Original Articles. Tomo Osako 1,2, Masahiko Oguchi 1,2, Madoka Kumada 1,2, Keiko Nemoto 1,2, Takuji Iwase 2 and Takashi Yamashita 1,2 INTRODUCTION

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1 Jpn J Clin Oncol 2008;38(5) doi: /jjco/hyn030 Original Articles Acute Radiation Dermatitis and Pneumonitis in Japanese Breast Cancer Patients with Whole Breast Hypofractionated Radiotherapy Compared to Conventional Radiotherapy Tomo Osako 1,2, Masahiko Oguchi 1,2, Madoka Kumada 1,2, Keiko Nemoto 1,2, Takuji Iwase 2 and Takashi Yamashita 1,2 1 Department of Radiation Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo and 2 Department of Breast Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Received January 21, 2008; accepted March 21, 2008; published online April 16, 2008 Objective: To evaluate acute morbidity, radiation dermatitis and pneumonitis, of Japanese patients treated with whole breast hypofractionated radiotherapy (RT) after breast-conserving surgery (BCS), compared to conventional RT. Methods: Japanese patients who received whole breast RT after BCS between October 2003 and September 2006 were retrospectively reviewed. Patients who had selected the conventional or hypofractionated schedule received whole breast irradiation of 50 Gy in 25 fractions plus boost or 40 Gy in 16 fractions plus boost. Radiation dermatitis and symptomatic pneumonitis were graded according to the Common Terminology Criteria for Adverse Events version 3.0. Results: Of 443 consecutive patients, 377 (85%) received the conventional schedule and 66 (15%) received the hypofractionated schedule. Of patients treated with the conventional schedule, Grade 0, 1, 2 and 3 radiation dermatitis were observed in 16 (4%), 278 (74%), 77 (20%) and 6 (2%), respectively. Of patients treated with the hypofractionated schedule, Grade 0, 1, 2 and 3 dermatitis were observed in 11 (17%), 49 (74%), 5 (8%) and 1 (1%), respectively. Grade 2 3 dermatitis by the hypofractionated schedule (9%) was observed less frequently than that by the conventional schedule (22%) (chi-square test; P ¼ 0.016). Moreover, of patients treated with the conventional schedule, 4 (1%) had Grade 2 radiation pneumonitis. No patient treated with the hypofractionated schedule had symptomatic pneumonitis. Conclusions: Radiation dermatitis and pneumonitis in Japanese patients treated with the hypofractionated schedule is acceptable. Especially, radiation dermatitis by the hypofractionated schedule is milder than that by the conventional schedule. Key words: breast cancer breast-conserving surgery whole breast hypofractionated radiotherapy radiation dermatitis radiation pneumonitis INTRODUCTION Breast-conserving surgery (BCS) followed by radiotherapy (RT) has become accepted as an appropriate treatment for women with early breast cancer (1). A meta-analysis had For reprints and all correspondence: Tomo Osako, Department of Pathology, The Cancer Institute of Japanese Foundation for Cancer Research, , Ariake, Koto-ku, Tokyo , Japan. tomo.osako@jfcr.or.jp demonstrated that RT reduced the 5-year local recurrence and 15-year breast cancer and overall mortality in post-bcs patients (2). Furthermore, two randomized trials showed that additional boost radiation to the tumor bed improved local control rates (3,4). There is no uniform agreement on which RT schedule should be used; however, the role of breast RT after BCS is widely accepted. Several different RT schedules were used # The Author (2008). Published by Oxford University Press. All rights reserved.

2 Jpn J Clin Oncol 2008;38(5) 335 in randomized trials that established the efficacy of postoperative breast RT after BCS. The National Surgical Adjuvant Breast and Bowel Project B06 trial evaluated 50 Gy in 25 fractions to the whole breast (1). The Swedish trial evaluated 54 Gy in 27 fractions (5). The Ontario Clinical Oncology Group trial evaluated 40 Gy in 16 fractions plus boost radiation (6). The Milan trial evaluated 50 Gy in 25 fractions plus boost (7). A schedule commonly used today in Japanese clinical practice is 50 Gy in 25 fractions to the whole breast plus boost radiation to the tumor bed. In Canada and the UK, the hypofractionated schedule for breast RT have been applied in clinical practice. This approach is based on the radio-biological linear quadratic model that is a larger dose per fraction given over a shorter period is just as effective as the conventional schedule (8). The hypofractionated schedules have ranged from 39 to 44 Gy in fractions with fraction size Gy over 3 5 weeks (9 16). Most retrospective studies and randomized trials have reported that acceptable local control rates and cosmesis (9 16). Moreover, the hypofractionated schedule has significant implications for patient convenience and resource utilization. However, the hypofractionated schedule had been studied in the Western countries, there are not enough data about that for Japanese patients. Therefore, in order to confirm the feasibility of the hypofractionated RT for Japanese breast cancer patients, we retrospectively evaluated acute morbidity, radiation dermatitis and pneumonitis, of the post-bcs patients treated with the hypofractionated compared to that with the conventional RT. PATIENTS AND METHODS STUDY PATIENTS Japanese patients with breast cancer treated with BCS followed by whole breast RT were retrospectively reviewed in the present study. The eligibility criteria of the present study were as follows: (i) pathologically proven primary breast carcinoma, (ii) BCS was performed at the Cancer Institute Hospital, Tokyo, (iii) RT was started between October 2003 and September 2006 and (iv) boost radiation to the tumor bed was given by electrons. The exclusion criteria were (i) synchronous bilateral breast RT and (ii) concurrent administration of chemotherapy and RT. All the post-bcs patients were given enough information of both the conventional and hypofractionated schedules of whole breast RT. Especially, we told them that the results of the Canadian randomized trail reported by Whelan (12); the cosmetic outcomes at five years were same between the two schedules, but longer term cosmetic outcomes than 5-years of both arms were not available at that time. Then, the post-bcs patients decided by their preference which they hope to receive. Patients background, concurrent endocrine therapy, prior chemotherapy and the used energy of the X-rays, of the two groups were compared by chi-square test. A value of P, 0.05 was considered significant. RT REGIMENS Patients who had selected the conventional schedule received the whole breast RT of 50 Gy in 25 fractions with fraction size 2 Gy over 35 days. After the whole breast RT, they received boost radiation of Gy with fraction size 2 Gy by electron beams. Regarding the regimen of the hypofractionated schedule, we referred to the clinical trial in the National Cancer Center Hospital, Tokyo (17), in which they used whole breast RT of 40 Gy in 16 fractions with fraction size 2.5 Gy plus boost radiation to the tumor bed of 10 Gy in four fractions with fraction size 2.5 Gy by electrons. In the present study, patients who had selected the hypofractionated schedule received whole breast RT of 40 Gy in 16 fractions with fraction size 2.5 Gy over 22 days. After the whole breast RT, they received boost radiation of Gy with fraction size 2.5 Gy by electrons. Patients were treated in the supine position with the ipsilateral arm raised above the shoulder and immobilized. The target volume, whole breast, was irradiated by the two opposing tangential photon fields, which were set up with simulators and/or RT computed tomography planning system (Eclipse, Varian Medical Systems, Palo Alto, CA and RenderPlan, Elekta Oncology Systems, Inc, Norcross, GA). The medial border was located at the mid-sternal line. The lateral border was at the posterior axillary line to include the breast with 1- to 2-cm margin and to limit the amount of lung at the central plane to less than 2.5 cm. The superior border was located at a horizontal line drawn through the super-sternal notch. The inferior border was located at a horizontal line 1 2 cm below the inframammary fold. The half beam technique has been applied for every patients treated with whole breast radiation. The median depth of the radiation ports, namely a half of chest wall separation, was 20 cm (range cm). Appropriate physical wedge compensations ( ) were installed in all the patients to ensure a uniform dose distribution throughout the target volume. The dose was prescribed at a point midway along the central plane, two-thirds of the distance from the skin to the base of tangent fields. Portal films were obtained in the treatment position with a therapeutic beam to confirm adequate coverage. Patients were treated with 4- to 6-MV X-rays. Boost radiation was added to the tumor bed by 4 11 MeV electron beams. EVALUATION AND ANALYSIS OF RADIATION DERMATITIS Radiation dermatitis by worst was graded according to the Common Terminology Criteria for Adverse Events version

3 336 Acute morbidity of hypofractionated breast RT 3.0 by the investigators, with a visual inspection of the breast at baseline, every week during RT, and 3 months after the end of RT. In the present study, Grade 0 was defined as no adverse event observed. We compared Grade 0 1 events with Grade 2 3 events of the two schedules by chi-square test. A value of P, 0.05 was considered significant. EVALUATION AND ANALYSIS OF RADIATION PNEUMONITIS Radiation pneumonitis was also graded according to the Common Terminology Criteria for Adverse Events version 3.0 by the investigators, with medical examination and chest X-ray film at three months after the end of RT. When symptomatic radiation pneumonitis was suspected, computer tomography was performed to confirm the diagnosis. In the present study, asymptomatic pneumonitis (Grade 1) was not evaluated. We compared symptomatic radiation pneumonitis of the two schedules by chi-square test. A value of P, 0.05 was considered significant. RESULTS PATIENT CHARACTERISTIC A total of 443 consecutive patients were assessed in the present study. All the patients were Japanese women. There was no patient with collagen vascular disease. Of the 433 patients, 377 (85%) selected RT with the conventional schedule and 66 (15%) selected RT with the hypofractionated schedule. The demographic characteristics of the present study population are present in Table 1. There are no statistical difference between the two groups regarding concurrent endocrine therapy (chi-square test; P ¼ 0.39), prior chemotherapy (P ¼ 0.51), and the used energy of the X-rays (P ¼ 0.21). Furthermore, there was no obvious difference between other patients characteristics of the two groups. Table 1. Patient characteristics Hypofractionated Conventional No. % No. % No. of patients Mean age (range) 55.5 (32 81) 52.2 (19 79) T classification Tis T T T T Stage Stage Stage I Stage II Stage III Concurrent endocrine therapy yes no Prior chemotherapy yes no Used energy 4 MV MV Boost radiation 10 Gy/5 fr Gy/6 fr Gy/8 fr Gy/4 fr Gy/5 fr Gy/6 fr 1 2 RADIATION DERMATITIS Of 377 patients treated with the conventional RT, 16 (4%) did not have any radiation dermatitis (Grade 0). Moreover, 278(74%),77(20%)and6(2%)hadGrade1,2and3radiation dermatitis, respectively (Table 2). On the other hand, of 66 patients treated with the hypofractionated RT, 11 (17%) did not have any radiation dermatitis (Grade 0). Furthermore, 49 (74%), 5 (8%) and 1 (1%) had Grade 1, 2 and 3 radiation dermatitis, respectively (Table 2). Compared to the proportion of Grade 2 3 radiation dermatitis by the hypofractionated schedule with that by the conventional schedule, radiation dermatitis by the hypofractionated schedule (9%) was significantly milder than that by the conventional schedule (22%) (chi-square test; P ¼ 0.016). fr, fraction. Table 2. Grades of radiation dermatitis Grade Hypofractionated Conventional No. % No. %

4 Jpn J Clin Oncol 2008;38(5) 337 RADIATION PNEUMONITIS Of 377 patients treated with the conventional schedule, 4 (1%) had Grade 2 radiation pneumonitis. Pneumonitis graded 3 or more was not observed. On the other hand, no patient treated with the hypofractionated schedule had symptomatic radiation pneumonitis. The difference was not significant (chi-square test; P ¼ 0.89). The four patients started to get symptoms related to radiation pneumonitis 2 5 months after the end of the RT. All the four patients recovered form radiation pneumonitis without steroid therapy. DISCUSSION The present retrospective study showed that acute dermatitis by the hypofractionated RT was milder than that by the conventional RT in Japanese patients. This result suggests that the hypofractionated RT may contribute to the patients quality of life (QOL) from the viewpoint of acute radiation dermatitis, in addition to reducing the burden of the way to and from hospitals. Several studies had shown that breast RT had physical and psychological effects on the patients QOL (18 24). Acute radiation dermatitis is one of the important physical factors that effect on the patients QOL during and shortly after the treatment (18,19). Especially, high RT dosage and long schedule was predictor of low QOL at the completion of RT (19) and acute skin toxicity was increased in high RT dosage and intensive schedule (25). However, cosmetic outcome had been often assessed in most studies about hypofractionated breast RT (9,10,12 16), acute dermatitis has not been assessed in spite of the possible impact on patients QOL. Two Japanese retrospective studies which compared acute dermatitis of hypofractionated whole breast RT (44 Gy in 16 fractions) with that of conventional RT (50 Gy in 25 fractions) (26,27). One of the studies showed that acute reaction rates were not higher in the hypofractionated schedule than the conventional one (26). Proportion of Grade 2 radiation dermatitis and use of steroid ointment in the hypofractionated schedule was about half of the conventional one (6 versus 12%, 37 versus 71%) (26). The other showed that there was no significant difference between subjective sequelae of the two groups (27). Another study using intensity modulated radiation therapy for breast showed Grade 2 acute skin toxicity was lower on the hypofractionated schedule compared to the standard fractionation (23 versus 70%) (28). It is unclear why the acute skin toxicity should be lower on the hypofractionated schedule. One of the reasons is that biologically effective dose of acute reaction of the hypofractionated schedule calculated by linear quadratic model (8) was smaller than that of the conventional schedule (29). But, the difference was small in the present and the former Japanese studies. Moreover, it is difficult to compare biologically effective dose of the two groups in the present study, because the boost radiation was added to the both group. Radiation pneumonitis by the hypofractionated RT is not inferior to that by the conventional RT. The former Japanese retrospective study (26) had shown that radiation pneumonitis by the hypofractionated RT was milder than that by the conventional RT (3 versus 11%). In the present study, although 1% (4 of 377) of the patients treated with the conventional RT suffered from symptomatic radiation pneumonitis, none of the patients treated with the hypofractionated RT suffered. In conclusion, acute morbidity, radiation dermatitis and pneumonitis, of post-bcs Japanese patients treated with the hypofractionated RT is acceptable. Especially, acute dermatitis by the hypofractionated RT is milder than that by the conventional RT. However, our data have some shortcomings, mainly based on the incomplete retrospective data. 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