January, 2015

Situational Biology

By Michael J. Katin, MD

The date was December 11, 2014. War was raging in Ukraine, Syria, Iraq, Nigeria, South Sudan, Yemen, and Afghanistan, among other locations. The Ebola epidemic had not gone away but thanks to a determined and calculated effort, based on modern and validated scientific principles, the chance of a pandemic had been averted. Tens of thousands of Central American children were entering the United States and being distributed around the country. Kris and Bruce Jenner were in the process of getting divorced. In the midst of all this activity, Brian Williams chose to come forth with the blockbuster revelation of the decade, undoubtedly to lead to the Edward R. Murrow Award or at least a second Cronkite Award and possibly a Nobel Prize (Peace, Medicine, or Economics, or all three?) : that many American women "got more radiation than they need" for breast cancer, with the headline "Some Breast Cancer Patients Receive Unnecessary Radiation."

It may not be pertinent that Mr. Williams, hipster and music connoisseur, has a history of accuracy that has not been totally flawless, especially when it comes to medical topics (for example, when PARP inhibitors were acclaimed as a major breakthrough in cancer treatment ), but it could be appropriate to call attention to several minor adjustments that could be made in his report. He was solemnly introducing a segment by Dr. Nancy Snyderman calling attention to proceedings of the San Antonio Breast Conference related to an article in the Journal of the American Medical Association which was published December 17, 2014, from the modestly-named Perelman Center for Advanced Medicine at the University of Pennsylvania (sorry, that was the University of Pennsylvania Perelman School of Medicine) addressing the concern about the relatively low use of hypofractionated whole breast irradiation. This review concluded that 34.5 per cent of patients with early stage breast cancer fulfilled all the criteria for hypofractionated treatment, and 21.2% more of them could more liberally be considered candidates for consideration of this approach. The JAMA publication summarized that the hypofractionated-endorsed criteria accepted by ASTRO in the 2011 evidence-based guideline were "age 50 years or older, pathologic stage T1 or T2N0, with no prior chemotherapy, and with radiation dose heterogeneity higher or lower than 7% of the prescription dose. " We in radiation oncology are accustomed to having non-radiation oncologists skip over details of dose distribution, total dose, treatment volume, and fractionation. . In fact, the criterion in the ASTRO publication is "homogeneity within plus or minus 7% in the central axis plane." Heterogeneity, homogeneity, whatever. Not to quibble. The authors of the JAMA article then use the "hypofractionation-permitted" classification to include any patients who "did not meet criteria for the first group" for at least 1 of the following reasons: age younger than 50 years, prior chemotherapy, or axillary lymph node involvement." I think we can safely assume the dose distribution calculations were not reviewed by the authors of the JAMA article, therefore seriously calling into question the validity of the "hypofractionation-permitted" group. In that case, wouldn't just about everyone have been "permitted?"

The Brian Williams report was delivered as which this were a major "expose," shining light on this inhuman abuse of women by the medical profession, exceeding the magnitude of evil of Watergate, ENRON, Whitewatergate, Iran-Contra, PED use, and Teapot Dome. Mr. Williams did not, to the best of my knowledge, come back with a correction that the point was not that women got "more radiation than they need" but rather that the number of treatments to get the same effective dose was in question We can only assume this clarification will be forthcoming. We then need to explore the nature of the controversy and what should be the resolution.

The disagreement about optimal treatment techniques can be attributed to any of three different reasons: habit, economics, and biology.

  1. Habit. As with all things in humankind, old habits are difficult to overcome. It took years for the general medical community to accept that conservative therapy and radiation therapy were equivalent to modified radical mastectomy, and prior to that, for modified radical mastectomy to be considered equivalent to radical mastectomy! Ironically , it was the NSABP series of studies that led many radiation oncologists to switch their fractionation preference to match that of the NSABP protocols. Many centers in Canada had actually stopped hypofractionation in 19 as a result of the NSABP data. Is it now necessary to retrain radiation oncologists to accept a new standard?
  2. Economics. The JAMA article assessed 52,777 cases between 2008 and 2013 and 37,134 were excluded because of factors such as the patients' having undergone mastectomy or brachytherapy, including 1,367 because the radiation therapy treatment was "unconfirmed by claims." 27,331 patients, more than HALF of the total, were excluded because of "No continuous medical coverage within 24 mo before diagnosis or < 90 d of medical coverage after radiation start recruited." It's quite remarkable that more than half the total number of patients treated for breast cancer didn't have adequate or continuous medical insurance, and it would be fascinating to know if they were treated differently than those who did. One can only suppose that there will be another article upcoming for Brian Williams to showcase. It would also seem to thoroughly confuse analysis of true practice patterns. Regardless, evaluation of the remaining much smaller number of patients. 15.643, only 29.6% of the original number, was performed. It was concluded that 8,924 would be considered "hypofractionation-endorsed" and 6,719 "hypofractionation-permitted." Of the "hypofractionation-endorsed" group, 3,029 were treated in free-standing facilities and 5,895 in the outpatient hospital setting. 17.5% of those treated in freestanding centers received hypofractionated therapy, and 21.6% in outpatient hospital centers received hypofractionated therapy. Of the 6,719 patients considered to be in the "hypofractionation-permitted" group, 11.7% of the 2,338 treated in freestanding centers received hypofractionation, and 13.2% of the 4,381 treated in the outpatient hospital setting received hypofractionation.
    First question: Do these differences in percentage warrant a major segment on NBC Nightly News?
    Second question: Are freestanding units more likely to want to give patients a greater number of fractions to make more money? Or could it be that hospital-based practices, with most of the staff on salary, would want to try to get away with a smaller number of fractions to get the patients' treatments finished faster and therefore generate less work?
    Why is the percentage of patients treated with hypofractionation in the hospital-based environment so very low? Why isn't it at least 70 or 80 per cent? The authors show that the percentage treated with hypofractionation has increased from 2008 to 2013, but even in 2013 the percentages were 34.5% for hypofractionation-endorsed cases and 21.2% for hypofractionation-permitted cases. In the discussion there is attention called to the fact that in 2008 in Ontario 71% received hypofractionated whole breast irradiation. Does that make Ontario correct? If hospital-based practices are supposed to represent the cutting -edge of academic excellence, why is the percentage so low even in 2013? Perhaps there is another reason.
  3. Biology. Radiobiology is an essential part of radiation oncology practice, at least until radiation oncologists get past that section on the radiation oncology boards. Certainly the earliest practitioners had to develop radiobiology principles by observing tumor (and patient) reaction to radiation. We who came afterward have been programmed to be very wary of causing normal tissue damage and techniques were developed to keep this to a minimum (whereas in chemotherapy these effects are considered obligatory and efforts were made to develop medications and other interventions to address collateral damage). It doesn't help that any problem a patient may have for the rest of his or her life will be blamed on radiation therapy. We were taught about the risk of exceeding normal tissue tolerance and about problems with short-term and, even more worrisome, long-term tissue damage from radiation. It was expected that a bigger doses per fraction were more detrimental to normal tissue than necessary and protracting the treatment schedule would still result in damage to cancer cells while allowing normal tissue recovery. The "Four R's" of radiation biology -- repair, redistribution, repopulation, and reoxygenation -- have been re-explored frequently, since there are few scientific axioms that don't go through revision, but perhaps it's necessary to find out if these principles are to be reinterpreted or even discarded. It was not long ago that hyperfractionation was thought to be the wave of the future. Amazing how things can change.

It may very well be that we have been too cautious and that treating the breast with higher doses in shorter treatment courses may be adequately safe, although this still doesn't explain why the recommendation is for this to be used in women 50 years of age or older rather than everyone (are they concerned that the extra years of life could be those in which late-term effects of irradiation are seen?). The average 60-year-old woman in the United States has a life expectancy of 24.34 years, which is still a long time for something to develop. If reducing the number of treatments from 25-28 down to 16 (plus boost) is worth it to save two weeks of a person's time and not just to save money, that might be an individual's decision.

Just one more observation: when we live in constant uncertainty regarding so many things -- what it takes to get into heaven, how to make the IRS happy -- why should the individual specialists always have to bear the burden of being responsible for what the best type of treatment should be? It puts us at risk of being accused of being mercenary versus causing patients problems in the long-term because we're trying to be politically correct. ASTRO has published a guideline rather than a decree, that states "widespread adoption of HF-WBI for appropriately selected patients has the potential to enhance the convenience of treatment and lower the costs of WBI" but also that "this guidelines should not be interpreted to prohibit or oppose the use of HF-WBI or patients not meeting all the criteria listed in Table 1." How definitive is this? Convenience is a relative term, and cost should not be the main criterion as to whether one treatment method is optimal. If this technique is truly the best, let CMS, ASTRO, ACR, and everybody else ban the use of conventional fractionation and take the potential liability away from us. Not that this will ever happen.

Ironically, the very same issue of JAMA has articles questioning the benefit of aspirin for prevention of cardiovascular events, the "harm" of breast cancer screening, and that high glycemic indices of dietary carbohydrates may actually not make a difference in factors associated with cardiovascular health. Is there anything that's not being re-visited?

Emanuel Countdown: Especially since Dr. Emanuel was an author on the JAMA paper, this month's column initiates the Emanuel Countdown, honoring his article "Why I Hope to Die at 75 " as well as honoring the December, 2014, column. Dr. Emanuel's biographies list his birth year as 1957 but, interestingly, do not list a birth date. Giving him every benefit of the doubt, he will have his 75th birthday no later than December 31, 2032. Including January 1, 2015, this leaves 6,575 days to his goal.