMA-1007 - the latest PSMA-based PET indicator

The development of new PET indicators for prostate cancer continues. As we've seen, the Ga-68-PSMA-11 indicator is already making a difference in clinical practice. Many of the new PET indicators have been developed in Germany, although the best one so far before this, F18-DCFPyL was developed at Johns Hopkins.

Researchers in Germany have developed a new PSMA-based PET indicator, F18-PSMA-1007, that seems to be even better. They tested it on 251 biochemically recurrent (after prostatectomy) patients at 3 academic centers.

  • 81% had a recurrence detected
  • 44% had a local (prostate bed) recurrence
  • 41% had a pelvic lymph node recurrence
  • 20% had a retroperitoneal lymph node recurrence
  • 12% in lymph nodes above the diaphagm
  • 40% had bone metastases
  • 4% had visceral organ metastases

Detection rates varied by PSA:

  • 62% in those with PSAs from 0.2-<0.5
  • 75%  in those with PSAs from 0.5-<1.0
  • 90%  in those with PSAs from 1.0-<2.0
  • 94%  in those with PSAs >2.0

Interestingly, those who had ADT in the last 6 months had higher detection rates (92%) compared to those who'd had no ADT recently (78%). This may be because those who had ADT recently had more advanced tumors. There was some early evidence in mice and lab studies (like this one and this one) that ADT upregulated PSMA. One clinical study indicated that ADT improved detection of PSMA. Two studies  (this one and this one) showed no effect of ADT on PSMA detection. More recent evidence indicates use of ADT negatively impacts detection rates. The patient should avoid ADT before getting a PSMA-based PET scan, if possible.

The detection rate among those with PSAs between 0.2-2.0 was 78%, which is comparable to the 88% detection rate reported for men with PSAs between 0.2-3.5 for F18-DCFPyL and much better than the detection rate of 66% reported for Ga-68-PSMA-11 in that PSA range. F18 has an advantage over Ga-68 in having a longer half-life (118 minutes vs 68 minutes) and is more tightly bound to the ligand. Because it is not appreciably excreted through the urinary tract, it can be seen more easily around the prostate - important when the recurrence is near the site of the anastomosis, as most recurrences are. In a mouse study, it was superior to F18-DCFPyL. In a clinical pilot study, they both detected the same tumors.

As of now, the F18 PSMA-based PET indicators seem to be superior, but others are working on ligands that detect other prostate cancer proteins more sensitively and more specifically. Leading candidates are hK2, FMAU, Citrate, Prostate-Stem-Cell-Antigen, , DHT/androgen receptor, uPAR receptor, VPAC receptor, or multiple ligands.

Also see:

Wednesday, July 25, 2018

The Danger of Complementary and Alternative Medicine

Researchers at Yale did two database analyses. They looked at the National Cancer Database and found 1,901,805 patients who were treated for either nonmetastatic prostate, breast, lung or colorectal cancer between 2004 and 2013. In one analysis they looked at use of complementary medicine; in the other, they looked at use of alternative medicine.

Complementary medicine was defined as use of “other-unproven: cancer treatments administered by nonmedical personnel” in addition to at least one conventional cancer treatment modality, defined as surgery, radiotherapy, chemotherapy, and/or hormone therapy. 258 patients who chose a complementary therapy were matched to 1032 patients who did not use any complementary medicine on age, clinical group stage, Charlson-Deyo comorbidity score (CDCS), insurance type, race/ethnicity, year of diagnosis, and cancer type using the propensity score matching technique.

After 5 years of follow-up, comparing users of complementary medicine to matched non-users:
  • There was no difference in delay of treatment, but there was a greater probability of refusal of surgery (7% vs 0.1%), chemo (34% vs 3%), radiotherapy (53% vs 2%), and hormone therapy (34% vs 3%).
  • 82% survived for 5 years vs 87% among non-users, and were 2.1 times more likely to die after adjustment.
  • The differences in survival were attributable to refusal of conventional treatment.
  • Differences in 5-year survival were significant for breast cancer (85% vs 90%), and colorectal cancer  (82% vs 84%), but not for lung cancer  or prostate cancer. 
Alternative medicine was defined as “other-unproven: cancer treatments administered by nonmedical personnel” and who also did not receive conventional cancer therapy, defined as chemotherapy, radiotherapy, surgery, and/or hormone therapy. 281 patients who used alternative medicine were matched to 560 patients with similar characteristics (cancer type, age, clinical group stage, CDCS, insurance type, race, and year of diagnosis) who did not use alternative therapies using propensity score matching.

After 66 months median follow-up, comparing users of alternative medicine to matched non-users:
  • 55% survived for 5 years vs 78% among non-users, and were 2.5 times more likely to die after adjustment.
  • Differences in 5-year survival were significant for breast cancer (58% vs 87%), lung cancer (20% vs 41%), colorectal cancer  (33% vs 88%), but not prostate cancer  (86% vs 95%)
  • The survival curves for prostate cancer had just begun to diverge at 5 years (75% were low or intermediate risk).
Complementary and alternative medicines consisted of herbs and botanicals, vitamins and minerals, probiotics, Ayurvedic medicine, traditional Chinese medicine, homeopathy and naturopathy, deep breathing, yoga, Tai Chi, Qi Gong, acupuncture, chiropractic or osteopathic manipulation, meditation, massage, prayer, special diets, progressive relaxation, and/or guided imagery.

Although these observational studies did not follow prostate cancer patients long enough to detect differences in survival, we see the damage that use of both complementary and alternative medicines had on patients with more virulent cancers. Patients who get complementary medicine are more likely to refuse conventional treatments (even though they received at least one conventional treatment) and are about twice as likely to die because of that decision.

(update 5/2019) The CAPSURE database shows that the use of complementary and alternative medicines among men with prostate cancer is increasing. Comparing the period of 2006-2010 to 2011-2016. They report that:

  • Use of complementary medicines increase +128% (from 24% to 54%)
  • Vitamin D use has more than doubled in spite of Level 1 evidence that supplementing confers no benefit.
  • Happily, Vitamin E use has decreased based on Level 1 evidence from the SELECT trial.
  • Almost a quarter of men with prostate cancer take omega-3 fatty acids. A secondary analysis of omega-3 use in the SELECT trial, confirming an earlier study, found an association between high omega-3 fatty acid serum levels and increased risk of prostate cancer. Level 1 evidence showed no association with prostate cancer incidence or prostate cancer death.

note: Level 1 evidence means that a cause/effect relationship was proven by a large randomized clinical trial (RCT). Interested readers may consult the Oxford definition, which is widely accepted. Many patients rely on mouse and lab studies which are almost always disproven when tried in clinical trials. They constitute the lowest quality of evidence (Level 5), and should only be used for hypothesis generation for clinical trials or to demonstrate plausibility for a cause/effect relationship found in an RCT. Additionally, the Bradford Hill checklist is used.

Sunday, July 22, 2018

Vitamin D has no effect on prostate cancer, heart disease, or bone mineral density*


Observational studies have reported conflicting effects of Vitamin D on prostate cancer - some reported no association (as in this study), some reported a positive association (as in this study), and some reported an inverse association (as in this study). We now have three large randomized clinical trials (Level 1a evidence) that show that large doses of Vitamin D have no effect on cancer incidence or deaths. This trumps all previous observational and epidemiological studies.

Manson et al.  reported the results of the VITAL randomized clinical trial (RCT) on 25,871 (including 5,000 African-Americans) men over 50 and women over 55 who were given either:
  1. Vitamin D3 at 2,000 IU per day and marine omega-3 fatty acids (1000 mg/day containing 840 mg EPA and DHA)
  2. Vitamin D3 placebo and fish oil placebo
  3. Fish oil and Vitamin D3 placebo
  4. Vitamin D3 and fish oil placebo
Blood samples were taken and questionnaires were administered to assure compliance. The group assignment was double-blind. Participants agreed to keep vitamin D from all other sources (like sunlight, milk, multi-vitamins, etc.) to under 800 IU per day.

After a year, serum 25-hydroxyVitamin D increased from 30 ng/ml to 42 ng/ml among those supplementing Vitamin D and didn't change in the placebo groups.

After 5.3 years of follow-up, there was:
  • No difference in incidence any kind of cancer (including prostate, breast and colorectal cancers) between Vitamin D3 and Placebo.
  • No difference in deaths from any kind of cancer
  • Low BMI  (<25) may potentiate the effect of Vitamin D on cancer.
  • No difference in any kind of cardiovascular disease, including myocardial infarction, stroke or death from myocardial causes or of interventions like PCI or coronary bypass.
  • There was no synergism with omega-3 fatty acids.
  • There were no statistically significant differences in any subgroup.

Manson et al. also did a separate analysis of omega-3 fatty acids. After 5.3 years of follow-up, there was:
  • No difference in incidence any kind of cancer (including prostate, breast and colorectal cancers) between omega-3 and Placebo.
  • No difference in deaths from any kind of cancer.
  • There was no synergism with Vitamin D.
  • Those with low fish consumption (<1.5 servings per week) may gain some cardiovascular benefit from omega-3 supplementation.
  • No difference in cardiovascular disease overall, stroke or death or of interventions like PCI or coronary bypass.
  • There was significant improvement in the rate of myocardial infarctions and total coronary heart disease among those taking omega-3s.
  • African-Americans, especially those with multiple CV risk factors, taking omega-3s had lower incidence of myocardial infarctions.
  • Myocardial infarctions (MI) were also better for those taking omega-3s among younger people (<67), men, smokers, diabetics, people with hypertension, people taking cholesterol medications, no parental history of MI, 3 or more risk factors, baseline aspirin use, and baseline statin use.
(update 11/18/20) Chandler et al. reported on an updated analysis of the VITAL RCT. They looked at whether Vitamin D supplementation affected the risk of developing metastatic or fatal cancer among people who were cancer-free at baseline. With a median intervention period of 5.3 years, there was almost no chance of finding metastatic or fatal prostate cancer in men who were prostate cancer-free at baseline (In the ProtecT trial, 10-year prostate cancer survival among men initially diagnosed with localized prostate cancer was 99%, and metastasis-free survival was 96%.) Because the metastasis-free and cause-specific survival with prostate cancer are so long when starting from a "no cancer" diagnosis, the authors looked for the effect on other cancers, excluding prostate cancer. They found:
  • there were no significant differences due to Vitamin D on the incidence of any cancer
  • there were no significant differences due to Vitamin D on the metastatic spread across all cancers
  • there were no significant differences due to Vitamin D on all-cancer mortality
  • Adding together metastases and fatalities due to all cancers, the difference (2.1% vs 1.7%) was statistically significant, especially after the first two years
  • The reduction was only statistically significant among those with a normal body-mass index (<25)
  • For prostate cancer patients, there were only 6 such cases among those who got Vitamin D and 14 such cases among those who got the placebo - not significantly different. Presumably, they were missed at diagnosis or had a rare virulent type of PCa.
(Update 3/16/2021) in an ancillary analysis of the VITAL trial data, Albert et al. reported that neither Vitamin D nor Omega-3 supplementation had any effect on the incidence of atrial fibrillation.

(update 2/19/2022) Neale et al. reported the results of the D-Health RCT. This was a randomized double-blind prospective trial among 21,315 Australians aged 60 or over.
  • 10,662 were given Vitamin D; 10,653 were given a placebo
  • Vitamin D3 was given as 60,000 IU/month for 5 years
  • A random sample of both groups was checked for compliance via a blood test for serum 25-hydroxyVitamin D; it was 115 nmol/L in the treatment group vs 77 nmol/L in the placebo group.

After 5 years of follow-up:
  • There was no statistically significant difference in the number of deaths (5% in each group)
  • There was no statistically significant difference in cardiovascular disease mortality
  • There was no statistically significant difference in cancer mortality
  • There was no statistically significant difference in all other causes of mortality
  • Excluding those who died during the first 2 years of follow-up, cancer mortality was 24% higher among those taking Vitamin D

Scragg et al. in a post-hoc analysis of the ViDA trial reported on 5,110 50-84 year-old people seen in community practice in NZ between 2011 and 2012. The study was originally set up to investigate cardiovascular benefit to Vitamin D supplementation (it found none), but they also asked about incidence of cancer and tracked deaths from cancer.
  • 2558 were given Vitamin D; 2552 were given a placebo
  • Vitamin D3 was initially given as one 200,000 IU pill, followed by 100,000 IU monthly pills
  • Serum 25-hydroxyVitamin D was 26.5 ng/ml (seasonally adjusted) at baseline
  • Serum 25-hydroxyVitamin D consistently increased by 20 ng/ml among a sample of treated patients
  • Compliance was excellent
  • There was no difference in the percent who took calcium or Vitamin D supplements or in sun exposure
After a median of 3.3 years of follow-up, there were:
  • 375 new cancer cases; 60 died of new cancers. 
  • 24% had a pre-existing cancer diagnosis; 29 died
  • no significant difference between the Vitamin D cohort and the placebo cohort in the number of new cancers or cancer deaths.
  • 6% had a pre-existing prostate cancer diagnosis; 7 died
  • 64 new cases of prostate cancer (1 died)
  • no significant difference between the Vitamin D cohort and the placebo cohort in the number of new prostate cancers or in prostate cancer deaths.
One can argue that a consistent daily Vitamin D3 intake might have had an effect, or that it takes more than 3 years for an effect (whether beneficial or increased risk) to be observed. There is, at present, only observational studies for either assertion. Sample size prevents consideration of the hypothesis that Vitamin D may prevent early growth of prostate cancer but may accelerate metastases (as in this mouse study).

Jiang et al. report the results of a Mendelian randomization study of the causal connection between serum Vitamin D levels and prostate cancer. They identified 6 genetic mutations associated with low serum levels and looked for them in 79,148 men who were diagnosed with prostate cancer. They found no greater incidence of those genetic mutations in men with prostate cancer or advanced prostate cancer. Nor was there any association in women with breast cancer. The genetic mutations were also not statistically different in 73,699 people who did not have breast or prostate cancer. This proves there is no causal connection between low Vitamin D and prostate cancer.

No Effect or Negative Effect on Bone Mineral Density*

Some men on hormone therapy take Vitamin D and calcium for the purpose of maintaining bone mineral density (BMD). 

(update 7/27/22) An update of the VITAL randomized clinical trial reported no difference in fractures among people supplementing Vitamin D vs. people not supplementing it. There were no differences by age, sex, race, BMI, baseline use of calcium or Vitamin D supplements, or serum Vitamin D levels.

Reid et al. reported that Vitamin D supplementation had no effect on bone mineral density. They further noted that lower doses had more effect than higher doses, probably because Vitamin D has been found to pull calcium out of bones at high doses. However, Datta and Schwartz reported that at 200-500 IU/day Vitamin D and 400 mg-1,000 mg calcium supplementation had no effect on men's bone mineral density. Calcium supplementation has been associated with increased risk of prostate cancer (see this link or this link). Trajanoska et al. found that mutations in the genes responsible for regulating serum Vitamin D levels had no effect on fracture risk, nor did the genes regulating the tolerance for dairy (which is correlated with calcium intake). They also question the routine use of Vitamin D and calcium supplements in men who are taking Xgeva or a bisphosphonate like Zometa to preserve bone mineral density. (Estrogen patches may also prevent loss of bone mineral density.) They wrote:

Studies seeking to show whether these supplements do increase the efficacy of osteoporotic treatment or decrease adverse events (that is, hypocalcaemia) are lacking. In either case, screening for vitamin D deficiency and seeking its correction should be warranted before the initiation of anti-resorptive treatment [e.g., Zometa or Xgeva].  Moreover, in a recent mendelian randomisation study investigating the role of vitamin D in maintaining bone mineral density, increased levels of vitamin D had no effect on bone mineral density measured by [DEXA scan]. However, increased 25-hydroxy-vitamin D was associated with a slight reduction in heel bone mineral density estimated by ultrasonography. These results are consistent with our mendelian randomisation findings of no causal effect of vitamin D levels on fracture.
(Update 9/2/2019) Burt et al. published the results of a randomized clinical trial (RCT) of three different doses of Vitamin D on the bone mineral density of 311 men with 3 years of follow up. The experiment was set up as follows:

  • 1/3 received 400 IU/day; 1/3 received 4000 IU/day; 1/3 received 10,000 IU/day
  • none had osteoporosis at baseline
  • all had baseline serum Vitamin D between 30-125 nmol/L (12-50 ng/ml)
  • those whose total intake of calcium (dietary+supplements) was < 1200 mg/day received calcium supplements
  • baseline serum calcium was 8.4-10.2 mg/dl
  • 53% were men
  • average age was 62 (range:55-70)

After 3 years on their vitamin D regimen:
  • Serum Vitamin D was 77 nmol/L, 132 nmol/L, and 144 nmol/L in those taking 400 IU/day, 4000 IU/day, and 10,000 IU/day, respectively
  • BMD in the radius bone of the arm decreased in all groups in a dose-dependent manner:
    • -1.2% in the 400 IU/day group
    • -2.4% in the 4,000 IU/day group
    • -3.5% in the 10,000 IU/day group
  • Hypercalcemia (too much calcium in the blood) and hypercalciuria (too much calcium in the urine) increased with increased Vitamin D dose
  • Kidney/liver dysfunction, falls, fractures and cancer did not vary with dose.

In a Medpage interview, the authors point out that this is plausible because of two effects of Vitamin D:
  • It increased bone resorption (more than bone formation), as measured by an increase in CTx.
  • It increased parathyroid hormone, either directly or by increasing calcium absorption from the gut

The study did not include people taking bisphosphonates, Zometa or Xgeva.

Also, the dose-dependent effect (higher doses were more damaging than lower doses) increases the plausibility of this being a real effect.

(update 3/23/24) *Peppone et al. found in a small randomized trial that ultra-high doses of Vitamin D (50,000 IU/wk!) could lessen the deleterious effect on BMD of  ADT in men who recently (last 6 months) started ADT and had low-end baseline serum Vitamin D (<27 ng/ml). Even so, they still lost BMD after 24 weeks of ADT but at about ⅓ the rate of those who only took much smaller amounts of Vitamin D. There were no differences in toxicity at 24 weeks. Of course, these men started with a deficiency, only took ADT for a short time, and they weren't followed long enough for the megadoses of Vitamin D to rob their bones of BMD.

 It’s worth noting that Vitamin D, unlike other vitamins, is a steroid. Steroids tend to interact and to have wide-ranging effects in humans. Overwhelming our steroid-control systems with massive doses of any one steroid is bound to have unintended consequences.

Possible increase in testosterone 

It should be remembered that Vitamin D is a steroidal hormone (like testosterone, estrogen, progesterone, and cortisol) and there are receptors for it on virtually all cells, healthy and cancerous. It has far-ranging effects. It also is part of the human biochemical factory that inter-converts many different kinds of steroids. In fact, Anic et al. showed there was a positive association between serum Vitamin D level and the amount of serum testosterone - not an effect that a man who is taking androgen deprivation wants.

Given that Vitamin D has no effect on incidence of cancer or cancer mortality, that it has no cardiovascular benefit, and no effect on bone mineral density, there is no reason to take supplemental Vitamin D unless serum levels are too low (below 20 ng/ml). 

Supplementing Vitamin D and Calcium increases risk of Myocardial Infarction

Li et al.Xiao et al., and Boland et al. reported that supplementing calcium, but not dietary calcium intake, was associated with a higher risk of myocardial infarction, and increased rates of plaque deposition (see this link). Kassis et al. found the association was true whether or not Vitamin D was supplemented with it. It is possible that increasing calcium absorption using Vitamin D may increase the risk of myocardial infarction. It also increases the risk of kidney stones.

Sunday, July 8, 2018

The Best Therapy for Gleason 10s

We recently saw (see this link) that men diagnosed with Gleason score (GS) of 9 or 10 had lower rates of metastases and better prostate-cancer survival if they were treated with a combination of external beam radiation (EBRT) plus a brachytherapy boost to the prostate ("brachy boost therapy" - BBT) than if they were initially treated with EBRT, or if they were initially treated with surgery (RP). The same researchers looked at a subset of patients who were initially diagnosed as GS 10.

There were only 112 patients who were biopsy-determined as GS 10. Of those,

  • 26 were initially treated with RP (median age 61)
  • 48 were initially treated with EBRT (median age 68)
  • 38 were initially treated with BBT (median age 67)

The median follow-up was relatively short:

  • 3.9 years for RP
  • 4.8 years for EBRT
  • 5.7 years for BBT

  • Upfront androgen deprivation was given to 98% of EBRT patients vs. 79% of BBT patients
  • Post RP radiation was given to 34%
  • Pre-RP systemic therapy was given to 35%

By 5 years of follow-up:

  • Only 3% of the BBT cohort received systemic salvage therapy vs. 23% of the RP group and 21% of the EBRT group
  • Distant-metastasis-free survival (adjusted) was 64% for RP,  62% for EBRT, and 87% for BBT
  • Prostate cancer-specific survival (adjusted) was 87% for RP. 75% for EBRT, and 94% for BBT
  • Overall survival was not significantly different in the 5-year time frame

While GS 10 is often more aggressive, it is noteworthy that 87% of those receiving BBT had no distant metastases detected within 5 years. Among men who received RP,  57% were upstaged to T3/4 and 41% were downgraded to GS 7-10 by post-prostatectomy pathology. We have no reason to believe those percentages would differ markedly among those who received radiation.

Although the numbers here are small, this is the largest analysis of Gleason 10s broken down by the therapy that they received that we have ever seen. Only a randomized clinical trial can provide a definitive answer. Given the aggressive course of GS 10, patients with this diagnosis are advised to talk to a radiation oncologist who specializes in this therapy.