NEGATIVE IMPACT OF HEAT EXPOSURE ON COSMESIS AFTER CONSERVATIVE TREATMENT FOR BREAST CANCER

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1 Tumori, 93: , 2007 NEGATIVE IMPACT OF HEAT EXPOSURE ON COSMESIS AFTER CONSERVATIVE TREATMENT FOR BREAST CANCER Eui Kyu Chie 1, Kyubo Kim 1, Dong-Young Noh 2, Kuk Jin Choe 2, Tae-You Kim 3, Seok-Ah Im 3, Yung-Jue Bang 3, and Sung W Ha 1,4 Departments of 1 Radiation Oncology, 2 Surgery, and 3 Internal Medicine, and 4 Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea Key words: breast cancer, cosmesis, heat, radiotherapy. Aim and background: To identify the factors influencing cosmesis after conservative treatment in breast cancer. Methods: Retrospective analysis was done on 424 patients who underwent postoperative radiotherapy after conservative surgery for breast cancer from February 1992 to January Most of the patients underwent quadrantectomy. Whole breast irradiation up to 50.4 Gy was delivered in 28 fractions followed by a 10 Gy boost in 5 fractions to the tumor bed. Regional lymph node irradiation was administered if indicated. Breast cosmesis was scored in 4 tiers. Breast symmetry was analyzed by the relative distance from the sternal notch to the nipple, using photos taken prior to radiotherapy and 2 years after its completion. Median follow-up was 64 months. Results: Breast cosmesis was excellent in 15%, good in 63%, fair in 19%, and poor in 3% of the patients. In multivariate analysis, tumors >2 cm (P = ), lower quadrant location (P = ), lymph node irradiation (P = ), and heat exposure (P = ) were related to poor cosmesis. The cosmesis score after radiotherapy compared to the pre-radiotherapy score was deteriorated in patients who had undergone lymph node irradiation (P <0.0001) and heat exposure (P = ). Breast symmetry was worse for patients who had tumors >2 cm (P <0.0001), upper quadrant tumor location (P <0.0001), chemotherapy in combination with radiotherapy (P = ), lymph node irradiation (P = ) and heat exposure (P = ). Changes in symmetry by radiotherapy were greater for lymph node-irradiated patients (P <0.0001). Conclusions: With larger tumor size, lymph node irradiation, and chemotherapy in combination with radiotherapy, heat exposure was found to have a negative impact on cosmesis in patients undergoing conservative treatment for breast cancer. Patients should therefore be advised to avoid heat exposure after breast irradiation. Introduction Breast conserving treatment including surgery, radiotherapy (RT), and/or chemotherapy and/or hormonal therapy is becoming more and more popular. Breast conserving treatment achieves local control and overall survival comparable to mastectomy 1-4 while providing cosmetic and psychological satisfaction to patients 5. Cosmetic outcome is an important endpoint of breast conserving treatment and is influenced by many patient and tumor characteristics as well as treatment-related issues. Most breast conserving treatment series evaluated cosmetic outcome at latest follow-up after the completion of scheduled treatment. Thus, influence of patient-, tumor-, and treatment-related factors, and possible post-treatment factors are intermingled and not separately interpreted. As a post-treatment factor, exposure to heat after RT is known to have an adverse effect on irradiated skin and connective tissue 6,7, and has not yet been evaluated in regard to the possible effect on cosmesis after breast conserving treatment. In this study, the role of exposure to heat after RT as well as other established parameters influencing cosmesis was investigated. Materials and methods Study population Between February 1992 and January 2002, 424 patients underwent RT after breast conserving surgery for newly diagnosed invasive cancer of the breast. The median age was 43 years (range, 24-70). Except for one patient with an ECOG score of 2, all patients had ECOG scores of 0 or 1. The most frequent histological subtype was infiltrating ductal carcinoma with 367 patients (86.6%). Three hundred and two patients (71.2%) had T1, and 122 patients (28.8%) had T2 disease. N stage was retrospectively restaged according to the American Joint Committee for Cancer Staging, sixth edition 8. Three hundred and seventeen patients (74.8%) presented without nodal involvement, whereas 79 patients (18.6%) had N1, 21 patients (5.0%) had N2, and 7 patients (1.7%) had N3 disease. Overall, there were 239 patients (56.4%) with stage I, 130 patients (30.7%) with stage IIA, 27 patients (6.4%) with stage IIB, 21 patients (5.0%) with stage IIIA, and 7 patients (1.7%) with stage IIIC disease. Patient distribution according to tumor location is summarized in Table 1. Correspondence to: Sung W Ha, MD, Department of Radiation Oncology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul , Republic of Korea. Tel ; fax ; swha@snu.ac.kr EK Chie and K Kim contributed equally to this study. Received January 26, 2007; accepted May 15, 2007.

2 592 Table 1 - Patient distribution according to tumor location Characteristics Treatment All patients underwent breast conserving surgery, either quadrantectomy (398 patients) or tumorectomy (26 patients). Most patients underwent R0 resection with clear (397 patients) or close resection margins (10 patients), whereas 5 patients had microscopically positive margins. In 12 patients, information on margin status was not available. Four hundred and six (95.8%) patients underwent axillary lymph node (LN) dissection. was administered to 231 patients (54.5%), mainly before RT (93 patients) or concomitant with RT (102 patients). Thirty-three patients had RT prior to chemotherapy, and 3 patients underwent treatment in sandwich style (chemotherapy RT chemotherapy). One hundred and seventy of these 231 patients received cyclophosphamide, methotrexate, and 5-fluorouracil, while 59 patients received anthracycline-containing regimens. One patient was treated with methotrexate and 5-fluorouracil while no chemotherapeutic regimen information was available for one patient. One hundred and thirty patients received hormonal therapy: 75 patients also received chemotherapy, and 55 patients hormonal therapy alone. In regard to RT, the whole breast was irradiated with Gy (median 50.4 Gy) at 1.8 Gy per fraction using 2 oblique opposed photon beams. Except in 2 patients, a tumor bed boost was added of 4-14 Gy (median 10 Gy) at 2 Gy per fraction using single en-face electron beams (400 patients) or photons (22 patients). Overall, the total dose to the tumor bed ranged from 50.4 Gy to 61.2 Gy (median 60.4 Gy). Regional lymphatics including axillary and supraclavicular LN were irradiated in 57 patients, and 30 of them also received internal mammary LN irradiation. Follow-up No. of patients Tumor side Right 195 Left Inner 115 Outer 302 Central/Multifocal 6/1 2 Upper 356 Lower 61 Central/Multifocal 6/1 At the end of RT, the patients were instructed to avoid exposure to heat such as hot baths because of the possible detrimental effect on cosmesis. Patients were followed every 3 months until the end of the second year, then every 4-6 months until the end of the fifth year, and every 6-12 months thereafter. At every visit, patients were asked about episodes of immersion baths with water temperatures exceeding 40 C or sauna visits; these episodes were recorded. In this study, 2 or more episodes were defined as heat exposure. For evaluation of cosmesis, photos were taken before and 1 and 2 years after RT. Cosmesis evaluation Cosmesis evaluation consisted of 2 parts, a subjective evaluation and an objective measurement. Using the cosmesis score proposed by Danoff et al. 9 (Table 2), subjective cosmesis was graded as excellent, good, fair, and poor by 3 investigators (KK, EKC and SWH). For objective measurement of cosmesis, a symmetry index was calculated. The distance from the sternal notch to each nipple was measured, and the subtraction of the 2 distances divided by the distance of the untreated breast was defined as the symmetry index, modified from Sacchini s method 10 (Figure 1). Cosmesis evaluation was based on photos taken at the time of simulation, and 1 and 2 years after RT. Changes in the cosmetic results over time were also evaluated. Statistical analysis EK CHIE, K KIM, DY NOH ET AL Statistical analysis was done using the SPSS software (release , SPSS Inc. Chicago, IL, USA). Univariate and multivariate logistic regression models were used to assess the statistical significance of associations between cosmesis and patient-, tumor- and treatment-related factors as well as heat exposure. Figure 1 - Estimation of symmetry index. Symmetry index = (A-B)/A. Modified from Sacchini et al. 10 Table 2 - Cosmesis score Category Excellent Good Fair Poor Description From Danoff et al. 9 Treated breast almost identical to untreated breast Minimal difference between treated and untreated breast Obvious difference between treated and untreated breast but without major distortion Major esthetic sequelae in treated breast

3 NEGATIVE IMPACT OF HEAT EXPOSURE ON COSMESIS AFTER BCS+RT 593 Results Clinical outcome During follow-up, ipsilateral breast recurrence was observed in 15 patients: 9 were invasive recurrences at the tumor bed and 2 presented as ductal carcinoma in situ, while 4 patients presented invasive carcinoma in other quadrants. Eight patients developed regional relapses, axillary LN in 1 patient and supraclavicular LN in 7 patients. Distant metastasis developed in 41 patients, and bone was the most common site of failure (70.7%). Cosmesis score Before the initiation of RT, the cosmesis score was excellent in 22.7%, good in 67.6%, fair in 8.9%, and poor in 0.7% of the patients. At the latest follow-up, the figures were 15.4%, 62.6%, 19.4%, and 2.6%, respectively. Adverse prognostic factors affecting cosmesis score after RT were tumors greater than 2 cm (P = ), lower quadrant location (P = ), regional LN irradiation (P = ), and heat exposure (P = ) in multivariate analysis (Table 3). Compared to the pre-rt status, the post-rt cosmesis score had deteriorated in 18.5% of patients while it was unchanged in the others. In multivariate analysis, the cosmesis score worsened in patients with regional LN irradiation (P <0.0001) and in patients exposed to heat (P = ) (Table 4). Symmetry index When arbitrarily divided into 3 ranges, the symmetry index at the time of simulation was 0.1 in 48.1%, in 42.7%, and 0.2 in 9.1% of patients. At the latest follow-up, the figures were 34.5%, 49.4%, and 16.1%, respectively. In multivariate analysis, breast symmetry was worse in patients with tumors greater than 2 cm (P <0.0001), upper quadrant location (P <0.0001), chemotherapy in combination with RT (P = ), regional LN irradiation (P = ), and heat exposure (P = ) (Table 5). With follow-up, the value increased only in 8 patients (2.4%), whereas it remained equal in the others. Changes in symmetry index after RT were greater for LN-irradiated patients (P <0.0001) in multivariate analysis (Table 6). Discussion According to the literature, about 80-90% of patients achieve good to excellent cosmetic results after breast conserving surgery In our study, however, the good to excellent cosmesis score was 78.0%, remaining at the lower end of the range. This may be due to the larger vol- Table 3 - Factors affecting cosmesis score after radiation therapy Cosmesis score (%) Ex Good Fair Poor Uni Multi Quadrantectomy Tumorectomy Yes No cm >2 cm Inner Outer Upper Lower < No Pre-RT Concomitant Post-RT Breast Ax, SCL IMN Yes No lymph nodes; SCL, supraclavicular lymph nodes; IMN, internal mammary lymph nodes; Ex, excellent; Uni, univariate analysis; Multi, multivariate analysis. *Three patients who received sandwich chemotherapy were excluded. Table 4 - Factors affecting difference in cosmesis score before and after radiotherapy Cosmesis score (%) No change Aggravated Uni Multi Quadrantectomy Tumorectomy Yes No cm >2 cm Inner Outer Upper Lower No Pre-RT Concomitant Post-RT Breast Ax, SCL < < IMN Yes No lymph nodes; SCL, supraclavicular lymph nodes; IMN, internal mammary lymph nodes; Uni, univariate analysis; Multi, multivariate analysis.

4 594 Table 5 - Factors affecting symmetry index after radiation therapy Symmetry index (%) Table 6 - Factors affecting difference in symmetry index before and after radiotherapy Symmetry index (%) Uni Multi Quadrantectomy Tumorectomy Yes No cm > 2 cm < < Inner Outer < Upper Lower < < No Pre-RT Concomitant Post-RT Breast Ax, SCL IMN Yes No lymph nodes; SCL, supraclavicular lymph nodes; IMN, internal mammary lymph nodes; Uni, univariate analysis; Multi, multivariate analysis. No change Aggravated Uni Multi Quadrantectomy Tumorectomy Yes No cm >2 cm Inner Outer Upper Lower No Pre-RT Concomitant Post-RT Breast Ax, SCL < IMN Yes No lymph nodes; SCL, supraclavicular lymph nodes; IMN, internal mammary lymph nodes; Uni, univariate analysis; Multi, multivariate analysis. EK CHIE, K KIM, DY NOH ET AL ume of breast resection. Most of the patients in our study (93.9%) underwent quadrantectomy rather than tumorectomy. It has been well documented that a larger excision volume is an adverse factor for cosmesis 13,16-20, and quadrantectomy has an unfavorable influence on cosmesis compared with tumorectomy 17,19,21. Another possible reason for the relatively unfavorable cosmesis in our study is the use of chemotherapy in a larger proportion of patients. Although controversy exists regarding the effect of adjuvant chemotherapy on breast cosmesis 9,15,22, many investigators agree that the addition of chemotherapy worsens the cosmetic results among other treatment-related morbidities, especially when given concomitantly rather than sequentially 19,20, Compared to other series in which 0-26% of patients received chemotherapy 11-14, chemotherapy was administered to more than half of the studied patients, and concomitant chemotherapy was associated with a good to excellent result in 67.5% of patients as compared with 80.9% of patients not receiving chemotherapy. Larger tumor size 10,12,19,20,27, addition of chemotherapy 19,20,23-26, and regional LN irradiation 15,16-19 have been considered as adverse factors affecting the cosmetic results by other investigators, and our study reaffirmed these findings. Concerning tumor location, lower quadrant location lowered the cosmesis score, whereas the symmetry index was influenced negatively by upper quadrant location. This may be due to the effect of greater surgical distortion in lower quadrant locations without necessarily causing any nipple displacement. These findings are in accordance with the data from the European Organization for Research and Treatment of Cancer trial 20. Given this observation, the symmetry index has limited value in the evaluation of the cosmetic result as a whole. Exposure to heat after RT has been known to have an adverse effect on irradiated skin and connective tissue 6,7. Heat increases blood flow and vascular permeability, and this increased perfusion leads to increased local inflammation and edema 28, especially after breast surgery because of impaired lymphatic drainage. However, increased inflammation and edema by heat could only explain the effect in the acute phase. Whether this mechanism could account for the sustained effect in the late phase is not certain. Another proposed mechanism is the inhibition of sublethal radiation damage repair by heat exposure, as has been demonstrated in the laboratory setting 29,30. It is still not known whether such a change can contribute to the late effect of heat on irradiated skin or connective tissue 31. Although the mechanism is uncertain, few authors have reported delayed effects of additional heat to radiation. Law et al. 32 reported that delayed heating at 3-12 months after irradiation enhanced radiation damage in the mouse ear model. Wondergem et al. 33 demonstrated that there was a memory of late radiation reaction in case of hyperthermia at 3 months after irradiation. Given these findings, we have hypothesized that heat exposure after RT may result in worsening fibrosis of

5 NEGATIVE IMPACT OF HEAT EXPOSURE ON COSMESIS AFTER BCS+RT 595 skin and connective tissue, distortion of the treated breast, and deterioration of the cosmetic results. In the present study, heat exposure negatively influenced both cosmesis score and symmetry index. When the temporal change between pre-rt and post-rt cosmesis was analyzed to evaluate the possible contribution of post-treatment factors to cosmesis, the cosmesis score worsened after heat exposure but the symmetry index did not. The retrospective nature of this study, however, gave rise to several limitations. Information concerning heat exposure was gathered qualitatively, not quantitatively. The definition of heat exposure included the number of episodes and the temperature of the immersion bath or sauna, but not the frequency and interval of such episodes. Moreover, the duration of each episode was not available at the time of analysis. All of these missing data might confound the results. In this study, cosmesis was evaluated with both subjective and objective measures by 3 investigators to exclude possible biases in evaluation, that is, the preconception of poor cosmesis in patients with heat exposure. However, the possible biases in questioning/recording of episodes of immersion baths or sauna were not controllable at the time of analysis, although our policy was that information on heat exposure was asked and recorded during every visit regardless of the apparent cosmetic results. In conclusion, apart from previously reported treatment-related parameters such as larger tumor size, LN irradiation, and chemotherapy in combination with radiotherapy, the lifestyle of patients, namely exposure to heat in this study, was found to have a negative impact on cosmesis after conservative treatment for breast cancer. Based on the results of this study, patients should be advised to avoid heat exposure after breast irradiation. References 1. 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