No need to endure 38 to 44 treatments with IMRT anymore

There have been several hypofractionation trials maturing in the last couple of years. With minor exceptions, they all tell the same story: external beam radiation therapy (EBRT) can be completed in less time without loss of efficacy or increase in toxicity. Hypofractionation means completing EBRT in fewer treatments or fractions using higher doses per fraction.

Catton et al. now report the 5-year outcomes of a multi-institutional, multi-national (27 centers in Canada, Australia and France), randomized clinical trial (called the “PROFIT” trial) among 1,206 intermediate-risk patients treated from 2006 to 2011. All patients received radiation doses now considered curative:

  • 78 Gy in 39 fractions (conventional fractionation — CFN) or
  • 60 Gy in 20 fractions (hypofractionation — HFN).

The doses are biologically equivalent for cancer control, no ADT was allowed.

After a median follow-up of 6.0 years:

  • 5-year freedom from biochemical or clinical failure was 85 percent in both groups.
  • Acute urinary toxicity was
    • Grade 2: 27 percent in both groups
    • Grade 3: 4 percent in both groups
  • Acute rectal toxicity was
    • Grade 2: 16 percent for HFN and 10% for CFN
    • Grade 3: < 1 percent in both groups
  • Late-term urinary toxicity was
    • Grade 2: 20 percent for HFN and 19 percent for CFN
    • Grade 3 and higher, 2 percent for HFN and 3 percent for CFN
  • Late-term rectal toxicity, grade 2: 7% for HFN, 11% for CFN*; grade 3+: 1% for HFN, 3% for CFN

Where there are asterisks (*) in the above listing of results, the asterisk means that the difference between the trial arms was statistically significant, but not meaningful.

The table below summarizes the key oncological (5-year biochemical progression-free survival) and late-term toxicity outcomes of the various hypofractionation trials:

References: 1. The PROFIT trial (Catton et al.). 2. The Fox Chase trial (Pollack et al.). 3. The CHHiP trial (Dearnaley et al.). 4. The M. D. Anderson trial (Hoffmann et al.). 5. The RTOG 0415 trial (Lee et al.). 6. The HYPRO trial (Incrocci et al.). 7. The HYPRO trial (Aluwini et al.). 8. The Cleveland Clinic trial (Kupelian et al.).

Hypofractionation has demonstrated equal efficacy and side effects compared to conventional fractionation. However, hypofractionation requires greater care on the part of the radiation oncologist. He must use advanced image guidance with placement of fiducials or radio transponders and localization with cone beam CT scans, set tighter margins, lower dose constraints for organs at risk, assure adequate bladder filling and lack of bowel distension at each treatment, use fused MRI/CT images if possible, and have very rapid linear accelerators (LINACs) to minimize intrafractional motion.

With this much cumulative level 1 evidence, it is hard to justify the use of conventionally fractionated EBRT anymore. Patients should not have to endure 38 or more treatments, and pay the extra cost of that, even if insurance or Medicare is willing to pay. Patients should shop for radiation oncologists who have experience with hypofractionation, or preferably, with extreme hypofractionation (SBRT).

8 Responses

  1. Thanks, and metformin as an emerging major factor in radiation success

    Thank you for this excellent summary and overview! Good news here!

    Here’s a bit of a tangent, but possibly very important to avoidance of recurrence with radiation: use of metformin, the diabetes drug that has been in use for decades. I have not seen discussion of this beyond certain doctors I consider leading experts in prostate cancer. While the article relays very important, practice-changing news, we need to keep in mind the overall environment that also affects success with radiation. As a radiation veteran at the 4-year point, I find the 5-year success rates reported here to be highly encouraging. I’m thinking they would be improved even further, and extended for more years, with metformin.

    The key paper is by Spratt, Zelefsky and colleagues at Memorial Sloan-Kettering Cancer Center in New York City, and a free link to the complete paper is available. Of course Dr. Zelefsky is well known to many of us for his great trailblazing work to deliver safe and effective modern radiation. The images show what strikes me as a spectacular difference in recurrence-free survival, distant metastasis-free survival, and prostate cancer-specific mortality at 10 years (and throughout follow-up) for those taking metformin compared with diabetics who were not on metformin, but also better performance against non-diabetics taking no metformin). In fact, Figure 3 shows that the diabetic/metformin group had, at just over 10 years of follow-up, less than a third of the mortality rate of the non-diabetic group! Here’s another blockbuster statement from the abstract: “Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83-119.89]; p=0.01).” Jeez — 15 to 1 in favor of metformin, which had an outside post position and a lousy jockey as all the metformin patients were diabetics!

    I’m going to talk to my oncologist at my upcoming consultation to try to add metformin to my post-radiation safety net against recurrence.

    Any thoughts?

    PS: My labs show I am clearly not diabetic.

  2. Any thoughts? Yes Jim. This is a retrospective analysis and therefore, at best, hypothesis generating. There is almost certainly an issue with selection bias in a study like this.

    Are these data interesting? Yes. Of course they are. Are they “practice changing”? No. They aren’t. We are going to need to see data from prospective trials before conclusions like that can be drawn.

    Metformin is not exactly a benign drug. Commonly reported side effects of metformin include lactic acidosis, diarrhea, nausea and vomiting (separately and in combination), and flatulence.

  3. Thanks very much for your comments. It’s interesting to view practice-changing research, as relayed in your article, with attention-grabbing research that, as you note, clearly lacks practice-changing caliber evidence. Still, for patients having to make decisions without such evidence, we have to either do nothing and wait or make our decision making based on lesser quality evidence.

    Your words on the side effects read so like the statement made by my regular oncologist when I indicated an interest in metformin several years ago, though he did not spell out the side effects. He thought it was a great drug, and he had been on it himself for diabetes for many years, but he clearly did not consider it benign. I ended up not taking the drug. I researched the side effects on the FDA site and found that the two major concerns are diarrhea (9.6% – 7% higher than placebo), and nausea/vomiting (6.5% – 5% higher than placebo), with no other side effects that exceeded placebo affecting more than 5% of those in the trial. It was also clear that dose mattered: in another trial that involved higher doses than the final approved dose, side effects were much more prominent, and that observation is related to the following tactic to have the benefit but avoid the side effects..

    Dr. Charles “Snuffy” Myers is now one of the doctors strongly recommending this drug for prostate cancer patients, but he has an interesting approach to addressing the side effects. Instead of starting patients on the accepted full dose of 2,000 mg daily, he has them start with one 500 mg pill at breakfast for 2 weeks. If well tolerated, they add a 500 mg pill at dinner and stay at that level for 2 weeks. If still well tolerated, they add a second 500 mg pill at breakfast for 2 weeks, for a total of three pills and 1,500 mg. If that dose is well tolerated they move to the final full dose of two 500 mg pills at breakfast and two 500 mg pills at dinner. A patient who develops one or more side effects at any of the levels moves back to the last level that was well tolerated. His clinical observation is that patients who stop at a lower dose because of the side effects appear to get the full benefit for cancer at the lower dose.

  4. Endorsement of mild hypofractionation by a leading radiation oncologist – Howard Sandler, MD

    Dr. Sandler is well known in the prostate cancer radiation community as a physician and researcher. He was at the University of Michigan for many years before moving to Cedars-Sinai in Los Angeles a few years ago.

    In his talk on “Early Stage Chemo and Breakthroughs in Radiation Therapy” at the 2016 Conference on Prostate Cancer (PCRI/US Too) in Los Angeles last September, he stated that mild hypofractionation, by which he meant 20 to 28 fractions, was tested, proven, and “ready for prime time.” That’s the short version. He spent eight and a half minutes on the subject, reviewing key trials with lots of graphics (Disc 1: 2:11:33-2:20).

    He does not judge that the case for 5 fractions, which he referred to as “extreme hypofractionation,” had yet been proven, though in his own practice he considers that approach acceptable for low-risk cases. He prefers moderate hypofractionation (28 doses) for intermediate-risk cases, and he likes standard fractionation for high risk, with docetaxel considered; I assume the docetaxel is in conjunction with ADT, which he had reviewed earlier in the talk.

  5. Jim,

    Old news gets outdated quickly. Dr Sandler has changed his mind since then. He now offers SBRT for both low- and intermediate-risk cases at Cedars-Sinai. Actually, he brought in Zach Zumsteg, formerly from MSKCC, to handle their SBRT.

  6. Hi Allen. Was there any research that increased his confidence in the SBRT approach for intermediate cases? o you know what led him to be more comfortable with SBRT for these men? I’m guessing it was adding someone to staff who was very comfortable doing this, as your post suggests. I see that Dr. Zumsteg has an impressive publication record.

  7. Jim,

    In case you haven’t followed it, there are dozens of studies of SBRT including a 9-year follow-up by Dr. Katz. Dr. Sandler is certainly a research maven who is well aware of it all. I doubt that there is one particular study that made the difference.

  8. Thanks Allen. The emergence of SBRT is certainly a most welcome development.

    Our support and education Us Too chapter will get an update on local radiation later this year, and I expect there will be further evolution toward use of SBRT for a wider range of cases.

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