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Journal of Clinical Oncology, Vol 22, No 4 (February 15), 2004: pp. 589-591 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.174
Hypofractionation Redux?
Department of Radiation Oncology, Eastern Virginia Medical School, Norfolk, VA
A carefully conducted Canadian study by Whelan et al [1], comparing 50 Gy in 25 fractions to 42.5 Gy in 16 fractions over 22 days, is going from an additional treatment option in our thinking on primary breast cancer irradiation straight into practice "South of the Border", as the senior author noted. As of June 2003, the National Surgical Adjuvant Breast and Bowel Project has permitted the Canadian formulation as an acceptable alternative to the more traditional 50 Gy in 25 fractions. An American College of Surgeons Oncology Group protocol has proposed using this as the sole form of radiation in a trial of radiation utilizing only the Canadian schedule, with or without exemestane, which rather establishes it as a new standard of care. This trial is designed for node-negative, age 60 and older patients with invasive cancers The concerns of many, including Sartor and Tepper [3] in an eloquent editorial accompanying the article by Whelan et al, have not slowed down the hypofractionation effort. The Canadian study compared 42.5 Gy in 16 fractions over 22 days to 50 Gy in 25 fractions and found absolutely no difference in cosmesis or survival at 5 years. In the United States, we have no equivalent study; in addition the Canadian study was a multicenter trial of impressive quality, although underpowered compared to many large Intergroup trials that accrue 2,000 to 3,000 patients. The problems with the conclusions of this study are many; however, it is frightening how quickly one very good article out of hundreds can suddenly steamroll over decades of knowledge on the long-term perils of hypofractionation. Radiation oncologists often have a minority representation in cooperative groups, and we have clearly not expressed our own legacy not understood by other disciplines: that when the balance of field size, fraction size, and total dose are grossly altered, the short- and long-term dangers are considerable, especially with respect to normal tissue injuries. Certainly, small focused fields appear to tolerate large fractions per day both in theory and practice; long-term results are not entirely clear. Bony metastases in the gravely ill can be treated quickly, although even these frail patients prefer a more protracted course, and most do not survive long enough to assess chronic morbidity [4]. The ultimate in hypofractionation, stereotactic radiation, has proved useful by tightly limiting field size and maximizing field number, although there are limited data on long-term side effects. The same three determinants of toxicity (field size, fraction size, and total dose) remain unchanged; what has changed is the ability to severely limit the field, with fast fall-off in neighboring tissue. Some have charged that the closure of schools for radiation technologists in Canada and a backlog of patients may have precipitated interest in getting patients through their treatment more quickly. This is unfair criticism. The Canadians, like the Danes, have studied other situations in breast cancer where radiation is not usually used—but should be considered—and have found radiation necessary and have moved to use it. However, some of the limitations of the Canadian hypofractionation trial raise concerns: (1) Five-year recurrence-free survival in both groups was roughly 97%, suggesting that rather low-risk cases were referred and enrolled. In fact, during a time when Canada had few therapists, significant numbers of patients were referred to American centers. Could these have been more difficult or aggressive cases? Approximately 30% of patients deemed initially eligible were not, and a slightly higher percent refused to be randomly assigned. Was this latter group getting subtle hints from their surgeons or reading concern in the eyes of the radiation oncologists? Taken together, 69% of patients deemed initially eligible were not placed on study. (2) The groups seemed well balanced, but only 17.6% of patients had grade 3 tumors, which seems rather low. Alterations in failure rates as a result of technique will likely be more rare in low-risk treatment groups, such as the one that was studied. At least 70% had T1c cancers and only 11% received cytotoxic chemotherapy. American medical oncologists would have been more likely to give cytotoxic chemotherapy to more of these patients. Radiation after doxorubicin can affect cosmesis [5]; the added effect of hypofractionation is unclear, and raises the additional problem of toxicity with hypofractionation when given with doxorubicin, if the technique is exported to the United States. (3) Global cosmetic outcome has thus far been rated good or excellent in both groups (roughly 77%). That appears approximately 10% lower than reported in the United States when a skilled breast surgeon is involved. European Organization for Research and Treatment of Cancer criteria were used. With due respect to cosmesis grading or expectations in other countries, comparing Canadian cosmesis and the expectation of cosmesis in the United States remains problematic, as we have little data on cross-country differences in cosmesis assessment. Again, either surgery and/or irradiation may be issues. The fact remains that cosmesis is the major reason for considering breast preservation. (4) Given the long history of problems with hypofractionation [6,7], 5-year actuarial follow-up does not suffice. Johansson et al [8,9] showed toxicities from hypofractionation as late as 25 years after treatment, with many injuries occurring greater than 10 years after irradiation. (5) In invasive disease, there are two randomized studies (one French [10] and one from the European Organization for Research and Treatment of Cancer [11], together totaling more than 6,000 patients) that show reduced local recurrence in patients that received radiotherapy with an added boost to the tumor bed. The Canadian study has no boost added despite the evidence of its proven utility in long-term control. (6) Even at 2 Gy per day, one can create extremely painful moist desquamation in the inframammary fold and axilla. Patients may be polite, but they report to others having been badly burned, and often spend a week to 10 days in very significant discomfort. Many physicians have switched to 1.8 Gy per day and also try to minimize the inframammary hot spot. Concerns mentioned in the paper about more acute toxicity in 50 Gy in 25 fractions can be and have been overcome in many centers. However, acute toxicities are a poor yardstick when hypofractionation is used—it is the chronic problems that are of greatest import. (7) Although apparently some patients had off-axis calculations, the Canadian paper [1] states that patients had only central axis dosimetry. Breast width had to be 25 cm or less and the patients were required to have received a given dose ± 7%. Since Cobalt, 4MV, and 6MV were the only permitted machines, it suggests that breasts of fairly modest size were enrolled. No mention is made of the routine use of tumor bed clips or computed tomography analysis of the tumor bed; both study arms therefore suffer from the real chance of under-dosing the most critical area using more traditional clinical set ups. Patients with significant pulmonary or cardiovascular disease were excluded. Although this makes sense for a study seeking as many long-term survivors as possible, it does not reflect real life. Cardiopulmonary toxicity of hypofractionation might thus be underestimated when applied to a larger population. (8) The Canadian study by Whelan et al did not define the specific breast sizes being treated or the quality of the surgical cosmesis [1]. Treating a 30 A cup breast may not bring out the same problems seen in a 42 C cup breast. Radiation at any fraction size cannot overcome the over-riding issue of the defects left by surgery and—to a lesser extent—breast size. If a study is to be done to vigorously compare fractionation schemes, at the least, breast size measurements with pre- and postirradiation photographs must be assessed by independent sources to assure comparability. (9) As for the National Surgical Adjuvant Breast and Bowel Project trials, current allowance for hypofractionation raises the risk that it is more likely to be used by intelligent radiation oncologists on small breasted women with modest separations and small hot spots. If so, we predict publication with equivalent cosmetic results in a nonrandomized portion of an American study, but potentially generalized to more full-figured women. At 2.5 Gy per day, a 7% hot spot near the entrance of the beams or in the region of the nipple areolar complex means a daily dose of 2.675 Gy per day. Off-axis doses can easily be 10% to 15% higher—that is, daily doses on the order of 3 Gy per day. Long-term, we may see marked fibrosis in other body regions in palliative cases that survive long enough, even when only 10 fractions are used. Sixteen doses of 3 Gy or more to a portion of the breast seems likely to lead to long-term problems. (10) With hypofractionated irradiation to a large area, including soft tissue, ribs, lung, and heart, we may see very significant differences in breast fibrosis, retraction, rib pain, cardiac problems, lung damage, and nerve damage that do not become clinically apparent for 10 to 20 years [8]. However, with the media involved, a simplistic description can be announced that may result in all patients pushing for faster radiation. Also, insurance companies will be supportive of a treatment economically beneficial to them. It could well take another decade to see that a return to more protracted treatment is necessary, and by then it will be tremendously hard to reverse the desire of carriers to give up on an economic gain. Patients hear sound bites from television that overplays any "new advance in cancer therapy." It can be difficult, for example, to tell a patient with inflammatory cancer that a 5-day implant would not be wise therapy. (11) If patients are on protocol in the United States with breast hypofractionation, the researchers involved must commit to at least a 15-year follow-up, and must allow for the difficult job of accepting referrals of all sizes, shapes, and ages of breasts, with multiple digital pictures of the patients, as there are regional variations in how cosmesis is graded and considerable variation in the cosmesis of surgery alone. To maximize accrual, a principal investigator is sorely tempted to allow flexibility of treatment technique, computer planning, and beam energies. Many of us see patients treated a decade or more ago, and it is not infrequent to feel significant fibrosis and see significant retraction in patients treated at a modest 2 Gy per day with a boost, with the fibrosis often in areas we now know to have high off-axis doses. Given the history of long-term high morbidity of past trials of hypofractionation for curative treatment, it would seem premature to reintroduce this discarded technique without a study involving many nations, and a great deal more technical data, with consideration of all the advances in treatment planning and breast pictures, in addition to limited regional ratings of cosmesis quality. The Canadian study, at the time when it was initiated, was methodologically precise, although the radiation techniques now may seem somewhat outdated. The potential for bias for primarily treating small breasts remains a concern, as do the 69% of patients who were ultimately deemed ineligible or who refused the protocol. Differences in the cosmetics of the surgery are worrisome, as our cosmetic efforts are overwhelmingly related to the sophistication of the lumpectomy. Critical 10- and 15-year data are needed to avoid repetition of an era of practice that harmed patients and earned us a very mixed reputation among other physicians and patients. Convenience now hardly seems worth unexpected and unpleasant complications later. Smaller doses per day have been utilized for sound radiobiologic reasons based on decades of experience. Greater chronic complications with hypofractionation, without large reductions in dose, field size, or extended overall treatment time, have been repeatedly documented for at least 60 years [6,7,12]. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Acknowledgment We would like to acknowledge the expert advice of Dr Beryl McCormick and Dr James D. Cox in the preparation of this article. REFERENCES
1. Whelan T, MacKenzie R, Julian J, et al: Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Nat Cancer Inst 94:1143–1150, 2002 2. Whelan T, as presented at American College of Surgeons Oncology Group, Breast Section, Montreal, Canada, June 5, 2003
3. Sartor CI, Tepper JE: Is less more? Lessons in radiation schedules in breast cancer. J Nat Cancer Inst 94:1114–1115, 2002
4. Shakespeare TP, Lu JJ, Back MF, et al: Patient preference for radiotherapy fractionation schedule in the palliation of painful bone metastasis. J Clin Oncol 21:2156–2162, 2003 5. Ray GR, Fish VJ, Marmor JB, et al: Impact of adjuvant chemotherapy on cosmesis and complications in stages I and II carcinoma of the breast treated by biopsy and radiation therapy. Int J Radiat Oncol Biol Phys 10:837–841, 1984[Medline] 6. Cox JD: Large-dose fractionation (hypofractionation). Cancer 55:2105–2111, 1985 (suppl 9)[CrossRef][Medline] 7. Fletcher GH: Hypofractionation: Lessons from complications. Radiother Oncol 20:10–15, 1991[CrossRef][Medline] 8. Johansson S, Svensson H, Denekamp J: Timescale of evolution of late radiation injury after postoperative radiotherapy of breast cancer patients. Int J Radiat Oncol Biol Phys 48:745–750, 2000[CrossRef][Medline] 9. Johansson S, Lofroth PO, Denekamp J: Left sided vocal cord paralysis: A newly recognized late complication of mediastinal irradiation. Radiother Oncol 58:287–294, 2001[CrossRef][Medline]
10. Romestaing P, Lehingue Y, Carrie C, et al: Role of a 10 Gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in Lyon, France. J Clin Oncol 15:963–968, 1997
11. Bartelink H, Horiot JC, Poortmans P, et al: Recurrence rates after treatment of the breast with standard radiotherapy with or without additional radiation. N Engl J Med 345:1378–1387, 2001 12. Ellis F: Tolerance dosage in radiotherapy with 200 kV X RAYS. Br J Radiol 15:348–350, 1942 Related Correspondence
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2 cm; it is not clear at this point whether all breast sizes and histologies would be included [
