Monday, August 13, 2018

Salvage Radiation Dose: Decision-Making Under Uncertainty

A large, well-done, confirmed randomized clinical trial (RCT) is the only evidence that proves that one therapy is better than another. According to current consensus, this is deemed "Level 1a" evidence. But this high level of evidence is seldom available. This is especially true of prostate cancer because it takes so long to achieve acceptable endpoints like overall survival, prostate cancer-specific survival, and metastasis-free survival. Such studies are very expensive and difficult to carry out.

Alexidis et al. analyzed the National Cancer Database for men treated with adjuvant or salvage radiation therapy (SRT) after prostatectomy failure from 2003 to 2012. SRT with doses above 66.6 Gy were labeled "high dose," and SRT with doses above 70.2 Gy were labeled "very high dose." Between 2003 and 2012:

  • High dose SRT utilization increased from 30% to 64%
  • Very high dose SRT utilization increased from 5% to 11%
  • Utilization of high and very high dose rates was greatest at academic centers, lowest at community centers.

The authors decry the fact that this doubling of high dose SRT took place in the absence of RCTs that would definitively establish proof. They point out that the evidence for it is based on observational studies (see, for example, King and Kapp and Ohri et al.), which are fraught with confounding due to stage migration,  selection bias and ascertainment bias. Stage migration was the result of better imaging becoming increasingly available to rule out SRT from patients already harboring occult distant metastases. Also, three randomized clinical trials published in the middle of the observational period convinced many radiation oncologists that earlier SRT led to better tumor control than waiting. Selection bias occurred because the patients selected to get higher doses of radiation were healthier and those whose cancer was less progressed -- they would have done better regardless of the dose. Ascertainment bias resulted from the longer observational period for patients treated in 2003 vs. 2012 - the opportunity for treatment failure increases with the amount of time that has passed. The authors also doubt that biochemical recurrence-free survival (which is what was used in observational studies) is a good enough surrogate endpoint for overall survival. They are right that all these factors may be confounding the previous retrospective analyses, and the only way to know with certainty is to conduct a trial where patients are randomized to receive high or low SRT doses,  and follow patients long enough so that median survival or at least metastasis-free survival is reached in the low dose group.

There has been one randomized clinical trial of SRT dose escalation in the modern era. The SAKK 09/10 trial found little difference in acute toxicity symptoms at 70 Gy compared to 64 Gy, but patient-reported urinary symptoms worsened. Unfortunately, many patients were treated with three-dimensional conformal radiation therapy (3D-CRT), which had higher toxicity than the IMRT in widespread use now. Also, it uses freedom from biochemical failure (not yet reported) as its surrogate endpoint.

So, what is a patient to do in the absence of Level 1a evidence? Should he accept the higher doses with possibly added toxicity and better tumor control, or should he go for a lower dose with possibly less toxicity and less tumor control?

As a compromise, Mantini et al. recently reported 5-year biochemical disease-free survival (bDFS) and other outcomes for patients who received higher dose SRT (70.2 Gy vs. 64.8 Gy) depending on their post-operative pathology. They also may have received (depending on pathology) whole pelvic radiation and adjuvant hormone therapy. Those patients who received the higher dose had equivalent 5-yr bDFS in spite of their worse disease characteristics. Those who received only 64.8 Gy still had a 5-year bDFS as high as 92%. We do not know how many of those recurrent men with favorable disease characteristics actually needed any SRT. They were all treated with 3D-CRT and toxicity was not reported.

The other thing we can do when our information is imperfect is go through the Bradford Hill checklist. It can give us more confidence if we have to make a decision based on less than Level 1 evidence. The factors that ought to be considered are:

  • Strength of Association (larger associations are more likely (but not necessarily) causal)
  • Consistency of Data (independent studies all lead to the same conclusion)
  • Specificity (a very specific population is differentially affected)
  • Temporality (the effect has to occur after the cause)
  • Biological gradient (too some extent, more drug/radiation dose leads to more effect) 
  • Plausibility (one can come up with a plausible explanation)
  • Coherence (lab studies demonstrate a plausible mechanism for the observed effect)
  • Experiment (has the effect been prevented by modifying the cause)
  • Analogy (similar factors may be considered)

Unfortunately, the authors did not refer to Dr. King's more recent analysis of SRT dose/response, which we discussed in depth here. He looked at 71 studies, demonstrating consistency. While it is not Level 1 evidence, it is Level 2a evidence. In it, he observes that the salvage radiation dose response conforms exactly to the primary radiation dose response.  In other words, the prostate tumor is equally radio-resistant whether it is in the prostate or the prostate bed. This increases the plausibility of a dose effect of SRT. What's more, dose escalation was proven to be beneficial for biochemical recurrence-free survival, metastasis-free survival, and freedom from lifelong ADT use, for primary radiation in intermediate risk men by a RCT (RTOG 0126). So, we also have greater confidence in SRT dose escalation by analogy.

RTOG 0126 did not find an increase with higher dose in 8-year overall survival or cancer-specific survival. This calls into question whether these longer-term effects are really useful endpoints if we are to be able to obtain and use the results of any clinical trial in a reasonable time frame.

Dr. King proposed a randomized clinical trial of 76 Gy vs. 66 Gy for SRT. Meanwhile, he is routinely giving his SRT patients at UCLA 72 Gy. Dr. Zelefsky at Memorial Sloan Kettering Cancer Center and other eminent radiation oncologists have also upped the radiation dose to 72 Gy. Such doses seem to be safe and effective, but it is one of many factors in the SRT treatment decision that must be carefully considered by patients and their doctors.

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.

Sunday, July 22, 2018

Megadoses of Vitamin D have no effect on prostate (or any other) cancer

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 a randomized clinical trial from New Zealand that shows that large doses of Vitamin D have no effect on cancer incidence or deaths.

Scragg et al. in a post-hoc analysis 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.

This provides Level 1 evidence that large monthly doses of Vitamin D3 did not prevent prostate cancer, nor did it change the progression of pre-existing prostate cancer. This trumps all previous observational and epidemiological studies.  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)

No Effect Bone Mineral Density

Some men on hormone therapy take Vitamin D and calcium for the purpose of maintaining bone mineral density. While I'm aware of no studies of Vitamin D supplementation in men, there was a major meta-analysis mainly in post-menopausal women. Reid et al. reported that Vitamin D supplementation had no effect on bone mineral density. They further noted that there 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).

Men on ADT can preserve bone mineral density by taking Xgeva or a bisphosphonate like Zometa. Estrogen patches may also prevent loss of bone mineral density.

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). 

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.

Monday, April 30, 2018

First randomized clinical trial of SBRT

In the first trial ever to randomly assign patients to extreme hypofractionation, primary radiation therapy delivered in just 7 treatments had the same effectiveness and safety as 39 treatments.

The top-line results of the HYPO-RT-PC randomized clinical trial were presented at a meeting of the European Society for Radiotherapy and Oncology (ESTRO). There was an earlier report on toxicity. Details of the trial specs are available here. Between 2005 and 2015, they enrolled 1200 intermediate- and high-risk patients at 12 centers in Sweden and Denmark to receive either:
  1. Conventional fractionation: 78 Gy in 39 fractions
  2. SBRT (stereotactic body radiation therapy): 42.7 Gy in 7 fractions
The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

The patients were all intermediate to high risk, defined as:
  1. Stage T1c-T3a
  2. PSA> 10 ng/ml 
  3. Gleason score ≥7
80% of the men were treated with a technology called three-dimensional conformal radiation therapy (3D-CRT), which is seldom used for prostate cancer external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic. SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

With follow-up of 1,180 patients for 5 years, they report biochemical recurrence-free survival of 84% in both arms of the study.

They also reported updated late-toxicity results. By 6 years after treatment:
  • Grade 2+ urinary toxicity was 3.5% for conventional fractionation, 2.5% for SBRT - no significant difference.
  • Grade 2+ rectal toxicity was 2.3% for conventional fractionation, 1.2% for SBRT - no significant difference.
Up until now, we've only had reports from clinical trials using SBRT (like this one) or conventional fractionation (like this one), and it could have been reasonably argued that SBRT results looked good because of selection bias. With this study, we now have Level 1 evidence of non-inferiority. This will not be surprising to those of us who have followed the randomized clinical trials of moderately hypofractionation vs. conventional fractionation (see this link). This will be hailed as a victory for patients who no longer have to endure and pay the high cost of 8 weeks of treatments. radiation oncologists, who are reimbursed by the number of treatments they deliver, probably will not be as thrilled.

Tuesday, March 27, 2018

Should perineural invasion influence active surveillance and radiation treatment options?

Perineural invasion (PNI) is a risk factor detected on a biopsy in 15%-38% of men with a prostate cancer diagnosis. It means that the pathologist saw nerves infiltrated with cancer cells. As they grow, tumors cause nerves to innervate them. The cancer infiltrates in and around small nerves that connect to nerve bundles (ganglia) outside the prostate, becoming a route of metastatic spread (see this link).  The data on whether it is independently prognostic for T3 stage after surgery are equivocal, although PNI is often the mechanism for extracapsular extension.  After considering Gleason score, PSA, stage, and tumor volume, PNI does not seem to add much to the risk of recurrence after surgery. PNI is not associated with higher surgical margin rates, and it is not considered sufficient to preclude nerve-sparing surgery. An open question is whether it raises risk enough to warrant more aggressive radiation options, like brachy-boost therapy, whole-pelvic radiation and long-term adjuvant ADT.

Peng et al. retrospectively examined the records of 888 men who were treated with external beam radiation at Johns Hopkins from 1993 to 2007. 21% of them had biopsy-detected PNI. Compared to men with no PNI, those with PNI had:

  • lower 10-year biochemical failure-free survival (40% vs 58%)
  • lower 10-year metastasis-free survival (80% vs 89%)
  • lower 10-year prostate cancer-specific survival (91% vs 96%)
  • similar 10-year overall survival (68% vs 78%)

It isn't surprising that PNI is associated with higher risk, but does it add any new information not already captured by Gleason score, stage, and PSA (i.e., the NCCN criteria for risk stratification)? After correcting for those other risk factors, PNI was still found to be associated with lower rates of biochemical failure-free survival, but not of metastasis-free survival, prostate cancer specific survival or overall survival.

PNI independently predicted for lower biochemical failure-free survival in low-risk and high-risk patients, but not for intermediate-risk patients.  Although it is a relatively rare finding among low-risk patients, when found, PNI also predicted for lower prostate cancer-specific survival. Biochemical failure in low-risk men with PNI differed according to whether they received adjuvant ADT or not:

  • 33% in men not treated with ADT
  • 8% in men treated with ADT

An earlier analysis of 651 men treated at the University of Michigan similarly found an association between PNI and biochemical failure-free survival, freedom from metastases, prostate cancer-specific survival, but not overall survival at 7 years after radiation treatment. They also found a more marked effect among high-risk patients. A meta-analysis of 5 studies among men who received EBRT found that PNI increased the risk of biochemical recurrence by 70%.

Although PNI may increase the risk associated with an unfavorable intermediate-risk or high-risk diagnosis markedly, brachy boost therapy is the best treatment for any such patient regardless of PNI, according to our best retrospective study and prospective studies like ASCENDE-RT. However, while adjuvant ADT may be optional for them ordinarily, this study suggests that adding ADT may be beneficial for these patients. Low and intermediate-risk patients with PNI who opt for conventional IMRT may also benefit from the addition of short-term ADT.

Biopsy-detected PNI may have implications for active surveillance. Cohn et al. detected PNI in only 8.5% of 165 men selected for active surveillance. Within 6 months, they were given a confirmatory biopsy. AS was excluded at the confirmatory biopsy due to higher Gleason grade in 57% of men with PNI vs. 13% of men without PNI. PNI should not automatically exclude active surveillance, but it should be recognized as a risk factor in the decision. It would be interesting to know if there is an association between PNI and genomic risk (based on Oncotype Dx, Prolaris, or Decipher tests). It has yet to be determined whether PNI is still a significant risk factor after NCCN risk category, % core involvement, and genomic risk have been accounted for.

It is worth noting that PNI is not always reported on biopsy cores by pathologists, and there is no uniform method for quantifying it. Whether nerve infiltration is small or large, or outside or inside the nerve sheath, it is just reported as PNI, if it is reported at all. It will be difficult to include PNI as part of any risk stratification system until its reporting has been standardized.

Note: Thanks to Daniel Song for allowing me to see the full text of the study.