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Concurrent chemoradiotherapy in adjuvant treatment of breast cancer

Concurrent chemoradiotherapy in adjuvant treatment of breast cancer Background: The optimal sequencing of chemotherapy and radiotherapy after breast surgery was largely studied but remains controversial. Concurrent chemo-radiotherapy is a valuable method for adjuvant treatment of breast cancer which is under ongoing research program in our hospital. We are evaluating the feasibility of the concomitant use of chemotherapy retrospectively. Methods: Two hundred forty four women having breast cancer were investigated in a retrospective study. All patients were either treated by radical surgery or breast conservative surgery. The study compares two adjuvant treatments associating concomitant chemotherapy and radiotherapy. In the first group (group A) the patients were treated by chemotherapy and radiotherapy in concomitant way using anthracycline (n = 110). In the second group (group B) the patients were treated by chemotherapy and radiotherapy in concomitant way using CMF treatment (n = 134). Chemotherapy was administered in six cycles, one each 3 weeks. Radiotherapy delivered a radiation dose of 50 Gy on the whole breast (or on the external wall) and/or on the lymphatic region. The Kaplan-Meier method was used to estimate the rates of disease free survival, loco- regional recurrence-free survival and overall survival. The Pearson Khi test was used to analyse the homogeneity between the two groups. The log-rank test was used to evaluate the differences between the two groups A and B. Page 1 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Results: After 76.4 months median follow-up (65.3 months mean follow up), only one patient relapsed to loco-regional breast cancer when the treatment was based on anthracycline. However, 8 patients relapsed to loco-regional breast cancer when the treatment was based on CMF. In the anthracycline group, the disease free survival after 5 years, was 80.4% compared to 76.4% in the CMF group (Log-rank test: p = 0.136). The overall survival after 5 years was 82.5% and 81.1% in the anthracycline and CMF groups respectively (Log-rank test: p = 0.428). The loco-regional free survival at 5 years was equal to 98.6% in group A and 94% in group B (Log-rank test: p = 0,033). The rate of grade II and grade III anaemia was 13.9% and 6.7% in anthracycline group and CMF group respectively (Khi -test: p = 0.009). The rate of grade II and grade III skin dermatitis toxicity was 4.5% in the group A and 0% in the group B (Khi -test: p = 0.013). Conclusion: From the 5 years retrospective investigation we showed similar disease free survival and overall survival in the two concurrent chemo-radiotherapy treatments based on anthracycline and CMF. However in the loco-regional breast cancer the treatment based on anthracycline was significantly better than that of the treatment based on CMF. There was more haematological and skin dermatitis toxicity in the anthracycline group. of chemotherapy cycles delivered with radiotherapy was 2 Background In the case of early breast cancer and after radical mastec- (ranging from 1 to 5). Eighty percent of the patients (195 tomy or conservative surgery, adjuvant radiotherapy is patients) received 2 or more chemotherapy cycles with mandatory for diminishing the risk of recurrence [1-9]. concomitant radiotherapy. Patient medical records were Adjuvant chemotherapy is equally mandatory for dimin- retrospectively analysed and the following parameters ishing metastasis recurrences [10-12]. However, the opti- were considered: demographic data, clinical stages, histo- mal sequence of treatments is not clearly defined and logical findings, treatment and outcome. Radiological, remains controversial. Several trials have shown that the pathological and surgical reports were reviewed to deter- incidence of spared metastasis is more important in the mine the stage of the disease at the time of surgery by case of delay of chemotherapy, and local's recurrences are using the 2002 TNM classification for breast cancer [15]. more frequents in the case of delay of radiotherapy The diagnostic instrumental examinations used to stage [13,14]. Current standard treatment sequence is chemo- patients were: chest radiograph performed in all patients; therapy followed by radiotherapy. We are trying by this abdominal ultrasound performed in all patients; and retrospective study to document and support the feasibil- bone scan performed in only 16% of the patients (39 ity and efficiency of concurrent chemo-radiotherapy. patients). Treatment plan Methods Patient selection Data about treatment, notably surgery, chemotherapy and From January 2001 to December 2002, a large group of radiotherapy, were extracted from patient medical 244 patients with early breast carcinoma were selected at records. The date and site of recurrence and, if applicable, the National Institute of Oncology in Rabat, for investiga- the date of death were also considered. The first group A tion during treatment and up to now follow up. The of 110 patients was treated with anthracycline based pro- patients were divided in two groups on the basis of chem- tocol and the second group B of 134 patients was treated otherapy treatment. In group A the treatment was based with CMF protocol. Additional file 1 and Diagram 1 sum- on anthracycline and in group B the treatment was based marizes the therapeutic strategy. According to the protocol on CMF. Eighty four percent of the investigated cases followed at our institute, 95.5% of the patients received a (81% in group A and 86.5% in group B; Pearson-Khi test: radiotherapy treatment delivered to the whole breast or to p = 0.23) had radical surgery [201 received Patey mastec- thoracic wall (99.1% in group A and 92.5% in group B); tomy and 4 received Halsted mastectomy (2 in group A in addition, the same 95.5% of the patients received a and 2 in group B)] and the remaining 16% of the cases radiotherapy treatment delivered to the regional lymph (19% in group A and 13.5% in group B; Pearson-Khi test: nodes. The 4.5% of patients left received a radiotherapy p = 0.23) had breast conservative surgery [34 received treatment delivered to the whole breast or to the thoracic tumorectomy and 5 received quadrentectomy (3 in group wall, in addition to a radiotherapy treatment delivered in A and 2 in group B)]. All the 244 patients underwent con- the regional lymph nodes. All patients were treated with current adjuvant chemo-radiotherapy. In the concurrent external beam radiotherapy using tangential fields of Co- chemo-radiotherapy both chemotherapy and radiother- 60-gamma-Ray. The total delivered dose was 50 Gy, apy were delivered at the same time. The median number divided as 2-Gy daily fractions. The complementary treat- Page 2 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 ment was given by electrons or by breast brachytherapy. teristics was partly imbalanced. The influence on survival The total complementary dose ranged from 10 to 20 Gy of several prognostic factors (age, lymph node involve- for 10 patients. Chemotherapy consisted of: a- intrave- ment, tumour volume, tumour grade, receptor status, and nous CMF (cyclophosphamide 500 mg/m , methotrexate treatment regime) was analyzed by Cox regression. Statis- 2 2 60 mg/m , and 5-fluorouracil 500 mg/m ) on day 1, tical evaluation was carried out using SPSS 13.0 statistical repeated every 21 days for six courses for 134 patients, b- software. intravenous AC60 (doxorubicin 60 mg/m and cyclo- phosphamide 600 mg/m ) on day 1, repeated every 21 Results days for six courses for 57 patients, c- intravenous FEC75 Patient characteristics 2 2 (5-fluorouracile 500 mg/m , epirubicin 75 mg/m , and Between January 2001 and December 2002, 244 women cyclophosphamide 500 mg/m ) on day 1, repeated every were retrospectively evaluated. One hundred ten patients 21 days for six courses for 23 patients and d- intravenous received concurrent chemo-radiotherapy with anthracy- FAC50 (5-fluorouracile 500 mg/m , doxorubicin 50 mg/ cline based regimen and 134 patients received concurrent 2 2 m , and cyclophosphamide 500 mg/m ) on day 1, chemo-radiotherapy with CMF based regimen. The demo- repeated every 21 days for six courses for 20 patients, and graphic, clinical, pathologic, and therapeutic characteris- e- sequential treatment, repeated every 21 days for six tics of the two groups of patients were summarized in courses for 10 patients (table 1, additional file 1 and dia- table 2. After the analysis of homogeneity characteristics gram 1). We retrospectively compared toxicity, disease of the two groups we found more women aged less than free survival and overall survival between two therapeutic 40 years (Khi -test: p = 0.039) and more lymph node groups A and B and between the sub-groups within A and involvement (Khi -test: p = 0.001) in the anthracycline B. group than in group B (table 2). The progesterone recep- tor status was the only statistically different subgroup Statistical analysis from the three most important anthracycline sub-groups Overall survival (OS) and disease free survival (DFS) were (Table 3). The homogeneity between the groups of analyzed statistically in all patients. Time to recurrence patients managed either with mastectomy or breast con- was calculated from the date of surgery to the date of first servative therapy (BCT) was also studied and summarized documented relapse or to the date of last follow up. Over- in table 4. For all patients, the mean delay of chemother- all survival was calculated from the date of histological apy after surgery was 6.9 weeks (ranging from 0.7 to 37.9 diagnosis (Fine Needle Aspiration, biopsy, or surgery) to weeks). And the mean delay of radiotherapy after surgery the date of death or to the date of last follow up. The Kap- was 12.4 weeks (ranging from 2.4 to 53.3 weeks). In the lan-Meier method was used to estimate the rates of DFS, two groups A and B respectively, 96.4% and 97.7% of the loco-regional recurrence-free survival (LRFS) and OS. The patients received the 6 courses of chemotherapy. All log-rank test was used to evaluate the differences between patients in the two groups received 100% of the planned the two groups A and B. The distribution homogeneity radiotherapy dose. was analyzed with the Pearson chi -test for both groups and for all subgroups. The distribution of patient charac- Treatment compliance Analysis of haematological toxicity showed that the rate of grade III-IV neutropenia was 9.3% vs 6.2% in group A and Table 1: Sequential treatments -test: p = 0.4). The rate of grade II-III B respectively (Khi Protocol Number of patients anaemia was 13.9% vs 6.7% in anthracycline group and CMF group respectively (Khi -test: p = 0.009) (Table 5). 2AC60 → 4CMF* 2 There was no cardiac toxicity that was clinically detectable 2FAC50 → 4CMF* 1 in the two arms. The left ventricular fraction ejection 6CMF* → 4AT 1 (LVFE) was evaluated in only 7 patients (2 patients in the 3FAC50 → 3CMF* 2 anthracycline group and 5 in the CMF group) and was 4CMF → 2FEC75* 1 normal (LVFE ranged between 63% and 87%). This con- 2AC60 → 4CMF* 1 2CMF* → 4 AC 1 stitutes the main limitation of our retrospective study. The 4AC* → 2CMF 1 second limitation was the skin dermatitis toxicity events which were noted in only few cases when the patients pre- * = regimen delivered in concomitant with radiotherapy; CMF = sented high toxicity grade. Therefore, we showed that 2 2 cyclophosphamide 500 mg/m , methotrexate 60 mg/m , and 5- 4.5% of the patients treated with anthracycline regimen fluorouracil 500 mg/m ; AC60 = doxorubicin 60 mg and 2 2 had poor cosmetic results (grade II-III skin dermatitis tox- cyclophosphamide 600 mg/m ; FEC75 = -fluorouracile 500 mg/m , 2 2 epirubicin 75 mg/m , and cyclophosphamide 500 mg/m ; FAC50 = 5- icity), but in no patient of the group B the skin dermatitis 2 2 fluorouracile 500 mg/m , doxorubicin 50 mg/m , and 2 toxicity was noted (Khi -test: p = 0.013). The third limita- 2 2 cyclophosphamide 500 mg/m ; AT = doxorubicin 50 mg/m and tion was the lake of pulmonary toxicity follow up in our docetaxel 75 mg/m Page 3 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 2: Demographic, clinical, histological, molecular and treatment characteristics of patients and analysis of groups homogeneity (test Pearson Khi ) Characteristic Group A [n = 110] No (%) Group B [n = 134] No (%) p value Age <40 31 (28.2%) 23 (17.2%) 0.039 ≥40 79 (71.8%) 111 (82.8%) Menopausal status No 75 (72.8%) 77 (62.1%) 0.087 Yes 28 (27.2%) 47 (37.9%) Side Right 48 (43.6%) 71 (53%) 0.146 Left 62 (56.4%) 63 (47%) Surgery Mastectomy (Patey or Halsted) 89 (80.9%) 116 (86.6%) 0.23 Conservative 21 (19.1%) 18 (13.4%) Histology DIC 99 (94,3%) 120 (90,9%) 0.33 LIC 6 (5.7%) 12 (9.1%) SBR I 6 (5.7%) 11 (8.5%) 0.567 II 69 (65.1%) 87 (66.9%) III 31 (29.2%) 32 (24.6%) Hormonal receptors ER Positive 77 (72%) 97 (73.5%) 0.793 Negative 30 (28%) 35 (26.5%) PR Positive 61 (57.5%) 82 (62.1%) 0.474 Negative 45 (42.5%) 50 (37.9%) Tumour pT1 16 (14.7%) 19 (14.5%) 0.732 pT2 62 (56.9%) 76 (58%) pT3 28 (25.7%) 29 (22.1%) pT4 3 (2.8%) 7 (5.3%) pN, axillary pN0 20 (18.2%) 40 (29.9%) 0.001 pN1 30 (27.3%) 42 (31.3%) pN2 31 (28.2%) 42 (31.3%) pN3 29 (26.4%) 10 (7.5%) Breast/thoracic wall irradiation Yes 109 (99.1%) 124 (92.5%) 0.014 No 1 (0.9%) 10 (7.5%) Prophylactic supraclavicular fossa radiotherapy Yes 104 (94.5%) 127 (94.8%) 0.936 No 6 (5.5%) 7 (5.2%) Internal mammary radiotherapy Yes 105 (95.5%) 128 (95.5%) 0.98 No 5 (4.5%) 6 (4.5%) Page 4 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 2: Demographic, clinical, histological, molecular and treatment characteristics of patients and analysis of groups homogeneity (test Pearson Khi ) (Continued) Axillary radiotherapy Yes 18 (16.4%) 31 (23.1%) 0.189 No 92 (83.6%) 103 (76.9%) SBR = Scarf-Bloom-Richardson; DIC = ductal invasive carcinoma; LIC = lobular invasive carcinoma; ER = estrogen receptor; PR = progesterone receptor data base. Nevertheless, only 2 patients in the AC60 sub- radiotherapy was delayed) and suggested that radiother- groups showed dry cough. apy should be delivered before chemotherapy [16]. How- ever, other retrospective studies have suggested an Outcomes increased rate of distant recurrences when RT was deliv- After 76.4 months median follow-up and 65.3 months ered before chemotherapy [17-20]. mean follow up (ranging between 9.6 to 106 months), only one patient developed loco-regional relapse when The current standard of care of early breast cancer was the the treatment was based on anthracycline. In contrast, 8 surgery followed by chemotherapy followed by radiother- patients relapsed to loco- regional breast cancer in the apy. Concurrent chemo-radiotherapy is a valuable CMF group. The 5 years loco-regional recurrence free sur- method because of two advantages: 1. delivering the vival rate was equal to 98.6% in group A vs 94% in group booths treatment in same time without any delay of B; Log-rank test: p = 0.033 (Figure 1). The 5 years rate of chemotherapy or radiotherapy; 2. adjunction of chemo- DFS was 80.4% in group A vs 76.4% in group B; Log-rank therapy to radiotherapy might produce a biological syn- test: p = 0.136 (Figure 2). The 5 years overall survival rate ergy effect that can increase the efficacy of the treatment was 82.5% in group A vs 81.1% in group B; Log-rank test: [21]. Chemotherapy treatments based on liposomal dox- p = 0.428 (Figure 3). Using univariate analysis, we found orubicin, paclitaxel and vinorelbine, with concomitant RT that the only prognosis factor influencing survival was the in non operable and recurrent disease, were found to be lymph node involvement status (p = 0.007) (Cox regres- of good efficacy and tolerability [21,22]. Reirradiation sion) (table 6). with concomitant chemotherapy was shown to have pos- itive effect [21,23]. Analysis of the data showed no difference in survival between the 3 anthracycline cycles regimen: AC60, FEC75 The promising results of concurrent chemo-radiotherapy and FAC 50; Log-rank test: p = 0.982 (Figure 4). And there showed in previous studies leaded us to investigate the was no difference in disease free survival and overall sur- efficacy and tolerability of this treatment in early breast vival between the patients treated by mastectomy or breast cancer. conservative therapy (DFS: p = 0.288; OS: p = 0.173) (Fig- ure 5 and 6). The objective of our contribution was to document and support the feasibility of concomitant treatment used at the national institute of oncology in Rabat and to con- Discussion Radiotherapy and chemotherapy after surgery are manda- front our results to the results of 3 randomised studies tory in the multidisciplinary management of early-stage published previously. Our work concerned the study of a breast cancer. Even if the optimal sequencing of theses data base of 244 patients treated by radical mastectomy treatments was largely studied during the last two dec- (84%) or by BCT (16%) to compare efficacy and tolerabil- ades, they remain controversial. Several retrospective ity of two concomitant protocols: the first with anthracy- studies have suggested an increase in local recurrence rates cline based regimen and the second with CMF regimen. when radiotherapy was delivered after the end of chemo- After 76.4 months median follow-up and 65.3 months therapy treatment [13,14]. Hartsell et al showed that mean follow up (ranging between 9.6 to 106 months) we delays in the irradiation treatment were associated with found no statistical difference in the DFS and the OS increased risk of relapse in the breast cancer and recom- between the two therapeutic groups A and B. 5 years rate mended that radiotherapy treatment should be delivered of DFS was 80.4% in group A vs 76.4% in group B; Log- within 120 days after breast surgery. Other authors rank test: p = 0.136 and the 5 year overall survival rate was showed that a delay in the initiation of RT for a period of 82.5% in group A vs 81.1% in group B; Log-rank test: p = 6 months or greater from diagnosis resulted in a higher 0.428. However, to better explain these results and dem- local failure rate with an increased rate of distant metas- onstrate the beneficial effect of one of the two protocols tases and a decreased overall survival rate. The Joint Cen- (anthracycline regimen and CMF regimen) over the other, tre for Radiation Therapy Trial (JCRT) confirmed theses the homogeneity of two groups was analysed. This analy- results (rate of local recurrences was 5% vs 14% when sis showed the presence of poorer prognosis factors in the Page 5 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 3: Analysis of anthracycline sub-groups (AC60, FEC75 and FAC50) homogeneity (test Pearson Khi ) Patients characteristics Group FEC75 [n = 23] No (%) Group FAC50 [n = 20] No (%) Group AC60 [n = 57] No (%) p value Age <40 8 (34.8%) 7 (35%) 14 (24.6%) 0.53 ≥40 15 (65.2%) 13 (65%) 43 (75.4%) Menopausal status No 20 (90.9%) 14 (77.8%) 35 (66%) 0.075 Yes 2 (9.1%) 4 (22.2%) 18 (34%) Side Right 14 (60.9%) 7 (35%) 24 (42.1%) 0.188 Left 9 (39.1%) 13 (65%) 33 (57.9%) Surgery Mastectomy 5 (21.7%) 5 (25%) 8 (14%) 0.457 Conservative 18 (78.3%) 15 (75%) 49 (86%) Histology CCI 20 (95.2%) 19 (95%) 52 (94.5%) 0.992 CLI 1 (4.8%) 1 (5%) 3 (5.5%) SBR I 0 1 (5%) 4 (7.1%) 0.31 II 14 (70%) 10 (50%) 39 (69.6%) III 6 (30%) 9 (45%) 13 (23.2%) Hormonal receptors ER Positive 18 (81.8%) 11 (55%) 42 (76.4%) 0.106 Negative 4 (18.2%) 9 (45%) 13 (23.6%) PR Positive 17 (77.3%) 7 (35%) 31 (57.4%) 0.022 Negative 5 (22.7%) 13 (65%) 23 (42.6%) Tumour pT1 6 (26.1%) 1 (5%) 9 (16.1%) 0.514 pT2 10 (43.5%) 13 (65%) 32 (57.1%) pT3 7 (30.4%) 5 (25%) 13 (23.2%) pT4 0 1 (5%) 2 (3.6%) pN, axillary pN0 6 (26.1%) 3 (15%) 9 (15.8%) 0.807 pN1 4 (17.4%) 4 (20%) 15 (26.3%) pN2 7 (30.4%) 5 (25%) 18 (31.6%%) pN3 6 (26.1%) 8 (40%) 15 (26.3%%) 2 2 2 2 FEC75 = 5-fluorouracile 500 mg/m , epirubicin 75 mg/m , and cyclophosphamide 500 mg/m ; FAC50 = 5-fluorouracile 500 mg/m , doxorubicin 50 2 2 2 mg/m , and cyclophosphamide 500 mg/m ; AC60 = doxorubicin 60 mg and cyclophosphamide 600 mg/m ; SBR = Scarf-Bloom-Richardson; DIC = ductal invasive carcinoma; LIC = lobular invasive carcinoma; ER = estrogen receptor; PR = progesterone receptor anthracycline group (younger women and more lymph test: p = 0.033. Overall, the patients in the two groups node involvement). In fact, there were significantly showed a very good loco-regional control. younger women (Pearson-Khi test: p = 0.039) and more positive lymph nodes (Pearson-Khi test: p = 0.001) in the In Europe, three recent randomised phase III trials were anthracycline group. In addition, we showed significantly conducted to compare the sequential protocol (chemo- better local control in the anthracycline group; Log-rank therapy first) to the concomitant protocol: 1- in the first Page 6 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 4: Analysis of demographic, clinical, histological, molecular and therapeutic characteristics of patients treated with mastectomy and breast conservative therapy (BCT) (test Pearson Khi ) Patients characteristics Mastectomy [n = 205] No (%) BCT [n = 39] No (%) p value Age <40 48 (23.4%) 6 (15.4%) 0.268 ≥40 157 (76.6%) 33 (84.6%) Menopausal status No 129 (67.5%) 23 (63.9%) 0.669 Yes 62 (32.5%) 13 (36.1%) Side Right 48 (43.6%) 71 (53%) 0.146 Left 62 (56.4%) 63 (47%) Histology DIC 183 (91.1%) 36 (100%) 0.062 LIC 18 (9%) 0 SBR I 13 (6.6%) 4 (10.5%) 0.53 II 130 (65.7%) 26 (68.4%) III 55 (27.8%) 8 (21.1%) Hormone receptors ER Positive 120 (60.3%) 28 (71.8%) 0.877 Negative 79 (39.7%) 11 (28.2%) PR Positive 61 (57.5%) 23 (59%) 0.877 Negative 45 (42.5%) 16 (41%) Tumour pT1 25 (12.4%) 10 (25.6%) 0.003 pT2 111 (55.2%) 27 (69.2%) pT3 55 (27.4%) 2 (5.1%) pT4 10 (5%) 0 pN, axillary pN0 49 (23.9%) 11 (28.2%) 0.285 pN1 57 (27.8%) 15 (38.5%) pN2 63 (30.7%) 10 (25.6%) pN3 36 (17.6%) 3 (7.7%) Protocol Anthracycline 89 (43.4%) 21 (53.8%) 0.23 CMF 116 (56.6%) 18 (46.2%) Breast/thoracic wall irradiation Yes 194 (94.6%) 39 (100%) 0.139 No 11 (5.4%) 0 Prophylactic supraclavicular fossa radiotherapy Yes 193 (94.1%) 38 (97.4%) 0.402 No 12 (5.9%) 1 (2.6%) Internal mammary radiotherapy Yes 195 (94.1%) 38 (97.4%) 0.523 No 10 (5.9%) 1 (2.6%) Axillary radiotherapy Yes 42 (20.5%) 7 (17.9%) 0.717 No 163 (79.5%) 32 (82.1%) SBR = Scarf-Bloom-Richardson; DIC = ductal invasive carcinoma; LIC = lobular invasive carcinoma; ER = estrogen receptor; PR = progesterone receptor Page 7 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 trial, 716 early breast cancers patients were treated by BCT breast cancer after conservative surgery. In our study we and randomised into tow groups (ACROSEIN study) [24]. found very good loco-regional control of the disease with In the first group, the patients were treated by the FNC only one loco-regional recurrence in the anthracycline protocol (5-fluoro-uracil 500 mg/m2, mitoxantrone 12 goup and 8 in CMF group (p = 0.033). The main limita- 2 2 mg/m and cyclophosphamide 500 mg/m ) with con- tion of the tree European trials was the use of CMF proto- comitant radiotherapy. In the second group, the patients col and FNC protocol without the use of anthracyclines were treated by the FNC protocol followed by radiother- and taxanes in the chemotherapy treatment. To our apy. The results showed no significant difference in both knowledge, our study is the first investigation which tests treatments for the 5-years DFS, LRFS, metastatic free sur- the efficacy and tolerability of the concomitant associa- vival, and OS. The two other studies [25,26] compared tion of anthracycline regimen with radiotherapy. Our concurrent and sequential chemotherapy and radiother- results confirm the superiority of this treatment to CMF apy after surgery for a reduced number of patients. In regimen in term of local control. Anthracycline adminis- Italy, Arcangely et al [25] followed 206 patients that were tered after RT showed a high incidence of severe skin der- randomly assigned to concurrent or sequential treat- matitis and oesophagitis, as reported by Recht et al [17]. ments. The two protocols were performed after quadran- In contrary to mitoxantrone, the anthracycline chemo- tectomy and axillary dissection for breast cancer with therapy induces free-radical production that may potenti- adjuvant chemotherapy (cyclophosphamide, methotrex- ate normal tissue reactions. In ACROSEIN study, acute ate, and fluorouracil [CMF]). No significant differences loco regional toxicities were moderate in the concomitant were found in 5-years breast recurrence-free, metastasis- arm. Rouessé et al [26] presented more frequent grade 2 free, disease-free, and overall survival for the two groups skin toxicities in the concomitant arm, and more sub clin- of patients. In the third trial, Rouessé et al [26] followed ical left ventricular ejection fraction events at 1 year (p = 638 patients with prior breast surgery and positive axillary 0.02). In our study we showed more haematological tox- dissection (from which 416 were breast conservative sur- icity when the treatment is based on anthracycline with gery) and were randomly assigned to receive concomitant significantly more grade II-III anaemia (13.9% vs 6.7%; radiotherapy and chemotherapy (FNC protocol) or chem- Khi test p = 0.009). Grade III-IV neutropenia (9.3% vs otherapy (fluorouracil, epirubicin, and cyclophospha- 6.2%) and thrombopenia (0.9% vs 0.8%) were equally mide protocol) followed by RT. No differences in 5-years more frequent in anthracycline group but the differences disease-free and overall survival were observed in the two were not significant. The lack of cardiac toxicity evalua- treatment groups. Nevertheless, in the ACROSEIN study tion constitutes the main limitation of our retrospective the authors identified a significant decrease in the risk of study. Other limitations were the lack of skin and pulmo- loco-regional recurrence by 39% with concurrent radio- nary toxicities evaluations. However, we can conclude therapy and chemotherapy for node-positive patients. that there was no clinical cardiac toxicity in the two Rouessé et al [26] showed that concurrent treatment has a groups and only 4.5% of the patients had poor cosmetic significantly better locoregional control in node-positive results in the anthracycline group versus 0% in the CMF group (Khi test: p = 0.039). Table 5: Haematological toxicity Conclusion Toxicity Group A No (%) Group B No (%) p value Concurrent chemo-radiotherapy is a valuable treatment Anemia protocol which shows promising results with good toler- ability in non operable and recurrent breast cancer. Grade I 35 (32.4%) 25 (19.2%) 0.009 Grade II 13 (12%) 7 (5.4%) Grade III 2 (1.9%) 1 (1.3%) In early breast cancer, the previous published studies Grade IV 0 failed to show superiority of concurrent chemo-radiother- Neutropenia apy in term of survival. Grade I 13 (12%) 15 (11.5%) 0.4 From the present five years retrospective investigation we Grade II 27 (25%) 26 (20%) showed a similarity of the concurrent chemo-radiother- Grade III 8 (7.4%) 8 (6.2%) apy treatment results in DFS and OS and we identified a Grade IV 2 (1.9%) 0 very good loco-regional control when this treatment was Thrombopenia based on anthracycline. Grade I 2 (1.9%) 2 (1.5%) 0.341 Grade II 2 (1.9%) 0 Waiting for the results of ongoing research the standard of Grade III 1 (0.9%) 0 care is the use adjuvant chemotherapy prior to radiother- Grade IV 0 1 (0.8%) apy. Page 8 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 L Figure 1 oco-regional-Free Survival (LRFS) Loco-regional-Free Survival (LRFS): the delay of LRFS was calculated by the date of surgery until the date of revealing of a loco-regional recurrence or until the date of death, or until the date of last news. The median follow-up, the rate of LRFS in five years, and the number of patients censored were presented. Group A (anthracycline): N = 110 (1 events, 109 censored); Group B (CMF): N = 134 (8 events, 126 censored); Survival probability at five years: 98.6% in group A vs 94% in group B; Log- rank test: p = 0.033. Disease- Figure 2 Free Survival (DFS) Disease-Free Survival (DFS): the delay of DFS was calculated by the date of surgery until the date of revealing of a progress or until the date of death, or until the date of last news. The median follow-up, the rate of disease free survival in five years, and the number of patients censored were presented. Group A (anthracycline): N = 110 (21 events, 89 censored); Group B (CMF): N = 134 (36 events, 98 censored); Survival probability at five years: 80.4% in group A vs 76.4% in group B; Log-rank test: p = 0.136. Page 9 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 O Figure 3 verall survival (OS) Overall survival (OS): the delay of OS was calculated by the date of histological diagnosis until the death or until the date of last news. The median follow-up, the rate of overall survival in five years, and the number of patients censored were presented. Group A (anthracycline): N = 110 (19 events, 91 censored); Group B (CMF): N = 134 (29 events, 105 censored); Survival probability at five years: 82.5% in group A vs 81.1% in group B; Log-rank test: p = 0.428. O Figure 4 verall survival (OS) Overall survival (OS): difference between the three anthracycline sub-groups: AC60, FEC75, and FAC50; Log-rank test: p = 0.982. Page 10 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Disease- Figure 5 Free Survival (DFS) Disease-Free Survival (DFS): mastectomy compared to breast conservative therapy; Log-rank test: p = 0.288. O Figure 6 verall survival (OS) Overall survival (OS): mastectomy compared to breast conservative therapy; Log-rank test: p = 0.173. Page 11 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 6: Univariate analysis of prognostic factors (Cox Acknowledgements regression) We acknowledge the help of the Department of Medical Oncology, National Institute of Oncology, Rabat, especially Bahri Hicham. Factor P value References Age: <40 vs ≥ 40 0.221 1. Pierce LJ, Lichter AS: Defining the role of post-mastectomy SBR: I vs SBR II-III 0.402 radiotherapy: The new evidence. Oncology (Williston Park) 1996, HR: positive vs negative 0.675 10:991-1002. Tumour: pT1–2 vs pT3–4 0.263 2. Fowble B: Postmastectomy radiotherapy: Then and now. Oncology (Williston Park) 1997, 11:213-239. Lymph node involvement: yes vs no 0.007 3. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Regimen: CMF vs Anthracycline 0.428 et al.: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemother- apy. N Engl J Med 1997, 337:949-955. SBR = Scarf-Bloom-Richardson; HR = Hormonal receptors; 4. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Anders- son M, et al.: Postoperative radiotherapy in high-risk postmen- Abbreviations opausal breast-cancer patients given adjuvant tamoxifen: CMF: cyclophosphamide 500 mg/m , methotrexate 60 Danish Breast Cancer Cooperative Group DBCG 82c rand- 2 2 , and 5-fluorouracil 500 mg/m ; DFS: disease free omized trial. Lancet 1999, 353:1641-1648. mg/m 5. Ragaz J, Olivotto I, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, et al.: survival; OS: overall survival; LRFS: loco-regional recur- Locoregional radiation therapy in patients with high-risk rence free survival; AC60: doxorubicin 60 mg/m and breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer cyclophosphamide 600 mg/m ; FEC75: 5-fluorouracile Inst 2005, 97:116-126. 2 2 500 mg/m , epirubicin 75 mg/m , and cyclophospha- 6. Early Breast Cancer Trialists' Collaborative Group: Effects of radi- 2 2 mide 500 mg/m ; FAC50: 5-fluorouracile 500 mg/m , otherapy and surgery in early breast cancer: An overview of the randomized trials. N Engl J Med 1995, 333:1444-1455. doxorubicin 50 mg/m , and cyclophosphamide 500 mg/ 7. Early Breast Cancer Trialists' Collaborative Group: Favourable and m ; BCT: breast conservative therapy; LVFE: left ventricu- unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomized tri- lar fraction ejection. FNC: 5-fluoro-uracil 500 mg/m2, als. Lancet 2000, 355:1757-1770. mitoxantrone 12 mg/m2 and cyclophosphamide 500 mg/ 8. Veronesi U, Marubini E, Mariani L, Galimberti V, Veronesi P, Salvadori m2. B, et al.: Radiotherapy after breast-conserving surgery in small breast carcinoma: Longterm results of a randomized trial. Ann Oncol 2001, 12:997-1003. Competing interests 9. Fisher B, Anderson S, Bryant J, Magolese RG, Deutch M, Fisher ER, et The authors declare that they have no competing interests. al.: Twenty-years follow- up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irra- diation for the treatment of invasive breast cancer. N Engl J Authors' contributions Med 2002, 347:1233-1241. 10. Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lemer H, et NI: conception and design, acquisition of data, analysis al.: Phenylalanine mustard (L- PAM) in the management of and interpretation of data, statistical analysis, literature primary breast cancer: a report of early findings. N Engl J Med review, drafting the manuscript and revising it critically 1975, 292:117. 11. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, for important intellectual content; NM: acquisition and Brambilla C, et al.: Combination chemotherapy as an adjuvant analysis of data; OM: acquisition and analysis of data; SE: treatment in operable breast cancer. N Engl J Med 1976, 294:405-410. acquisition and analysis of data; SA: acquisition and anal- 12. Early Breast Cancer Trialists' Collaborative Group. Sys- ysis of data; IB: acquisition and analysis of data; SA: acqui- temic treatment of early breast cancer by hormonal cyto- sition and analysis of data; ZB: drafting the discussion; toxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths along 75,000 women. MAT: statistical analysis; AE: acquisition of data; OE: Lancet 1992, 339:1-15. 71–84. review of finale manuscript; NB: review of finale manu- 13. Hartsell WF, Recine DC, Griem KL, Muthy AK: Delaying the initi- script; BEKEG: review of finale manuscript; MI: involved ation of intact breast irradiation for patients with lymph node positive breast cancer increases the risk of local recur- in drafting the manuscript and revising it critically for rence. Cancer 1995, 76:2497-2503. important intellectual content; SA: statistical analysis; HE: 14. Buchholz TA, Austin-Seymour MM, Moe RE, Ellis GK, Livingston RB, Pelton JG, et al.: Effect of delay in radiation in the combined conception, design and review of final manuscript. modality treatment of breast cancer. Int J Radiat Oncol Biol Phys 1993, 26:23-35. Additional material 15. Greene FL, Page DL, Fleming ID: AJCC cancer staging manual. 6th edition. New York: Springer-Verglag; 2002. 16. Recht A, Come SE, Gelman RS, Goldtein M, Tishler S, Gore SM, et al.: Integration of conservative surgery, radiotherapy and chem- Additional file 1 otherapy for the treatment of early-stage, node-positive Diagram. Diagram to summarize therapeutic strategy. breast cancer: Sequencing, timing, and outcome. J Clin Oncol Click here for file 1991, 9:1662-1667. 17. Recht A, Come SE, Henderson IC, Gelman RS, Silver B, Hayes DF, et [http://www.biomedcentral.com/content/supplementary/1748- al.: The sequencing of chemotherapy and radiation therapy 717X-4-12-S1.doc] after conservative surgery for early-stage breast cancer. N Engl J Med 1996, 334:1356-1361. Page 12 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 18. Vujovic O, Perera F, Dar AR, Stitt L, Yu E, Voruganti SM, et al.: Does delay in breast irradiation following conservative breast sur- gery in nodenegative cancer patients have an impact on risk of recurrence? Int J Radiat Oncol Biol Phys 1998, 40:869-874. 19. Buchholz TA, Hunt KK, Amoss CM, Tucker SL, Strom EA, McNeese MD, et al.: Sequencing of chemotherapy and radiation in lymph node-negative breast cancer. Cancer J Sci Am 1999, 5:159-164. 20. Leonard CE, Wood ME, Zhen B, Rankin J, Waitz DA, Notron L, et al.: Does administration of chemotherapy before radiotherapy in breast cancer patients treated with conservative surgery negatively impact local control? J Clin Oncol 1995, 13:2906-2915. 21. Kouloulias VE, Dardoufas CE, Kouvaris JR, Gennatas CS, Polyzos AK, Gogas HJ, Sandilos PH, Uzunoglu NK, Malas EG, Vlahos LJ: Lipo- somal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial. Clin Cancer Res 2002, 8(2):374-82. 22. Kao J, Conzen SD, Jaskowiak NT, Song DH, Recant W, Singh R, Mas- ters GA, Fleming GF, Heimann R: Concomitant radiation therapy and paclitaxel for unresectable locally advanced breast can- cer: results from two consecutive phase I/II trials. Int J Radiat Oncol Biol Phys 2005, 61(4):1045-53. 23. Würschmidt F, Dahle J, Petersen C, Wenzel C, Kretschmer M, Bas- tian C: Reirradiation of recurrent breast cancer with and without concurrent chemotherapy. Radiat Oncol 2008, 3:28. 24. Toledano A, Azria D, Garaud P, Fouquet A, Serin D, Bosset JF, et al.: Phase III trial of concurrent or sequential adjuvant chemora- diotherapy after conservative surgery for early-stage breast cancer: Final results of the ARCOSEIN trial. J Clin Oncol 2007, 25(4):405-10. 25. Arcangeli G, Pinnaro P, Rambone R, Giannarelli D, Benassi M, et al.: A phase III randomized study on the sequence of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer. Int J Radiat Oncol Biol Phys 2006, 64:161-167. 26. Rouessé J, De la Lande B, Bertheault-Cvitkovic F, Serin D, Graic Y, Combe M, et al.: A phase III randomized trial comparing adju- vant concomitant chemoradiotherapy versus standard adju- vant chemotherapy followed by radiotherapy in operable node-positive breast cancer: Final results. Int J Radiat Oncol Biol Phys 2006, 64:1072-1080. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." 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Medicine & Public Health; Oncology; Radiotherapy
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Abstract

Background: The optimal sequencing of chemotherapy and radiotherapy after breast surgery was largely studied but remains controversial. Concurrent chemo-radiotherapy is a valuable method for adjuvant treatment of breast cancer which is under ongoing research program in our hospital. We are evaluating the feasibility of the concomitant use of chemotherapy retrospectively. Methods: Two hundred forty four women having breast cancer were investigated in a retrospective study. All patients were either treated by radical surgery or breast conservative surgery. The study compares two adjuvant treatments associating concomitant chemotherapy and radiotherapy. In the first group (group A) the patients were treated by chemotherapy and radiotherapy in concomitant way using anthracycline (n = 110). In the second group (group B) the patients were treated by chemotherapy and radiotherapy in concomitant way using CMF treatment (n = 134). Chemotherapy was administered in six cycles, one each 3 weeks. Radiotherapy delivered a radiation dose of 50 Gy on the whole breast (or on the external wall) and/or on the lymphatic region. The Kaplan-Meier method was used to estimate the rates of disease free survival, loco- regional recurrence-free survival and overall survival. The Pearson Khi test was used to analyse the homogeneity between the two groups. The log-rank test was used to evaluate the differences between the two groups A and B. Page 1 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Results: After 76.4 months median follow-up (65.3 months mean follow up), only one patient relapsed to loco-regional breast cancer when the treatment was based on anthracycline. However, 8 patients relapsed to loco-regional breast cancer when the treatment was based on CMF. In the anthracycline group, the disease free survival after 5 years, was 80.4% compared to 76.4% in the CMF group (Log-rank test: p = 0.136). The overall survival after 5 years was 82.5% and 81.1% in the anthracycline and CMF groups respectively (Log-rank test: p = 0.428). The loco-regional free survival at 5 years was equal to 98.6% in group A and 94% in group B (Log-rank test: p = 0,033). The rate of grade II and grade III anaemia was 13.9% and 6.7% in anthracycline group and CMF group respectively (Khi -test: p = 0.009). The rate of grade II and grade III skin dermatitis toxicity was 4.5% in the group A and 0% in the group B (Khi -test: p = 0.013). Conclusion: From the 5 years retrospective investigation we showed similar disease free survival and overall survival in the two concurrent chemo-radiotherapy treatments based on anthracycline and CMF. However in the loco-regional breast cancer the treatment based on anthracycline was significantly better than that of the treatment based on CMF. There was more haematological and skin dermatitis toxicity in the anthracycline group. of chemotherapy cycles delivered with radiotherapy was 2 Background In the case of early breast cancer and after radical mastec- (ranging from 1 to 5). Eighty percent of the patients (195 tomy or conservative surgery, adjuvant radiotherapy is patients) received 2 or more chemotherapy cycles with mandatory for diminishing the risk of recurrence [1-9]. concomitant radiotherapy. Patient medical records were Adjuvant chemotherapy is equally mandatory for dimin- retrospectively analysed and the following parameters ishing metastasis recurrences [10-12]. However, the opti- were considered: demographic data, clinical stages, histo- mal sequence of treatments is not clearly defined and logical findings, treatment and outcome. Radiological, remains controversial. Several trials have shown that the pathological and surgical reports were reviewed to deter- incidence of spared metastasis is more important in the mine the stage of the disease at the time of surgery by case of delay of chemotherapy, and local's recurrences are using the 2002 TNM classification for breast cancer [15]. more frequents in the case of delay of radiotherapy The diagnostic instrumental examinations used to stage [13,14]. Current standard treatment sequence is chemo- patients were: chest radiograph performed in all patients; therapy followed by radiotherapy. We are trying by this abdominal ultrasound performed in all patients; and retrospective study to document and support the feasibil- bone scan performed in only 16% of the patients (39 ity and efficiency of concurrent chemo-radiotherapy. patients). Treatment plan Methods Patient selection Data about treatment, notably surgery, chemotherapy and From January 2001 to December 2002, a large group of radiotherapy, were extracted from patient medical 244 patients with early breast carcinoma were selected at records. The date and site of recurrence and, if applicable, the National Institute of Oncology in Rabat, for investiga- the date of death were also considered. The first group A tion during treatment and up to now follow up. The of 110 patients was treated with anthracycline based pro- patients were divided in two groups on the basis of chem- tocol and the second group B of 134 patients was treated otherapy treatment. In group A the treatment was based with CMF protocol. Additional file 1 and Diagram 1 sum- on anthracycline and in group B the treatment was based marizes the therapeutic strategy. According to the protocol on CMF. Eighty four percent of the investigated cases followed at our institute, 95.5% of the patients received a (81% in group A and 86.5% in group B; Pearson-Khi test: radiotherapy treatment delivered to the whole breast or to p = 0.23) had radical surgery [201 received Patey mastec- thoracic wall (99.1% in group A and 92.5% in group B); tomy and 4 received Halsted mastectomy (2 in group A in addition, the same 95.5% of the patients received a and 2 in group B)] and the remaining 16% of the cases radiotherapy treatment delivered to the regional lymph (19% in group A and 13.5% in group B; Pearson-Khi test: nodes. The 4.5% of patients left received a radiotherapy p = 0.23) had breast conservative surgery [34 received treatment delivered to the whole breast or to the thoracic tumorectomy and 5 received quadrentectomy (3 in group wall, in addition to a radiotherapy treatment delivered in A and 2 in group B)]. All the 244 patients underwent con- the regional lymph nodes. All patients were treated with current adjuvant chemo-radiotherapy. In the concurrent external beam radiotherapy using tangential fields of Co- chemo-radiotherapy both chemotherapy and radiother- 60-gamma-Ray. The total delivered dose was 50 Gy, apy were delivered at the same time. The median number divided as 2-Gy daily fractions. The complementary treat- Page 2 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 ment was given by electrons or by breast brachytherapy. teristics was partly imbalanced. The influence on survival The total complementary dose ranged from 10 to 20 Gy of several prognostic factors (age, lymph node involve- for 10 patients. Chemotherapy consisted of: a- intrave- ment, tumour volume, tumour grade, receptor status, and nous CMF (cyclophosphamide 500 mg/m , methotrexate treatment regime) was analyzed by Cox regression. Statis- 2 2 60 mg/m , and 5-fluorouracil 500 mg/m ) on day 1, tical evaluation was carried out using SPSS 13.0 statistical repeated every 21 days for six courses for 134 patients, b- software. intravenous AC60 (doxorubicin 60 mg/m and cyclo- phosphamide 600 mg/m ) on day 1, repeated every 21 Results days for six courses for 57 patients, c- intravenous FEC75 Patient characteristics 2 2 (5-fluorouracile 500 mg/m , epirubicin 75 mg/m , and Between January 2001 and December 2002, 244 women cyclophosphamide 500 mg/m ) on day 1, repeated every were retrospectively evaluated. One hundred ten patients 21 days for six courses for 23 patients and d- intravenous received concurrent chemo-radiotherapy with anthracy- FAC50 (5-fluorouracile 500 mg/m , doxorubicin 50 mg/ cline based regimen and 134 patients received concurrent 2 2 m , and cyclophosphamide 500 mg/m ) on day 1, chemo-radiotherapy with CMF based regimen. The demo- repeated every 21 days for six courses for 20 patients, and graphic, clinical, pathologic, and therapeutic characteris- e- sequential treatment, repeated every 21 days for six tics of the two groups of patients were summarized in courses for 10 patients (table 1, additional file 1 and dia- table 2. After the analysis of homogeneity characteristics gram 1). We retrospectively compared toxicity, disease of the two groups we found more women aged less than free survival and overall survival between two therapeutic 40 years (Khi -test: p = 0.039) and more lymph node groups A and B and between the sub-groups within A and involvement (Khi -test: p = 0.001) in the anthracycline B. group than in group B (table 2). The progesterone recep- tor status was the only statistically different subgroup Statistical analysis from the three most important anthracycline sub-groups Overall survival (OS) and disease free survival (DFS) were (Table 3). The homogeneity between the groups of analyzed statistically in all patients. Time to recurrence patients managed either with mastectomy or breast con- was calculated from the date of surgery to the date of first servative therapy (BCT) was also studied and summarized documented relapse or to the date of last follow up. Over- in table 4. For all patients, the mean delay of chemother- all survival was calculated from the date of histological apy after surgery was 6.9 weeks (ranging from 0.7 to 37.9 diagnosis (Fine Needle Aspiration, biopsy, or surgery) to weeks). And the mean delay of radiotherapy after surgery the date of death or to the date of last follow up. The Kap- was 12.4 weeks (ranging from 2.4 to 53.3 weeks). In the lan-Meier method was used to estimate the rates of DFS, two groups A and B respectively, 96.4% and 97.7% of the loco-regional recurrence-free survival (LRFS) and OS. The patients received the 6 courses of chemotherapy. All log-rank test was used to evaluate the differences between patients in the two groups received 100% of the planned the two groups A and B. The distribution homogeneity radiotherapy dose. was analyzed with the Pearson chi -test for both groups and for all subgroups. The distribution of patient charac- Treatment compliance Analysis of haematological toxicity showed that the rate of grade III-IV neutropenia was 9.3% vs 6.2% in group A and Table 1: Sequential treatments -test: p = 0.4). The rate of grade II-III B respectively (Khi Protocol Number of patients anaemia was 13.9% vs 6.7% in anthracycline group and CMF group respectively (Khi -test: p = 0.009) (Table 5). 2AC60 → 4CMF* 2 There was no cardiac toxicity that was clinically detectable 2FAC50 → 4CMF* 1 in the two arms. The left ventricular fraction ejection 6CMF* → 4AT 1 (LVFE) was evaluated in only 7 patients (2 patients in the 3FAC50 → 3CMF* 2 anthracycline group and 5 in the CMF group) and was 4CMF → 2FEC75* 1 normal (LVFE ranged between 63% and 87%). This con- 2AC60 → 4CMF* 1 2CMF* → 4 AC 1 stitutes the main limitation of our retrospective study. The 4AC* → 2CMF 1 second limitation was the skin dermatitis toxicity events which were noted in only few cases when the patients pre- * = regimen delivered in concomitant with radiotherapy; CMF = sented high toxicity grade. Therefore, we showed that 2 2 cyclophosphamide 500 mg/m , methotrexate 60 mg/m , and 5- 4.5% of the patients treated with anthracycline regimen fluorouracil 500 mg/m ; AC60 = doxorubicin 60 mg and 2 2 had poor cosmetic results (grade II-III skin dermatitis tox- cyclophosphamide 600 mg/m ; FEC75 = -fluorouracile 500 mg/m , 2 2 epirubicin 75 mg/m , and cyclophosphamide 500 mg/m ; FAC50 = 5- icity), but in no patient of the group B the skin dermatitis 2 2 fluorouracile 500 mg/m , doxorubicin 50 mg/m , and 2 toxicity was noted (Khi -test: p = 0.013). The third limita- 2 2 cyclophosphamide 500 mg/m ; AT = doxorubicin 50 mg/m and tion was the lake of pulmonary toxicity follow up in our docetaxel 75 mg/m Page 3 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 2: Demographic, clinical, histological, molecular and treatment characteristics of patients and analysis of groups homogeneity (test Pearson Khi ) Characteristic Group A [n = 110] No (%) Group B [n = 134] No (%) p value Age <40 31 (28.2%) 23 (17.2%) 0.039 ≥40 79 (71.8%) 111 (82.8%) Menopausal status No 75 (72.8%) 77 (62.1%) 0.087 Yes 28 (27.2%) 47 (37.9%) Side Right 48 (43.6%) 71 (53%) 0.146 Left 62 (56.4%) 63 (47%) Surgery Mastectomy (Patey or Halsted) 89 (80.9%) 116 (86.6%) 0.23 Conservative 21 (19.1%) 18 (13.4%) Histology DIC 99 (94,3%) 120 (90,9%) 0.33 LIC 6 (5.7%) 12 (9.1%) SBR I 6 (5.7%) 11 (8.5%) 0.567 II 69 (65.1%) 87 (66.9%) III 31 (29.2%) 32 (24.6%) Hormonal receptors ER Positive 77 (72%) 97 (73.5%) 0.793 Negative 30 (28%) 35 (26.5%) PR Positive 61 (57.5%) 82 (62.1%) 0.474 Negative 45 (42.5%) 50 (37.9%) Tumour pT1 16 (14.7%) 19 (14.5%) 0.732 pT2 62 (56.9%) 76 (58%) pT3 28 (25.7%) 29 (22.1%) pT4 3 (2.8%) 7 (5.3%) pN, axillary pN0 20 (18.2%) 40 (29.9%) 0.001 pN1 30 (27.3%) 42 (31.3%) pN2 31 (28.2%) 42 (31.3%) pN3 29 (26.4%) 10 (7.5%) Breast/thoracic wall irradiation Yes 109 (99.1%) 124 (92.5%) 0.014 No 1 (0.9%) 10 (7.5%) Prophylactic supraclavicular fossa radiotherapy Yes 104 (94.5%) 127 (94.8%) 0.936 No 6 (5.5%) 7 (5.2%) Internal mammary radiotherapy Yes 105 (95.5%) 128 (95.5%) 0.98 No 5 (4.5%) 6 (4.5%) Page 4 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 2: Demographic, clinical, histological, molecular and treatment characteristics of patients and analysis of groups homogeneity (test Pearson Khi ) (Continued) Axillary radiotherapy Yes 18 (16.4%) 31 (23.1%) 0.189 No 92 (83.6%) 103 (76.9%) SBR = Scarf-Bloom-Richardson; DIC = ductal invasive carcinoma; LIC = lobular invasive carcinoma; ER = estrogen receptor; PR = progesterone receptor data base. Nevertheless, only 2 patients in the AC60 sub- radiotherapy was delayed) and suggested that radiother- groups showed dry cough. apy should be delivered before chemotherapy [16]. How- ever, other retrospective studies have suggested an Outcomes increased rate of distant recurrences when RT was deliv- After 76.4 months median follow-up and 65.3 months ered before chemotherapy [17-20]. mean follow up (ranging between 9.6 to 106 months), only one patient developed loco-regional relapse when The current standard of care of early breast cancer was the the treatment was based on anthracycline. In contrast, 8 surgery followed by chemotherapy followed by radiother- patients relapsed to loco- regional breast cancer in the apy. Concurrent chemo-radiotherapy is a valuable CMF group. The 5 years loco-regional recurrence free sur- method because of two advantages: 1. delivering the vival rate was equal to 98.6% in group A vs 94% in group booths treatment in same time without any delay of B; Log-rank test: p = 0.033 (Figure 1). The 5 years rate of chemotherapy or radiotherapy; 2. adjunction of chemo- DFS was 80.4% in group A vs 76.4% in group B; Log-rank therapy to radiotherapy might produce a biological syn- test: p = 0.136 (Figure 2). The 5 years overall survival rate ergy effect that can increase the efficacy of the treatment was 82.5% in group A vs 81.1% in group B; Log-rank test: [21]. Chemotherapy treatments based on liposomal dox- p = 0.428 (Figure 3). Using univariate analysis, we found orubicin, paclitaxel and vinorelbine, with concomitant RT that the only prognosis factor influencing survival was the in non operable and recurrent disease, were found to be lymph node involvement status (p = 0.007) (Cox regres- of good efficacy and tolerability [21,22]. Reirradiation sion) (table 6). with concomitant chemotherapy was shown to have pos- itive effect [21,23]. Analysis of the data showed no difference in survival between the 3 anthracycline cycles regimen: AC60, FEC75 The promising results of concurrent chemo-radiotherapy and FAC 50; Log-rank test: p = 0.982 (Figure 4). And there showed in previous studies leaded us to investigate the was no difference in disease free survival and overall sur- efficacy and tolerability of this treatment in early breast vival between the patients treated by mastectomy or breast cancer. conservative therapy (DFS: p = 0.288; OS: p = 0.173) (Fig- ure 5 and 6). The objective of our contribution was to document and support the feasibility of concomitant treatment used at the national institute of oncology in Rabat and to con- Discussion Radiotherapy and chemotherapy after surgery are manda- front our results to the results of 3 randomised studies tory in the multidisciplinary management of early-stage published previously. Our work concerned the study of a breast cancer. Even if the optimal sequencing of theses data base of 244 patients treated by radical mastectomy treatments was largely studied during the last two dec- (84%) or by BCT (16%) to compare efficacy and tolerabil- ades, they remain controversial. Several retrospective ity of two concomitant protocols: the first with anthracy- studies have suggested an increase in local recurrence rates cline based regimen and the second with CMF regimen. when radiotherapy was delivered after the end of chemo- After 76.4 months median follow-up and 65.3 months therapy treatment [13,14]. Hartsell et al showed that mean follow up (ranging between 9.6 to 106 months) we delays in the irradiation treatment were associated with found no statistical difference in the DFS and the OS increased risk of relapse in the breast cancer and recom- between the two therapeutic groups A and B. 5 years rate mended that radiotherapy treatment should be delivered of DFS was 80.4% in group A vs 76.4% in group B; Log- within 120 days after breast surgery. Other authors rank test: p = 0.136 and the 5 year overall survival rate was showed that a delay in the initiation of RT for a period of 82.5% in group A vs 81.1% in group B; Log-rank test: p = 6 months or greater from diagnosis resulted in a higher 0.428. However, to better explain these results and dem- local failure rate with an increased rate of distant metas- onstrate the beneficial effect of one of the two protocols tases and a decreased overall survival rate. The Joint Cen- (anthracycline regimen and CMF regimen) over the other, tre for Radiation Therapy Trial (JCRT) confirmed theses the homogeneity of two groups was analysed. This analy- results (rate of local recurrences was 5% vs 14% when sis showed the presence of poorer prognosis factors in the Page 5 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 3: Analysis of anthracycline sub-groups (AC60, FEC75 and FAC50) homogeneity (test Pearson Khi ) Patients characteristics Group FEC75 [n = 23] No (%) Group FAC50 [n = 20] No (%) Group AC60 [n = 57] No (%) p value Age <40 8 (34.8%) 7 (35%) 14 (24.6%) 0.53 ≥40 15 (65.2%) 13 (65%) 43 (75.4%) Menopausal status No 20 (90.9%) 14 (77.8%) 35 (66%) 0.075 Yes 2 (9.1%) 4 (22.2%) 18 (34%) Side Right 14 (60.9%) 7 (35%) 24 (42.1%) 0.188 Left 9 (39.1%) 13 (65%) 33 (57.9%) Surgery Mastectomy 5 (21.7%) 5 (25%) 8 (14%) 0.457 Conservative 18 (78.3%) 15 (75%) 49 (86%) Histology CCI 20 (95.2%) 19 (95%) 52 (94.5%) 0.992 CLI 1 (4.8%) 1 (5%) 3 (5.5%) SBR I 0 1 (5%) 4 (7.1%) 0.31 II 14 (70%) 10 (50%) 39 (69.6%) III 6 (30%) 9 (45%) 13 (23.2%) Hormonal receptors ER Positive 18 (81.8%) 11 (55%) 42 (76.4%) 0.106 Negative 4 (18.2%) 9 (45%) 13 (23.6%) PR Positive 17 (77.3%) 7 (35%) 31 (57.4%) 0.022 Negative 5 (22.7%) 13 (65%) 23 (42.6%) Tumour pT1 6 (26.1%) 1 (5%) 9 (16.1%) 0.514 pT2 10 (43.5%) 13 (65%) 32 (57.1%) pT3 7 (30.4%) 5 (25%) 13 (23.2%) pT4 0 1 (5%) 2 (3.6%) pN, axillary pN0 6 (26.1%) 3 (15%) 9 (15.8%) 0.807 pN1 4 (17.4%) 4 (20%) 15 (26.3%) pN2 7 (30.4%) 5 (25%) 18 (31.6%%) pN3 6 (26.1%) 8 (40%) 15 (26.3%%) 2 2 2 2 FEC75 = 5-fluorouracile 500 mg/m , epirubicin 75 mg/m , and cyclophosphamide 500 mg/m ; FAC50 = 5-fluorouracile 500 mg/m , doxorubicin 50 2 2 2 mg/m , and cyclophosphamide 500 mg/m ; AC60 = doxorubicin 60 mg and cyclophosphamide 600 mg/m ; SBR = Scarf-Bloom-Richardson; DIC = ductal invasive carcinoma; LIC = lobular invasive carcinoma; ER = estrogen receptor; PR = progesterone receptor anthracycline group (younger women and more lymph test: p = 0.033. Overall, the patients in the two groups node involvement). In fact, there were significantly showed a very good loco-regional control. younger women (Pearson-Khi test: p = 0.039) and more positive lymph nodes (Pearson-Khi test: p = 0.001) in the In Europe, three recent randomised phase III trials were anthracycline group. In addition, we showed significantly conducted to compare the sequential protocol (chemo- better local control in the anthracycline group; Log-rank therapy first) to the concomitant protocol: 1- in the first Page 6 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 4: Analysis of demographic, clinical, histological, molecular and therapeutic characteristics of patients treated with mastectomy and breast conservative therapy (BCT) (test Pearson Khi ) Patients characteristics Mastectomy [n = 205] No (%) BCT [n = 39] No (%) p value Age <40 48 (23.4%) 6 (15.4%) 0.268 ≥40 157 (76.6%) 33 (84.6%) Menopausal status No 129 (67.5%) 23 (63.9%) 0.669 Yes 62 (32.5%) 13 (36.1%) Side Right 48 (43.6%) 71 (53%) 0.146 Left 62 (56.4%) 63 (47%) Histology DIC 183 (91.1%) 36 (100%) 0.062 LIC 18 (9%) 0 SBR I 13 (6.6%) 4 (10.5%) 0.53 II 130 (65.7%) 26 (68.4%) III 55 (27.8%) 8 (21.1%) Hormone receptors ER Positive 120 (60.3%) 28 (71.8%) 0.877 Negative 79 (39.7%) 11 (28.2%) PR Positive 61 (57.5%) 23 (59%) 0.877 Negative 45 (42.5%) 16 (41%) Tumour pT1 25 (12.4%) 10 (25.6%) 0.003 pT2 111 (55.2%) 27 (69.2%) pT3 55 (27.4%) 2 (5.1%) pT4 10 (5%) 0 pN, axillary pN0 49 (23.9%) 11 (28.2%) 0.285 pN1 57 (27.8%) 15 (38.5%) pN2 63 (30.7%) 10 (25.6%) pN3 36 (17.6%) 3 (7.7%) Protocol Anthracycline 89 (43.4%) 21 (53.8%) 0.23 CMF 116 (56.6%) 18 (46.2%) Breast/thoracic wall irradiation Yes 194 (94.6%) 39 (100%) 0.139 No 11 (5.4%) 0 Prophylactic supraclavicular fossa radiotherapy Yes 193 (94.1%) 38 (97.4%) 0.402 No 12 (5.9%) 1 (2.6%) Internal mammary radiotherapy Yes 195 (94.1%) 38 (97.4%) 0.523 No 10 (5.9%) 1 (2.6%) Axillary radiotherapy Yes 42 (20.5%) 7 (17.9%) 0.717 No 163 (79.5%) 32 (82.1%) SBR = Scarf-Bloom-Richardson; DIC = ductal invasive carcinoma; LIC = lobular invasive carcinoma; ER = estrogen receptor; PR = progesterone receptor Page 7 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 trial, 716 early breast cancers patients were treated by BCT breast cancer after conservative surgery. In our study we and randomised into tow groups (ACROSEIN study) [24]. found very good loco-regional control of the disease with In the first group, the patients were treated by the FNC only one loco-regional recurrence in the anthracycline protocol (5-fluoro-uracil 500 mg/m2, mitoxantrone 12 goup and 8 in CMF group (p = 0.033). The main limita- 2 2 mg/m and cyclophosphamide 500 mg/m ) with con- tion of the tree European trials was the use of CMF proto- comitant radiotherapy. In the second group, the patients col and FNC protocol without the use of anthracyclines were treated by the FNC protocol followed by radiother- and taxanes in the chemotherapy treatment. To our apy. The results showed no significant difference in both knowledge, our study is the first investigation which tests treatments for the 5-years DFS, LRFS, metastatic free sur- the efficacy and tolerability of the concomitant associa- vival, and OS. The two other studies [25,26] compared tion of anthracycline regimen with radiotherapy. Our concurrent and sequential chemotherapy and radiother- results confirm the superiority of this treatment to CMF apy after surgery for a reduced number of patients. In regimen in term of local control. Anthracycline adminis- Italy, Arcangely et al [25] followed 206 patients that were tered after RT showed a high incidence of severe skin der- randomly assigned to concurrent or sequential treat- matitis and oesophagitis, as reported by Recht et al [17]. ments. The two protocols were performed after quadran- In contrary to mitoxantrone, the anthracycline chemo- tectomy and axillary dissection for breast cancer with therapy induces free-radical production that may potenti- adjuvant chemotherapy (cyclophosphamide, methotrex- ate normal tissue reactions. In ACROSEIN study, acute ate, and fluorouracil [CMF]). No significant differences loco regional toxicities were moderate in the concomitant were found in 5-years breast recurrence-free, metastasis- arm. Rouessé et al [26] presented more frequent grade 2 free, disease-free, and overall survival for the two groups skin toxicities in the concomitant arm, and more sub clin- of patients. In the third trial, Rouessé et al [26] followed ical left ventricular ejection fraction events at 1 year (p = 638 patients with prior breast surgery and positive axillary 0.02). In our study we showed more haematological tox- dissection (from which 416 were breast conservative sur- icity when the treatment is based on anthracycline with gery) and were randomly assigned to receive concomitant significantly more grade II-III anaemia (13.9% vs 6.7%; radiotherapy and chemotherapy (FNC protocol) or chem- Khi test p = 0.009). Grade III-IV neutropenia (9.3% vs otherapy (fluorouracil, epirubicin, and cyclophospha- 6.2%) and thrombopenia (0.9% vs 0.8%) were equally mide protocol) followed by RT. No differences in 5-years more frequent in anthracycline group but the differences disease-free and overall survival were observed in the two were not significant. The lack of cardiac toxicity evalua- treatment groups. Nevertheless, in the ACROSEIN study tion constitutes the main limitation of our retrospective the authors identified a significant decrease in the risk of study. Other limitations were the lack of skin and pulmo- loco-regional recurrence by 39% with concurrent radio- nary toxicities evaluations. However, we can conclude therapy and chemotherapy for node-positive patients. that there was no clinical cardiac toxicity in the two Rouessé et al [26] showed that concurrent treatment has a groups and only 4.5% of the patients had poor cosmetic significantly better locoregional control in node-positive results in the anthracycline group versus 0% in the CMF group (Khi test: p = 0.039). Table 5: Haematological toxicity Conclusion Toxicity Group A No (%) Group B No (%) p value Concurrent chemo-radiotherapy is a valuable treatment Anemia protocol which shows promising results with good toler- ability in non operable and recurrent breast cancer. Grade I 35 (32.4%) 25 (19.2%) 0.009 Grade II 13 (12%) 7 (5.4%) Grade III 2 (1.9%) 1 (1.3%) In early breast cancer, the previous published studies Grade IV 0 failed to show superiority of concurrent chemo-radiother- Neutropenia apy in term of survival. Grade I 13 (12%) 15 (11.5%) 0.4 From the present five years retrospective investigation we Grade II 27 (25%) 26 (20%) showed a similarity of the concurrent chemo-radiother- Grade III 8 (7.4%) 8 (6.2%) apy treatment results in DFS and OS and we identified a Grade IV 2 (1.9%) 0 very good loco-regional control when this treatment was Thrombopenia based on anthracycline. Grade I 2 (1.9%) 2 (1.5%) 0.341 Grade II 2 (1.9%) 0 Waiting for the results of ongoing research the standard of Grade III 1 (0.9%) 0 care is the use adjuvant chemotherapy prior to radiother- Grade IV 0 1 (0.8%) apy. Page 8 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 L Figure 1 oco-regional-Free Survival (LRFS) Loco-regional-Free Survival (LRFS): the delay of LRFS was calculated by the date of surgery until the date of revealing of a loco-regional recurrence or until the date of death, or until the date of last news. The median follow-up, the rate of LRFS in five years, and the number of patients censored were presented. Group A (anthracycline): N = 110 (1 events, 109 censored); Group B (CMF): N = 134 (8 events, 126 censored); Survival probability at five years: 98.6% in group A vs 94% in group B; Log- rank test: p = 0.033. Disease- Figure 2 Free Survival (DFS) Disease-Free Survival (DFS): the delay of DFS was calculated by the date of surgery until the date of revealing of a progress or until the date of death, or until the date of last news. The median follow-up, the rate of disease free survival in five years, and the number of patients censored were presented. Group A (anthracycline): N = 110 (21 events, 89 censored); Group B (CMF): N = 134 (36 events, 98 censored); Survival probability at five years: 80.4% in group A vs 76.4% in group B; Log-rank test: p = 0.136. Page 9 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 O Figure 3 verall survival (OS) Overall survival (OS): the delay of OS was calculated by the date of histological diagnosis until the death or until the date of last news. The median follow-up, the rate of overall survival in five years, and the number of patients censored were presented. Group A (anthracycline): N = 110 (19 events, 91 censored); Group B (CMF): N = 134 (29 events, 105 censored); Survival probability at five years: 82.5% in group A vs 81.1% in group B; Log-rank test: p = 0.428. O Figure 4 verall survival (OS) Overall survival (OS): difference between the three anthracycline sub-groups: AC60, FEC75, and FAC50; Log-rank test: p = 0.982. Page 10 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Disease- Figure 5 Free Survival (DFS) Disease-Free Survival (DFS): mastectomy compared to breast conservative therapy; Log-rank test: p = 0.288. O Figure 6 verall survival (OS) Overall survival (OS): mastectomy compared to breast conservative therapy; Log-rank test: p = 0.173. Page 11 of 13 (page number not for citation purposes) Radiation Oncology 2009, 4:12 http://www.ro-journal.com/content/4/1/12 Table 6: Univariate analysis of prognostic factors (Cox Acknowledgements regression) We acknowledge the help of the Department of Medical Oncology, National Institute of Oncology, Rabat, especially Bahri Hicham. Factor P value References Age: <40 vs ≥ 40 0.221 1. Pierce LJ, Lichter AS: Defining the role of post-mastectomy SBR: I vs SBR II-III 0.402 radiotherapy: The new evidence. Oncology (Williston Park) 1996, HR: positive vs negative 0.675 10:991-1002. 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Radiation OncologySpringer Journals

Published: Apr 7, 2009

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