Friday, December 8, 2017

Exercise may make radiation more successful by overcoming hypoxia

Radiation therapy does not often fail in prostate cancer patients who are not already metastatic. Many had thought that most radiation failures are attributable to undetected micrometastases. However, two recent studies (see this link and this one) showed that about half of all failures of IMRT as primary therapy were due to failure to kill all the cancer within the prostate. One of the reasons that radiation may not destroy all the cancer is due to a condition called hypoxia.

Hypoxia refers to tissues that are not well oxygenated. Most solid tumors are hypoxic to some degree. The tumor tissue is denser than benign tissue, and although the tumor does generate its own blood supply, the blood vessels are leaky and haphazard. Cancer can often thrive in an hypoxic environment that would atrophy healthy tissue.

Good tissue oxygenation is essential for radiation to work. X-rays cause a chemical reaction with water and oxygen to generate what is called "reactive oxygen species (ROS)." The most important ROS is a molecule called a hydroxyl radical. The hydroxyl radical (a free radical) is powerful enough to tear apart DNA in a reaction called a "double strand break." This is where the magic of radiation happens. Healthy cells can repair double strand breaks or commit suicide (apoptosis) if they can't. Cancer cells lack the ability to repair double strand breaks. Then, when they eventually try to replicate (and that may be delayed for years), they fail to do so and die trying. So radiation irreversibly kills cancer cells but leaves most benign cells intact. But under hypoxic conditions not enough hydroxyl radicals are formed, and some of the cancer is left alive.

(Incidentally, it should be obvious from this that supplements that are marketed as antioxidants or free-radical absorbers (e.g., Vitamin E, Vitamin C, glutathione, alpha-lipoic acid, etc.), which are of questionable value at any time, should be especially avoided during radiation therapy.)

The most common solutions to overcome hypoxia are to increase the radiation dose and to use some fractionation. Increasing the dose blasts through the tumor like a steam blaster cleaning debris. Fractionation - smaller, multiple doses - kills the outer, oxygenated layer of the tumor. Then, as the outer layer falls away and the next layer gets a fresh blood supply, the next fraction kills that layer. It's like peeling away the layers of an onion. Prostate cancer is particularly vulnerable to a more intense radiation dose, which is why radiation techniques that increase dose per fraction (i.e., SBRT, HDR brachytherapy, and hypofractionated IMRT) are so effective. But at least some fractionation seems to be important too. Attempts to use just one fraction of HDR brachytherapy seem to have higher-than-expected failure rates (see this link).

Good tissue oxygenation seems to play a role in keeping healthy cells healthy following radiation. Kapur et al. in one small study found that moderate aerobic exercise throughout the radiation treatments reduced the incidence of acute rectal side effects. We recently saw that exercise reduces radiation-induced fatigue (see this link). Hyperbaric oxygen therapy has been used to reverse radiation-induced cystitis and proctitis (see this link) and hematuria, although one randomized controlled trial found it did not improve bowel inflammation or rectal bleeding.

So far, the evidence that exercise reduces tumor hypoxia has been limited to a study in rats (see this link). In the first study in humans that I'm aware of, a group at the University Hospital of North Norway are conducting a small clinical trial among 32 men who plan to have a prostatectomy. Half will undergo 4-5 weeks of moderate to intense supervised aerobic exercise. Half will not be told to exercise. They hypothesize that the aerobic exercise will increase the vascularity of the prostate tumors and thereby cause a sustained reduction in hypoxia. Before prostatectomy, they will all be injected with pimonidazole, a non-toxic drug that has particular affinity for hypoxic tissue. In post-prostatectomy pathology, it will be detected in prostate tissue using a specific antibody. They will also look at blood flow in the tumor prior to prostatectomy using MRI.

While this trial may prove that exercise reduces prostate cancer tumor hypoxia, it will remain for a future clinical trial to prove that radiation oncological and toxicity outcomes are improved by it. That will take several years, if it ever gets studied.

Meanwhile, this intervention is harmless for most patients (with doctor's permission, of course), and may improve the results of their prostate radiation treatment. While it may be ideal to undertake a 4-5 week supervised aerobic exercise program to permanently increase tumor vasculature or undergo hyperbaric oxygen therapy, as little as 15 minutes on a treadmill or an exercise bike within an hour of radiation treatment may be enough to temporarily increase tumor oxygenation.

Wednesday, December 6, 2017

Use of mpMRI and PSMA PET/CT to aid in salvage radiation decision-making

Because the success or failure of salvage radiation (SRT) hinges upon whether micrometastases are already systemic at the time of treatment, evidence that the cancer is still local improves the odds that SRT will be successful.. One way of finding local tumors is to use multiparametric MRI (mpMRI). mpMRI can detect tumors down to about a limit of 4 mm, and may be able to find tumors even when their PSA output is low.

Sharma et al. at the Mayo Clinic retrospectively examined the records of 473 men who were treated with SRT and who had an mpMRI prior to treatment from 2003 to 2013. Among men with a pre-treatment PSA ≤ 0.5 ng/ml, 5-year biochemical failure was:

  • 39% among those with a negative mpMRI
  • 12% among those with a positive mpMRI

Adding mpMRI to the updated Stephenson nomogram (see this link) increased its predictive accuracy for PSA recurrence after SRT from 71% to 77%. Perhaps its accuracy would increase even further if the MRI was confirmed by a biopsy of the suspicious tissue to eliminate any false positives.

Like the detection of a positive margin in post-prostatectomy pathology, detection of a local tumor using mpMRI increases the probability that SRT will be successful. Although the radiation dose to the suspicious lesion can be boosted (see this link), it is unknown whether such a boost actually increases efficacy when the entire prostate bed is adequately treated. It is also unknown what effect it might have on toxicity. Moreover, it is hard to argue for a reduced dose elsewhere in the prostate bed because of the known limitation of mpMRI in detecting smaller tumors, and the multi-focal nature of prostate cancer spreading.

Emmett et al. at St. Vincent Hospital in Sydney performed a Ga-68-PSMA-11 PET/CT on 164 men with rising PSA (PSA range: 0.05-1.0 ng/ml) after prostatectomy who received SRT. After eliminating patients who also had systemic therapy, there were 140 evaluable patients. They had a pre-SRT PSA of 0.23 (interquartile range 0.14-0.35).  As expected, detection rates went up with increasing PSA;

  • <0.2 ng/ml: 50%
  • 0.20-0.29 ng/ml: 64%
  • 0.30-0.39 ng/ml: 67%
  • ≥0.40 ng/ml: 81% 
They only had 10.5 months of median follow-up, and defined a favorable PSA response to SRT as a decrease of at least 50% in PSA and a PSA ≤ 0.1 ng/ml (those receiving adjuvant ADT were eliminated from the follow-up PSA-response analysis). The results should be interpreted with caution because of the very short follow up and low sample sizes. A short-term PSA response only indicates local control, and may not endure if systemic micrometastases were present.

PET/CT was negative in 38% (62/164). 45% of those men (27/60) had SRT to the prostate bed, and 7/27 had SRT to the pelvic lymph nodes field too. In the "negative" detection group, 86% had a favorable PSA response to SRT. Unfortunately, more than half of the PET-negative men never received SRT. This should serve as a caution against over-reliance on PET/CT. PET/CT is not good at detecting micrometastases in the prostate bed. The prostate bed is also a difficult place to detect PSMA-avid cancer because of masking from urinary excretion. We also know little about the natural history of PSMA development in prostate cancer -- it  may very well be that earlier forms of the cancer that may not express PSMA may be most vulnerable to SRT. SRT should never be withheld from an area based solely on negative PSMA findings.

PET/CT was positive in the prostate bed only in 23% (38/164). All of them had SRT to the prostate bed, and 17/36 had SRT to the pelvic lymph node field too. In the "prostate-bed only" detection group, 81% had a favorable PSA response to SRT. Recent evidence indicates that pelvic lymph node SRT increases effectiveness (see this link). Radiation of the pelvic lymph nodes should be considered in spite of negative nodal PSMA findings.

PET/CT was positive in pelvic lymph nodes in 25% (41/164). 87% (26/30) of them had SRT to the prostate bed and to the targeted pelvic lymph nodes. In the "pelvic lymph node" detection group, 61.5% had a favorable PSA response to SRT. The entire pelvic lymph node field and not just isolated lymph nodes should receive SRT for the reasons stated above.

PET/CT was positive for distant metastases in 14% (23/164). Nevertheless, 60% (10/15) of them had SRT to the prostate bed (and, I suppose, to the entire pelvic lymph node field), and 6/10 had metastasis-directed SBRT too. In the "distant metastasis" detection group, only 30% had a favorable PSA response to SRT. Only 1 of the 6 who had metastasis-directed SBRT had a favorable PSA response. When there are known distant metastases, treatment of the prostate bed, pelvic lymph nodes, and of metastases remains a controversial treatment.

The PET/CT was a better predictor of SRT response than PSA, Gleason score, stage, or surgical margin status. The most valuable finding of this small, short-term analysis was that metastases can sometimes be detected at fairly low PSA (as low as 0.1 ng/ml), and it may be possible to rule out SRT in those cases. Conversely, when distant metastases cannot be detected, SRT success rates may be very good.

We will require longer follow-up, larger sample size, prospective studies to establish the utility of mpMRI and PSMA PET/CT in SRT decision making. The two imaging techniques are complementary - the MRI is not as PSA-dependent and is not masked by the urinary excretion of the radiotracer, while the PET scan is highly specific for cancer. Both are useless in detecting tumors with a dimension smaller than 4 mm, so it would be a mistake to think that what is detected is all there is.

Monday, December 4, 2017

Questions for an adjuvant or salvage radiation doctor

Questions for a Adjuvant or Salvage Radiation Interview.

1. How many prostate cancer patients have you treated with adjuvant/salvage radiation?

2. How has your practice of salvage treatment changed, if at all?

3. Is there any kind of scan that you recommend to rule out metastases that might be useful at my current PSA?

4. What is the probability that I need salvage treatment? Do you calculate that from a nomogram?

5. Do you think I should get a Decipher test to find my probability of metastasis in the next 5/10 years? Do you know if my insurance covers it? What do you think about their PORTOS score?

6. How large a dose do you propose for the prostate bed? (should be near 70 Gy -72 Gy)

7. Do I need pre-treatment, concurrent or adjuvant ADT?

     a. Why?

     b. What's the evidence that it's useful?

     c. For how long?

8.How do you decide whether to treat the pelvic lymph nodes?

     a. If so, at what dose?

     b. How do you plan to prevent bowel toxicity?

     c. How will you account for the separate movement of that area and the prostate bed?

9. What do you think of doing this in fewer treatments (hypofractionation)?

10. What kind of machine do you use? (e.g., RapidArc, Tomotherapy, etc.) Why do you prefer that one?

11. What is the actual treatment time for each treatment? (faster is better)

12. What kind of image guidance do you propose? fiducials in the prostate bed? Using the fixed bones only? Soft tissue?

13. How will inter- and intra-fractional motion be compensated for?

14. What measures do you propose to spare the bladder and rectum?​ (ask about treatment margins and dose constraints)

15. What side effects can I reasonably expect, and how do we handle them?​(discuss in detail!)

16. What probability of a cure can I reasonably expect, given my stats? Is there a nomogram you use to come up with that?

17. How will we monitor my progress afterwards, both oncological and quality of life?

18.What's the best way for us to communicate if I have a question or issue?

Questions for a focal ablation therapist

Questions for focal ablation therapists (read this link first)
1.     Am I a good candidate for focal ablation? Why do you say that?
2.     What about proximity to other organs – urethra, bladder neck, rectum?
3.     How would you assess my risk of urethral stenosis requiring catheterization?
4.     Is there a risk of recto-urethral fistula?
5.     Should I expect some incontinence for a while? For how long?
6.     What about damage to the neuro-vascular bundles on one or both sides?
7.     What is the risk of losing the ability to have erections? Orgasms? or have painful orgasms?
8.     What is the likelihood that I will still be able to ejaculate at orgasm?
9.     Should I expect blood in semen? In urine? Is climacturia ever an issue?
10. Should I expect bleeding and sloughing of necrotic tissue through my penis?
11. How long after the procedure can I have anal receptive sex?
12. What is the likelihood that undetected cancer in the untreated area will become a problem? How will we monitor that?
13. What is the likelihood that cancer in the treated area will not be fully killed off? How will we monitor that?
14. Will we use imaging (mpMRI or PET/CT) to assure the cancer is gone? Will we do a follow-up biopsy? Is there a pathologist here who is expert at reading biopsies of ablated tissue?
15. How will we monitor progression after the procedure? Since my PSA from the unablated zone will always be there, how do we know if progression has occurred?
16. What is the cost of the procedure? Does that include anesthesia?
17. What is the cost of a re-do, if I need one?
18. Are any of the costs covered by insurance?
19. How many focal ablations (as a primary therapy) have you done?
20. Have you always used the same equipment?
21. How has your practice changed over the years?
22. Are you going to be doing all of the really important parts of my procedure yourself?
23. What percent of those required re-dos?
24. What percent eventually needed other salvage therapies? What kinds of salvage therapies were used? Radiation? Surgery? Were they successful? What kinds of side effects occurred from the salvage?
25. What is the longest follow-up you’ve done of patients you’ve treated?
26. How long should follow-up be before we deem it a success, or am I always on “active surveillance”?
27. What kind of aftercare will you provide, and how will we monitor side effects, and for how long? Will you regularly monitor my urinary and erectile recovery progress with validated questionnaires like EPIC and IPSS?
28. What is the best way for us to communicate? May I ask short questions by email?

Questions not to ask:
1.     What treatments should I consider and which is the best for me? (this would be asking your doctor to be an expert in treatments outside of his specialty, and also to know which benefits and risks are most important to you – he doesn’t have time or inclination to be expert in all therapies, and he’s not a mind reader.)
2.     If I were your father, what would you recommend? (You don’t know how he feels about his father (lol), and more importantly, what he would feel most comfortable with is not necessarily what you would feel most comfortable with. This is your decision to make and live with – don’t give up your power!)

Questions to ask an SBRT doctor

SBRT doctor questions
1.     How many have you performed?
2.    How has your practice of SBRT changed over the years?
3.    What is your 5-yr freedom from recurrence rate for patients at my risk level? What proportion of your recurrences were local-only?
4.    What kind of urinary and rectal reactions can I expect? How long can I expect them to last? What medications or interventions do you typically give for that? Should I expect those symptoms to recur later?
5.     What is your rate of serious (Grade 3) adverse events? Do you see urinary strictures? Urinary retention requiring catheterization? Fistulas? Rectal bleeding requiring argon plasma or other interventions?
6.    What is the margin you will treat around the prostate? Is it less on the rectal side?
7.     What is the prescribed dose to the planned target volume?
8.    Do you work off a fused MRI/CT scan?
9.    What machine do you use (e.g., VMAT, CyberKnife, step-and-shoot, Tomotherapy, etc.)?
·      If CyberKnife: Do you use the IRIS or a new multileaf collimator?
·      Do you set a limit on “hot spots”?
10.  Do you use fiducials or Calypso transponders? Do you do transperineal placement of them?
o   What system do you use for inter-fractional tracking?
o   What system do you use for intra-fractional tracking?
11.   In my treatment plan, what do you identify as “organs at risk” and what dose constraints do you put on them?
o   What dose will my penile bulb receive?
12.  How long does each treatment take?
13.  How will I be immobilized during each treatment?
14.  Are there any bowel prep or dietary requirements?
15.  Should I avoid taking antioxidant supplements during treatment?
16.  In your practice, among men who were fully potent, what percent remained fully potent 3-5 years later?
o   Have any men retained some ability to produce semen?
o   What is your opinion of taking Viagra preventatively?
17.  Do you monitor side effects with the EPIC questionnaire?
o   In your practice, what percent of men experience acute urinary side effects?
o   In your practice, what percent of men experience acute rectal side effects?
o   In your practice, what percent of men experience late term urinary side effects?
o   In your practice, what percent of men experience late term rectal side effects?
18.  What kind of PSA pattern should I expect following treatment?
19.  What is the median PSA nadir you are seeing in your practice, and how long does it take to reach that, on the average?
20. In your practice, what percent of men experience biochemical recurrence?
o   What % of those have been local?
o   If there should be a biochemical (PSA) recurrence, what would the next steps be?
o   Have you ever used SBRT, brachy, or cryo for salvage after a local SBRT failure, and was that focal or whole gland?
21.  Are you open to email communications between us?