Concurrent Cyclophosphamide, Methotrexate, and 5-Fluorouracil Chemotherapy and Radiotherapy for Breast Carcinoma

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1 696 Concurrent Cyclophosphamide, Methotrexate, and 5-Fluorouracil Chemotherapy and Radiotherapy for Breast Carcinoma A Well Tolerated Adjuvant Regimen Neil Isaac, B.Sc. 1 Tony Panzarella, M.Sc. 2 Anthea Lau, 2 Catherine Mayers, B.Sc.N. 3 Peter Kirkbride, M.D. 1 Ian F. Tannock, M.D., Ph.D. 3 Katherine A. Vallis, M.D., Ph.D. 1 1 Department of Radiation Oncology, Princess Margaret Hospital/University Health Network and University of Toronto, Toronto, Ontario, Canada. 2 Department of Biostatistics, Princess Margaret Hospital/University Health Network and University of Toronto, Toronto, Ontario, Canada. 3 Department of Medical Oncology and Hematology, Princess Margaret Hospital/University Health Network and University of Toronto, Toronto, Ontario, Canada. Presented in part at the Annual Meeting of the Canadian Association of Radiation Oncologists, Edmonton, Alberta, Canada, September 20 24, Dr. Kirkbride s current address: Department of Radiotherapy, Weston Park Hospital, Sheffield, United Kingdom. Address for reprints: Katherine A. Vallis, M.D., Ph.D., Department of Radiation Oncology, Princess Margaret Hospital/University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada; Fax: (416) ; katherine. vallis@rmp.uhn.on.ca Received October 29, 2001; revision received November 30, 2001; accepted March 20, BACKGROUND. The current study was conducted to assess the toxicity of concurrent adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and radiotherapy (RT) for early breast carcinoma. METHODS. In the current study, the authors reviewed the records of 680 consecutive breast carcinoma patients who received adjuvant CMF at the Princess Margaret Hospital between Surgery was comprised of mastectomy in 64% of patients, breast conservation in 35% of patients, and was unknown in 1% of patients. Two hundred two patients received concurrent CMF/RT that was defined as an overlap in CMF and RT administration of at least 21 days. Forty-seven patients received sequential CMF/RT (defined as no overlap or an overlap of 7 days in CMF and RT administration). Other patients received CMF alone. Adverse effects of RT were graded retrospectively using the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) system. Reasons for interruption or failure to complete RT were recorded. The magnitude of chemotherapy dose reductions and delays also were noted. RESULTS. The median age of the patients was 44 years (range, years) and 88% of the patients had lymph node-positive disease. RT was interrupted or discontinued due to side effects in 4% of patients (95% confidence interval [95% CI], %) and 0% (95% CI, 0 7.6%), respectively, of the concurrent and sequential groups (P 0.36). The incidence of Grade 3 or Grade 4 RT toxicity was 1.5% (95% CI, %) and 2.1% (95% CI, %), respectively, for the concurrent and sequential groups (P 0.57). The median relative dose intensity of chemotherapy for patients receiving concurrent CMF/RT, sequential CMF/RT, and CMF alone was 0.87, 0.84, and 0.85, respectively (P 0.22). CONCLUSIONS. The results of the current study demonstrate that the concurrent administration of CMF and RT is associated with a low risk of serious toxicity and is an acceptable adjuvant regimen for patients with breast carcinoma. Cancer 2002;95: American Cancer Society. DOI /cncr KEYWORDS: adjuvant radiotherapy (RT); cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); concurrent chemoradiotherapy; breast carcinoma; toxicity. Breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) is the accepted standard treatment for early breast carcinoma. RT also has been shown to decrease locoregional recurrence after mastectomy. 1 Recent reports of randomized clinical trials suggest a survival benefit for patients who receive locoregional RT in addition to adjuvant cyclophosphamide, methotrexate, and 5-flu American Cancer Society

2 Concurrent Chemoradiotherapy for Breast Carcinoma/Isaac et al. 697 orouracil (CMF) chemotherapy. 2,3 Although it has been established that both adjuvant RT and chemotherapy reduce the risk of disease recurrence, the optimum sequence of delivery of these treatments remains uncertain. There is evidence that prolongation of the interval between surgery and RT is detrimental, resulting in suboptimal local recurrence rates. 4,5 Delaying the initiation of chemotherapy has been shown to result in a higher rate of distant recurrence. 4 Because a delay in administering either RT or chemotherapy may result in a suboptimal outcome for patients with breast carcinoma, concomitant chemoradiotherapy might be regarded as an optimal strategy. One advantage of the concurrent approach is that the simultaneous administration of chemotherapy and RT may lead to enhanced cell killing; concurrent chemotherapy and RT has been shown to improve local control in several sites including head and neck tumors and cervical carcinoma. 6,7 In addition, the overall treatment time is reduced and consequently there is less social disruption for patients compared with when treatments are administered sequentially. However, some reports suggest that concurrent chemoradiotherapy may lead to greater toxicity 8 and impact adversely on quality of life 9 and cosmetic outcome 10 compared with sequential treatment. At the Princess Margaret Hospital, our policy for patients who have been selected to receive CMF and RT has been to initiate chemotherapy shortly after definitive surgery and to administer RT concurrently. During the period a group of patients received CMF alone either because they were participating in a trial in which RT was a randomized option or because RT was not recommended. A minority of patients received sequential CMF and RT. In the current study, we performed a review of medical records to evaluate the toxicity associated with concurrent CMF/ RT. MATERIALS AND METHODS Patients Patients were identified from computer-based files using the following selection criteria: 1) diagnosis of primary breast carcinoma, 2) receipt of CMF chemotherapy between , and 3) TNM classification of T1 (tumor 2 cm), T2 (tumor 2cmbut 5 cm), T3 (tumor 5 cm), N0 (no regional lymph node metastases), N1 (metastasis to movable ipsilateral axillary lymph nodes), or M0 (no distant metastases). 11 Patients with locally advanced disease (T4 [tumor involving skin or muscle] or N2 [fixed ipsilateral axillary lymph node metatases]) or metastatic disease or who received the majority of their chemotherapy at another hospital were excluded. Six hundred eighty patients were eligible for inclusion. Their medical records were reviewed and a subgroup of 202 patients who received concurrent CMF/RT were identified. Concurrent treatment was defined as an overlap of at least 21 days in the administration of CMF and RT. Forty-seven patients received sequential CMF/RT (defined as no overlap or an overlap of 7 days in CMF and RT administration). Eight patients received RT and CMF but did not conform to the definitions of concurrent or sequential treatment and were not considered further. The remaining 423 patients received CMF alone. Information was abstracted from the medical records either as part of a previous study of the prognostic effect of inclusion in a clinical trial on the survival of breast carcinoma patients 12 or using a form custom-designed for the current study of concurrent CMF/RT. The following information was collected: demographic data (age, height, and weight), tumor characteristics based on pathologic evaluation (T classification, number of lymph nodes involved, histologic grade, and hormone receptor status), type of surgery (BCS or mastectomy), details of RT (total dose, number of fractions, field arrangement, overall treatment time, toxicity, treatment interruptions and discontinuation), and details of chemotherapy (schedule [ classic CMF or oral CMF], date of each course, and dose of each drug). Adverse events associated with RT were assigned a grade retrospectively, using the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) guidelines for acute and late RT toxicity. 13 Side effects recorded within 3 months of the initiation of RT were regarded as early and those recorded after 3 months were regarded as late. Minor skin reactions generally were not recorded in detail and so we chose to group Grade 0 and Grade 1 early toxicity together as a single category. Data Management and Statistics Data were recorded on abstraction forms by three investigators. For quality assurance, 10% of the patient records were reabstracted. A small number of outlying data were detected; these were checked against the medical record and corrected as necessary. Data subsequently were entered into an SAS database. 14 Toxicity due to RT was assessed using the RTOG/ EORTC system. 13 Differences in the proportion of patients with Grade 3 or Grade 4 RT toxicity and in the proportion of patients who experienced RT interruption or discontinuation among the concurrent and sequential treatment groups were compared using the Fisher exact test. The 95% confidence intervals (95% CI) for individual proportions represent exact confidence intervals for a binomial proportion. The chi-

3 698 CANCER August 15, 2002 / Volume 95 / Number 4 square test was used to compare the proportion of patients in the three treatment groups with four or more positive lymph nodes and the proportion of patients in these groups who received intravenous CMF. Recurrence-free and overall survival rates were calculated from the date of surgery using the Kaplan Meier estimate. The relative dose intensity of the three groups was compared for statistical significance using the nonparametric Kruskal Wallis test (because there was some indication that the assumptions of the oneway analysis of variance [the parametric equivalent] were in violation). Exact tests and 95% CIs were calculated using StatXact, Version 4 15 whereas other results were calculated using SAS, Version Surgery Surgery was comprised of wide local excision of the tumor or modified radical mastectomy with or without axillary lymph node dissection. Radiotherapy Patients received RT to the breast or chest wall using a pair of coplanar, tangential opposed fields. RT to the whole breast was followed by a boost to the primary site in the majority (77%) of concurrently treated patients. A minority (9%) of the concurrent CMF/RT group also received regional RT to the supraclavicular fossa, the axilla, the internal mammary chain of lymph nodes (IMC), or a combination of these. The most commonly used RT protocol for treatment to the breast and the regional lymph nodes was 40.0 grays (Gy) in 16 fractions of 2.5 Gy each, 5 days per week using 6-megaelectron volt photons or Co 60 irradiation. The most commonly used protocol for the boost to the tumor bed was 12.5 Gy in 5 fractions. An alternative protocol of 50.0 Gy in 25 fractions to the breast or chest wall was given to a small group of patients. This regimen did not include a boost to the tumor bed. The supraclavicular fossa and axilla generally were treated using a pair of anterior and posterior fields. For treatment of the IMC lymph nodes, an anterior hemimantle field was used to encompass both the IMC and supraclavicular fossa. Chemotherapy Patients were scheduled to receive either classic CMF therapy (cyclophosphamide, 100 mg/m 2 orally on Days 1 14; methotrexate, 40 mg/m 2 intravenously [i.v.] on Days 1 and 8; and 5-fluorouracil, 600 mg/m 2 i.v. on Days 1 and 8 in a 28-day cycle) for 6 or 12 cycles or i.v. CMF (cyclophosphamide, 600 mg/m 2 ; methotrexate, 40 mg/m 2 ; and 5-fluorouracil, 600 mg/m 2 ) given i.v. every 3 weeks for 8 cycles. At the study institution during the 1980s there was a tendency to move away from the classic regimen because of the perception of greater toxicity from oral cyclophosphamide, and a move back to it after the initial presentation of the results of the European trial for advanced disease that suggested better efficacy of classic CMF. 16 For this reason, patients in the current series were treated with either regimen. The chemotherapy dose intensity was calculated for each drug as the total dose divided by the duration of time over which it was given. Relative dose intensity then was calculated as the ratio of received dose intensity to the ideal value (had planned doses been given on schedule) and was averaged for the three drugs. Relative dose intensity could be calculated for 614 patients (188, 44, and 382 of whom received concurrent CMF/RT, sequential CMF/RT, and CMF alone, respectively). RESULTS Patient Characteristics Patient characteristics are summarized in Table 1. The median age of the patients at diagnosis was 44 years (range, years). Five hundred ninety patients (88%) had lymph node-positive disease. This reflects the policy of the period to administer adjuvant chemotherapy mainly to premenopausal women with lymph node-positive breast carcinoma. The median length of follow-up was 8.4 years (range, years). The majority of patients (75%) in the concurrent group underwent BCS. The proportion of patients who underwent mastectomy was higher in those patients who received sequential treatment or CMF alone compared with those treated with concurrent CMF/RT (53% and 84%, respectively, vs. 25%). The proportion of patients with 4 involved lymph nodes was higher in the CMF alone group compared with the concurrent and sequential groups (36% vs. 28% and 21%, respectively) (P 0.036). This suggests that this group had more advanced disease on average. Outcome The overall survival and locoregional recurrence-free rates for patients treated with concurrent CMF/RT were 74% and 82%, respectively, at 5 years. The equivalent figures at 10 years were 59% and 66%, respectively. Toxicity of RT Details regarding RT are shown in Table 2. Skin and subcutaneous toxicity associated with RT for the concurrent and sequential groups is summarized in Table 3. Late RT toxicity is summarized in Table 4. There were no cases of brachial plexopathy or rib fracture. Treatment-related toxicity resulted in the interruption of RT in eight patients receiving concurrent CMF/RT. The reasons for treatment interruption were neutro-

4 Concurrent Chemoradiotherapy for Breast Carcinoma/Isaac et al. 699 TABLE 1 Patient Characteristics and Pathology Concurrent (n 202) Sequential (n 47) CMF alone (n 423) Primary surgery Mastectomy 51 (25) 25 (53) 355 (84) Breast-conserving surgery 151 (75) 22 (47) 62 (15) Other 0 (0) 0 (0) 6 (1) Axillary lymph node dissection 199 (99) 43 (91) 380 (90) T classification T1 59 (29) 11 (23) 55 (13) T2 84 (42) 22 (47) 202 (48) T3 26 (13) 4 (9) 40 (9) Unknown 33 (16) 10 (21) 126 (30) Lymph node status 0 6 (3) 3 (6) 17 (4) (64) 22 (47) 219 (52) 4 57 (28) 10 (21) 152 (36) Unknown 9 (4) 12 (26) 35 (8) Hormone receptor status ER positive 104 (51) 19 (40) 190 (45) PR positive 112 (55) 16 (34) 175 (41) CMF: cyclophosphamide, methotrexate, and 5-fluorouracil; ER: estrogen receptor; PR: progesterone receptor. TABLE 2 Details of Radiotherapy TABLE 3 Summary of Radiation Toxicity Concurrent (n 202) Sequential (n 47) RTOG/EORTC score No. of concurrent patients (n 202) (%) Breast/chest wall RT 202 (100) 47 (100) Median dose (Gy) Median no. of fractions Breast boost RT 151 (75) 22 (47) Median additional dose (Gy) Median no. of fractions 5 5 Regional RT a 13 (6) 6 (13) Median additional dose (Gy) Median no. of fractions Regional RT including IMC 5 (2) 18 (38) Median dose (Gy) Median no. of fractions RT: radiotherapy; Gy: grays; IMC: internal mammary chain lymph nodes. a Radiotherapy given to the ipsilateral supraclavicular fossa or axilla or both. 0/ Early Skin 173 (86) 26 (13) 2 (1) 0 Late Skin 193 (96) 4 (2) 0 1 (0.5) Subcutaneous 192 (95) 6 (3) 0 0 No. of sequential patients (n 47) (%) 0/ Early Skin 40 (85) 4 (9) 1 (2) 0 Late Skin 42 (89) Subcutaneous 41 (87) 2 (4) 0 0 RTOG: Radiation Therapy Oncology Group; EORTC: European Organization for Research and Treatment of Cancer. penia (five patients) chemotherapy-related emesis (two patients), and surgical wound infection (one patient). There were no treatment interruptions among the patients who received sequential CMF/RT. Two patients in the concurrent CMF/RT group received incomplete courses of RT. One patient experienced dehisence of the surgical wound and the other developed an unusually severe acute radiation reaction. In total, RT was interrupted or discontinued due to side effects in 4% (95% CI, %) and 0% (95% CI, 0 7.6%), respectively, of the concurrent and sequential groups (P 0.36). The incidence of acute Grade 3 or 4 radiation toxicity was 1.5% (95% CI, %) and 2.1% (95% CI, %), respectively, for the concurrent and sequential groups (P 0.57). The late radiation effects of radiation pneumonitis, arm lymphedema, and esophagitis rarely were recorded in

5 700 CANCER August 15, 2002 / Volume 95 / Number 4 TABLE 4 Late Radiation Toxicity Concurrent (n 202) Radiation pneumonitis 0 1 (2) Arm lymphedema 15 (7) 10 (21) Esophagitis 3 (1) 6 (13) Sequential (n 47) the concurrently treated patients (0%, 7%, and 1%, respectively) (Table 4). Toxicity of Chemotherapy Overall, 414 patients (62%) received classic and 238 patients (35%) received i.v. CMF chemotherapy. Information regarding the CMF regimen used was incomplete or missing for 28 patients. The proportion of patients who received i.v. CMF was statistically significantly different for the 3 treatment groups (136 of 407 vs. 90 of 198 vs. 12 of 47 for the CMF alone, concurrent, and sequential groups, respectively; P 0.004). Among the 202 patients who received concurrent CMF/RT, there was a delay in chemotherapy administration for at least 1 cycle in 116 patients (57%). Of these, 59 patients (51%) experienced delays for 1 cycle of treatment. A delay in treatment was slightly more likely among patients receiving oral (52%) versus those receiving i.v. (47%) CMF. The median relative dose intensity of chemotherapy, averaged over the entire duration of chemotherapy, was 0.87, 0.84, and 0.85 for patients receiving concurrent CMF/RT, sequential CMF/RT, and CMF alone, respectively (P 0.22) (Fig. 1). DISCUSSION It is established that both adjuvant chemotherapy and RT can reduce the risk of disease recurrence in patients with breast carcinoma but to our knowledge the optimum sequence of delivery of these treatments is uncertain. Several investigators have correlated the length of time between surgery and RT with subsequent risk of local recurrence. The results are contradictory. 4,17 20 As part of the International Breast Cancer Study Group (IBCSG) Trial VI, 433 premenopausal, lymph node-positive breast carcinoma patients who had undergone BCS randomly were assigned to receive either 3 or 6 cycles of CMF and subsequently received RT to the breast. 21 No statistically significant difference in local recurrence rates was noted in the two groups. 18 Similarly, as part of the IBCSG Trial VII, 285 postmenopausal, lymph node-positive patients were randomly assigned to receive 3 cycles of CMF followed by tamoxifen or tamoxifen alone. 22 RT to the breast was delivered after CMF in the combined treatment group or immediately after surgery in the tamoxifen-only group. The length of time between surgery and the initiation of RT did not appear to correlate with local recurrence rates. 18 Conversely, others have found that delaying RT does have an adverse impact on outcome. In a study from the Institute Gustave- Roussy, the locoregional failure rate at 5 years was 5% in patients for whom the interval between surgery and RT was 7 weeks but was 14% when the interval exceeded 7 weeks. 19 In a clinical trial performed at the Joint Center for Radiation Therapy, patients were randomized to receive breast irradiation either before or after anthracycline-based chemotherapy. Patients who received delayed chemotherapy experienced a higher rate of distant recurrence compared with those who received chemotherapy immediately after surgery (57% vs. 25%) at a median follow-up of 58 months. 4 Conversely, patients in whom RT was delayed while chemotherapy was administered experienced a higher local recurrence rate (14% vs. 5%). Although it is recognized that a delay in the initiation of RT or chemotherapy may result in a suboptimal outcome, to our knowledge there are few reports of concurrent chemoradiation therapy in the adjuvant setting. For this reason, we have reviewed our experience at the Princess Margaret Hospital, where our policy since the 1980s has been to administer RT concurrently with chemotherapy when CMF is selected as adjuvant systemic therapy. Another nonrandomized study of simultaneous adjuvant CMF and RT for early breast carcinoma has been reported by the Trans- Tasman Radiation Oncology Group (TROG). 23,24 Between 1981 and 1995, 268 patients from 4 cancer centers participated in the study. RT was delivered during the first two cycles of CMF although it was omitted on the days that the i.v. component of the chemotherapy was administered. There appeared to be no increase in acute soft tissue reactions or impaired cosmetic outcomes. 23 The first site of recurrence was recorded and for patients who had undergone BCS the 4-year local and regional/distant recurrence rates were 6.3% and 27%, respectively. These results were considered to be comparable to those achieved in trials of anthracycline-based adjuvant chemotherapy with delayed RT. 24 The locoregional recurrence rate for the patients treated with concurrent CMF/RT in our study was 18% at 5 years. This figure includes isolated locoregional recurrences and those that occurred at the same time or after the diagnosis of distant disease. The overall survival rates at 5 years and 10 years were 74% and 59%, respectively, for the concurrent CMF/RT group. These locoregional recurrence and survival statistics for patients treated with concurrent CMF/RT are typ-

6 Concurrent Chemoradiotherapy for Breast Carcinoma/Isaac et al. 701 FIGURE 1. Relative dose intensity of chemotherapy for patients receiving concurrent cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)/radiotherapy (RT), sequential CMF/RT, and CMF alone. ical of a group of operable breast carcinoma patients with lymph node-positive disease. 25 Concurrent treatment is attractive for a number of reasons. First, the overall treatment time is reduced, which minimizes social disruption for the patient and allows an early return to employment or full participation in family life. In a recent study of patient participation in medical decision-making, women with breast carcinoma were offered concurrent or sequential adjuvant chemotherapy plus RT. 26 The majority chose concurrent treatment even though this was predicted to cause greater toxicity. The most frequently stated reasons for preferring the concurrent option was the shorter treatment time and less disruption of family life. There may be therapeutic advantages to combining chemotherapy and RT. 27 Chemotherapyresistant cells may be killed by radiation and radioresistant cells may be killed by chemotherapy when the mechanisms of resistance for the two modalities differ. If such conditions exist, they might lead to an improved local control rate for concurrent compared with sequential therapy. The use of concurrent chemotherapy and RT has been established for several malignancies. 28 One advantage of concurrent chemotherapy is that it may reduce tumor cell repopulation in the tumor bed, resulting in fewer tumor clonogens for eradication by RT. 29 However, the role of repopulation in the adjuvant setting is not known. A major concern is that toxicity may be enhanced by concomitant chemoradiotherapy. In one study of concurrent chemoradiation therapy after BCS for breast carcinoma, Fernando et al. reported no difference in acute skin toxicity compared with RT alone. However, four patients who received concurrent treatment developed radiation pneumonitis compared with none of those patients receiving sequential treatment. 30 Bentzen et al. studied skin and subcutaneous toxicity in 90 patients who had received concomitant CMF or cyclophosphamide chemotherapy within the context of Danish Breast Cancer Co-operative Group trials after mastectomy. 31 There was a significant increase in acute skin reactions in the concomitant chemotherapy arms. Moist desquamation was observed in 10 50% of the RT field in 14% of those receiving concurrent cyclophosphamide, in 26% of those receiving concurrent CMF, and in 9% of those who were treated with RT alone. Serin et al. reported the use of concurrent CMF and RT in 154 patients with TNM Stage I or II breast carcinoma. 32 Mild skin toxicity (RTOG/EORTC Grade 1) was observed in 63% of patients and Grade 3 toxicity, requiring temporary interruption of treatment, occurred in 4.5% of patients. These toxicity scores are similar to those in the current study, in which 86% of patients receiving concurrent CMF/RT had an early skin reaction of Grade 0 or 1, and only 1% experienced Grade 3 toxicity. Although we are aware of the limitations of assigning RT toxicity scores retrospectively according to the clinical notes made at the time, it is likely that significant moist desquamation (leading to a grade of 2) or ulceration (leading to a grade of 3) were recorded accurately. Dubey et al. recently reported the results of a prospective pilot study of concurrent CMF and RT that included 112 patients with early breast carcinoma. 33 The

7 702 CANCER August 15, 2002 / Volume 95 / Number 4 dose of RT was reduced from a standard dose of Gy to 39.6 Gy in 22 fractions to avoid excessive toxicity. Despite this precaution, 50% of patients developed moist desquamation, a somewhat higher rate than we and others have observed. One possible explanation for this was that all patients received the classic CMF regimen, which provides a higher absolute dose intensity of the three drugs than the intravenous regimen. Markiewicz et al. reported arm edema in 8% of patients receiving concurrent chemotherapy compared with 2% in those receiving sequential treatment. 34 Lingos et al. reported that concurrent therapy is associated with an increased rate of radiation pneumonitis compared with sequential treatment. 8 In the current study none of the patients who received CMF/RT developed pneumonitis and the incidence of arm lymphedema was modest (7%). Only 18 of 202 patients in the concurrent group (9%) received lymph node irradiation and it is possible that the low incidence of both pneumonitis and lymphedema is due to the infrequent use of regional RT in this group. The link between regional RT and these complications may explain the elevated risk of both radiation pneumonitis and lymphedema in the sequential group because regional RT was used in 24 of 47 patients (51%) in this group. Several published articles report that concurrent CMF/RT results in a worse cosmetic outcome than sequential treatment, 10 although this is not a universal finding. 34 One limitation of the current study is that information regarding the appearance of the breast was not collected systematically and therefore it is not possible for us to comment on this issue. Cosmetic outcome is an important aspect of breastconserving therapy and ideally would be assessed as part of a prospective study of the effects of concurrent CMF/RT. Several reports 35 and an overview of randomized trials of polychemotherapy 25 for early breast carcinoma have suggested a survival advantage for some patients who receive anthracycline-based adjuvant chemotherapy compared with those that receive CMF. As a result of these findings, anthracycline-based regimens such as doxorubicin and cylophosphamide (AC) are now used more commonly than CMF. However, occasionally CMF is still selected for patients with a low number of involved lymph nodes, for those with lymph node-negative disease, or for those in whom anthracyclines are contraindicated because of preexisting cardiac disease. Some patients choose not to receive anthracycline-based regimens because of greater toxicity, including a small but significant risk of leukemogenesis. The results of the current study suggest that when CMF is the adjuvant chemotherapy regimen of choice it then is feasible and safe to administer RT simultaneously. Although acknowledging the limitations of a retrospective analysis, we found no evidence of excessive radiotoxicity or reduced chemotherapy dose intensity in a large group of patients who received concomitant CMF and RT. This leads us to conclude that concurrent CMF/RT is a well tolerated adjuvant regimen for patients with breast carcinoma. REFERENCES 1. Harris JR, Halpin-Murphy P, McNeese M, Mendenhall NP, Morrow M, Robert NJ. Consensus statement on postmastectomy radiation therapy. Int J Radiat Oncol Biol Phys. 1999; 44: Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337: Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med. 1997;337: Recht A, Come SE, Henderson I, et al. 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