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Background: Despite broad advances in multimodal treatment of locally advanced breast cancer (LABC), 30 to 40% of patients develop loco-regional relapse. The aim of this study was to analyze in a retrospective manner the effectiveness of concurrent chemo-radiotherapy (CCRTh) after neoadjuvant chemotherapy (NCT) in patients with LABC. Methods: One hundred twelve patients with LABC (stage IIB-IIIB) were treated with NCT (5-fluorouracil 500 2 2 2 2 mg/m , doxorubicin 50 mg/m , and cyclophosphamide 500 mg/m (FAC), or doxorubicin 50 mg/m and cyclophosphamide 500 mg/m (AC) IV in four 21-day courses) followed by CCRTh (60 Gy breast irradiation and 2 2 2 weekly mitomycin 5 mg/m , 5-fluorouracil 500 mg/m , and dexamethasone 16 mg, or cisplatin 30 mg/m , gemcitabine 100 mg/m and dexamethasone 16 mg), and 6–8 weeks later, surgery and two additional courses of FAC, AC, or paclitaxel 90 mg/m weekly for 12 weeks, and in case of estrogen-receptor positive patients, hormonal therapy. Results: Stages IIB, IIIA and -B were 21.4, 42.9, and 35.7%, respectively. Pathological complete response (pCR) in the breast was 42% (95% CI, 33.2–50.5%) and, 29.5% (95% CI, 21.4–37.5%) if including both the breast and the axillary nodes. Multivariate analysis showed that the main determinant of pCR was negative estrogen-receptor status (HR = 3.8; 95% CI, 1.5–9; p = 0.016). The 5-year disease-free survival (DFS) was 76.9% (95% CI, 68.2– 84.7%). No relationship between pCR and DFS was found. Multivariate analysis demonstrated that the main DFS determinant was clinical stage (IIB and IIIA vs. IIIB, HR = 3.1; 95% CI, 1.02–9.74; p = 0.04). Only one patient had local recurrence. Five-year overall survival was 84.2% (95% CI, 75–93.2%). The toxicity profile was acceptable. Conclusion: This non-conventional multimodal treatment has good loco-regional control for LABC. Randomized clinical trials of preoperative CCRTh following chemotherapy, in patients with LABC are warranted. Page 1 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:24 http://www.ro-journal.com/content/4/1/24 breast cancer confirmed by histopathology who presented Background Breast cancer is the second leading cause of cancer death loco regional disease (stages IIB, IIIA and -B, according to the 6th edition of the American Joint Committee on Can- among women in developed countries and in Mexico [1,2]. In Mexico, only a small percentage of women have cer TNM classsification and staging system and evaluated regular mammography screening; therefore the propor- by thoracic computed tomography (CT) scans, bone scin- tion of patients with locally advanced disease at diagnosis thigraphy and/or PET-CT) , without clinical response is high. In 2003, only 5–10% of newly diagnosed cases in (according to the attending physician, based on an Mexico were clinical stages 0 or I . In fact, nearly 70% increase in the breast tumor and/or pathologic axillary of breast cancer cases of patients seen at the Instituto lymph node diameters ≥50%) after completion of anthra- Nacional de Cancerología (INCan: a cancer-referral teach- cycline-containing neoadjuvant chemotherapy, and with- ing hospital for adult patients, located in Mexico City) are out evidence of distant metastases at diagnosis were stage IIB-IIIB, locally advanced breast cancer (LABC, 6th enrolled; this primary CT was followed by concurrent edition of the AJCC Cancer Staging) [3,4]. chemo-radiotherapy (CCRTh), modified radical mastec- tomy, and adjuvant systemic treatment. Exclusion criteria Current treatment of LABC requires a combination of sys- comprised other clinical stages from IIB, IIIA, and -B, temic chemotherapy (CT), surgery, and radiotherapy (RT) Phyllodes tumour as histological diagnosis, and treatment . Between six and eight courses of anthracycline- and variations. Biopsies were examined and classified by a taxane-based regimens administered sequentially or in pathologist specialized in this tumor type. The Breast Can- combination are now recommended, and CT should be cer Classification proposed by the World Health Organi- followed by segmental or modified radical mastectomy zation was employed to classify each biopsy. We utilized for operable tumors. Patients with inoperable tumors the Scarff-Bloom-Richardson (SBR) scale that is based on after maximal CT (i.e., taxane if initial therapy was anthra- nuclear pleomorphism and mitotic count, to stratify each cycline-based) could proceed to definitive RT. Patients tumor's tissue differentiation. Hormonal status was treated with surgery should receive post-operative RT to obtained by immunohistochemistry on sections of forma- minimize the risk of local recurrence. In addition, women lin-fixed, paraffin-embedded tissue, from incisional biop- with hormone-receptor-positive tumors should receive sies and subsequent surgical specimens. hormonal therapy (HT) . Treatment However, only 10–20% of patients with LABC achieve Neoadjuvant CT was instituted in four 21-days courses. clinical complete response, and 50–60%, partial response The following two treatment schedules were utilized: a) 5- 2 2 [6-8]. Pathological complete response (pCR) rate in LABC fluorouracil (500 mg/m ), adriamycin (50 mg/m ), and is poor, 8–12%, and often does not correlate with clinical cyclophosphamide (500 mg/m ) (FAC), or b) adriamycin 2 2 response [6,8-11]. Approximately, 30–40% of patients (50 mg/m ) and cyclophosphamide (500 mg/m ) (AC). with LABC develop loco-regional relapse (LRR) . CCRTh after the previously mentioned regimen was as fol- lows: RT 60 Gy (3-D CT-based simulation) to the whole- Despite improvements in local control rates and overall out- breast and nodal areas divided into 50 Gy in 5 weeks plus comes with current therapy, 5-year survival for LABC boost to palpable residual disease with a 10 Gy electron remains low (50% vs. 87% for stage I) . Moreover, con- beam in 1 week, and CT based on mitomycin C (5 mg/ 2 2 ), 5-fluorouracil (500 mg/m ), and dexamethasone current chemo-radiotherapy (CCRTh) with anthracycline m drugs is theoretically more toxic; therefore, in patients with (16 mg), or cisplatin (30 mg/m ), gemcitabine (100 mg/ LABC, this treatment modality has not been widely used. m ) and dexamethasone (16 mg), weekly during RT (six However, CCRTh has successfully improved both local con- cycles in total). Radiation Therapy Oncology Group trol and overall survival (OS) in other cancers such as (RTOG) scale was used for toxicity assessment. esophageal, lung, head and neck, and cervix [13-16]. Modified radical mastectomy and axillary lymph-node The aim of this study was to determine disease-free sur- dissection were performed post-CCRTh. Six to eight weeks vival (DFS), pathologic complete response (pCR) and after surgery, patients received adjuvent systemic treat- associated factors using a multimodal therapy (neoadju- ment with FAC or AC for two additional courses, as previ- vant chemotherapy followed by concurrent CCRTh, sur- ously described. Patients in another subgroup were gery, and CT) in patients with locally advanced breast treated with paclitaxel at a dose of 90 mg/m weekly for 12 cancer. weeks. Adjuvant hormonal treatment was administered to patients with positive tissue hormonal receptors. Methods Patients and samples Response From January 2000 to December 2003, patients seen at Pathological complete response (pCR) was defined as no the INCan Department of Breast Tumors with diagnosis of presence of tumor or microscopic disease (presence of Page 2 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:24 http://www.ro-journal.com/content/4/1/24 Table 1: Baseline patient characteristics microscopic foci in histologic sample) in breast (pCRB) samples, resected axillary (pCRA) lymph nodes and both Variable Median ± SE Number sites (pCR). Pathological response was classified as resid- N = 112 (%) ual if any tumour was present. Age (years) 50 ± 11 Statistical analysis Tumor size 5 ± 1.56 For descriptive purposes, continuous variables were sum- (cm) Mean, 3.93 marized as arithmetic means and standard deviations (SDs, errors), and categorical variables comprised relative Clinical T stage* frequencies and proportions. Inferential comparisons T2 22 (19.6) were performed with the Student t test or the Mann-Whit- T3 50 (44.6) ney U test according to the distribution (normal and non- T4 40 (35.7) normal) determined by the Kolmogorov-Smirnov test. Clinical N stage* The Chi-squared or Fisher exact test was utilized to com- N1 55 (49.1) pare clinical variables and pCR. Logistical regression anal- N2 56 (50) ysis was employed in significant (or near significant; p = N3 1 (0.9) 0.1) variables. Disease-free (DFS) and overall survivals (OS) were analyzed with the Kaplan-Meier technique, and Clinical stage* comparisons among subgroups were performed with a IIB 24 (21.4) IIIA 48 (42.9) log-rank test. All variables were dichotomized for survival IIIB 40 (35.7) analysis. Adjustment of potential confounders was con- ducted by log-rank analysis stratification and by Cox pro- Histological grade† portional hazards regression multivariate analysis. All Low/moderate 45 (40.2) tests were two-sided, and the significance value was set at High 67 (59.8) p = 0.05. SPSS (version 10.0; SPSS, Inc., Chicago, IL, USA) and STATA (StataCorp, College Station, TX) software Estrogen receptors Positive 48 (42.9) packages were employed for data analysis. Negative 64 (57.1) Results Progesterone receptors Patients and Samples Positive 46 (41.1) Between January 2000 and December 2003, 112 patients Negative 66 (58.9) met the selection criteria for this study. Mean age was 50 ± 11 years, and median tumour size was 5 ± 1.56 cm. Treatment after CCRTh Anthracycline 54 (48.2) Patients with tumor at stages T2, -3 and -4 represented Taxanes 58 (51.8) 19.6, 44.6 and 35.7% of cases, respectively. Thus, patients were in clinical stages IIB, IIIA, and -B were 21.4, 42.9, and Abbreviations: SE = standard error; CCRTh = concurrent chemo- 35.7%, respectively (Table 1). All neoplasms were infil- radiotherapy. trating ductal carcinoma. ER-positive expression was * 6th edition of the American Joint Committee on Cancer TNM classification found in 42.9%, and in 41.1% for PgR. Low/moderate and staging system. histological grade was 40.2, while and high grade stood at † Scarff-Bloom-Richardson (SBR) scale. 59.8%. Human epithelial growth factor receptor 2 (HER2) expression was not included in data analysis because only two patients (1.7%) were positive. Post-sur- Table 3 shows the relationship between pCR and clinico- gical systemic treatment was based on anthracycline in pathological factors. Multivariable analysis demonstrated 48.2% and on taxane drugs in 51.8% of patients (Table 1). that the main determinant of pCR was negative ER status (HR = 3.8; 95% CI, 1.5–9; p = 0.016). Pathological Complete Response Pathological response was independently assessed in the Outcomes primary site and in the axillary lymph nodes. In the breast, Mean follow-up was 43 months (range 7–125 months). pCRB was present in 42% (95% Confidence interval [95% Median DSF has not been achieved. Five-year DFS was CI], 33.2–50.5), microscopic disease in 27.7% (95% CI, 76.9% (95% CI, 68.2–84.7%). No relationship between 19.2–36.8), and residual disease in 30.4% (95% CI, 25.3– pCR and DFS was found. As independent factors, clinical 38.9) of patients, while in the axilla, pCRA was found in stages IIB and IIIA were associated with a longer disease- 58% (95% CI, 52.8–65.1) and persistent disease in 42% free survival (HR = 3.1; 95% CI, 1.02–9.74; p = 0.04) as (95% CI, 30.2–47.3) of patients. At both sites (breast and compared to clinical stage IIIB (Table 4). Only one patient axilla), pCR was 29.5% (95% CI, 21.4–37.5) (Table 2). had local recurrence. Tumor relapse occurred in 12.5, 3.6, Page 3 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:24 http://www.ro-journal.com/content/4/1/24 Table 2: Frequency of pathological-complete response at enhances the possibility of surgery [7,17,18]. Advances in primary site and axilla neoadjuvant systemic CT for LABC include not only ear- lier treatment of sub-clinical distant micrometastases and Primary site/axilla Frequency primary-tumour downstaging, but also the possibility of N = 112 (%) in vivo assessment of response to specific systemic agents. Negative/negative 29.5 Thus, it is not only rational, but also current practice, to Negative/positive 12.5 apply this approach in inoperable LABC . However, Positive/negative 28.6 the magnitude of benefit from neoadjuvant CT on sur- Positive/positive 29.5 vival in breast cancer remains unclear due to the few com- parative trials conducted specifically on LABC . 2.7, and 1.8% as bone, lung, liver and brain metastasis, Comparative trials of neoadjuvant vs. adjuvant CT in pri- respectively. Three patients had more than one recurrence mary operable breast cancer demonstrate equivalent sur- site. OS at 5 years was 84.2% (95% CI, 75–93.2%). Toxic- vival outcomes . Despite multimodal therapy ity exhibited during CCRTh was as follows: grade 1–2 neu- improvements in LABC, 11–30% of patients develop local tropenia in 32.2%, grade 1–2 anemia in 5.2%, and grade relapse [5,20]. Moreover, poor reponse to neoadjuvant CT 3 radioepithelitis in 22.4% of patients. is known to be associated with a higher probability of loco-regional recurrence (LRR) . In our study, no Discussion patient responded to neoadjuvant CT; thus, patients pre- Use of neoadjuvant systemic CT and post-mastectomy RT sented a high risk for LRR. Additionally, approximately has become standard for patients with LABC because this 60% were ER-negative, which represents an additional treatment course improves prognosis substantially and Table 3: Relationship between pathological-complete response at breast and axilla with clinico-pathological factors Variable pCR Univariate analysis Multivariate analysis N = 112 % (95% CI) p HR (95% CI) Age (years) 0.204 >50 64 (54–74) <50 75 (67–83) Clinical T stage* 0.218 T2 54 (45–62) T3 72 (64–80) T4 75 (67–83) Clinical N stage* 0.072 N1 59(51–67) N2/N3 78 (70–85) Clinical stage* 0.656 IIB 66 (58–74) IIIA 66 (58–74) IIIB 75 (67–83) Estrogen receptors 0.002 3.8 (0.149–0.087) 0.016 Negative 81 (74–88) Positive 54 (45–63) Progesterone receptors 0.090 1.1 (0.391–3.571) 0.767 Negative 75 (67–83) Positive 60 (52–68) Histological grade† 0.06 0.5 (0.244–1.038,) 0.063 Low/moderate 60 (52–68) High 76 (68–84) Abbreviations: pCR = pathological complete response; 95% CI = 95% confidence interval; HR = hazard ratio. * 6th edition of the American Joint Committee on Cancer TNM classification and staging system. † Scarff-Bloom-Richardson (SBR) scale. Page 4 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:24 http://www.ro-journal.com/content/4/1/24 Table 4: Relationship between disease-free survival with clinico-pathological factors Variable 1-year DFS 2-year DFS 5-year DFS Univariate analysis Multivariate analysis N = 112 (months ± SD) (months ± SD) (months ± SD) p HR (95% CI) Age (years) 0.09 >50 92 ± 3 82 ± 5 82 ± 5 <50 96 ± 2 94 ± 2 92 ± 3 Clinical T stage* 0.05 T2 90 ± 6 86 ± 7 86 ± 7 T3 98 ± 2 96 ± 2 96 ± 2 T4 87 ± 5 82 ± 6 78 ± 6 Clinical N stage* 0.79 N1 92 ± 3 90 ± 4 90 ± 4 N2/N3 92 ± 3 87 ± 4 84 ± 5 Clinical stage* 0.03 3.1 (1.02–9.74,) 0.0406 IIB/IIIA 95 ± 2 93 ± 3 93 ± 3 IIIB 87 ± 5 82 ± 6 78 ± 6 Estrogen receptors 0.012 0.3 (0.91–1.22,) 0.97 Negative 92 ± 3 85 ± 4 83 ± 4 Positive 97 ± 2 93 ± 3 93 ± 3 Histological grade† 0.04 3.5 (0.79–16.28,) 0.98 Low/moderate 100 97 ± 2 94 ± 3 High 91 ± 3 83 ± 4 83 ± 4 Pathological response 0.56 pCR/microscopic 92 ± 3 88 ± 3 86 ± 4 Residual 94 ± 4 91 ± 4 91 ± 4 Abbreviations: DFS = disease-free survival; SD = standard deviation; HR = Hazard ratio; 95% CI = 95% confidence interval. * 6th edition of the American Joint Committee on Cancer TNM classification and staging system. † Scarff-Bloom-Richardson (SBR) scale. risk factor for patients with LRR in LABC treated with neo- the higher radiation-neumonitis frequency in patients adjuvant chemotherapy, mastectomy, and RT . with lung cancer treated with radiotherapy combined with gemcitabine [26,27], none of enrolled patients Clinical trials regarding the role and benefit of RT in the developed severe lung or cardiac toxicity as late effects. management of patients with LABC are sparse. The lim- Moreover, a phase I study showed a reduction of local ited data and guidelines available do suggest that loco- recurrence rate with the addition of gemcitabine to chem- regional RT should be employed in post-mastectomy otherapy in unresectable chest wall recurrences . LABC to reduce LRR rates [17,18,21,22]. We administered first neoadjuvant chemotherapy, because it is the standard Many issues remain unclear, such as best timing for radi- treatment for LABC. Nevertheless, all included patients otherapy in relation to surgery. We added CCRTh to did not present clinical response, thus we proposed standard anthracycline-based chemotherapy to improve CCRTh. We employed two regimens of CCRTh. The first local control in this group of patients, obtaining a 5-years was based on 5-FU and mitomycin C, because of previ- DFS of 76.9% and only one LRR among these 112 patients ously good reported results with this treatment in patients (1%). RT as pre-operative or unique modality has been with anal carcinoma . The second regimen was based described for some time with variable outcomes and on cisplatin and gemcitabine, because of good results reports of 5-year clinical cure in different breast-cancer with this multimodal treatment in head and neck carci- clinical stages [29-31]. In another retrospective study, pre- noma and cervical cancer reported in our Institution operative RT was administered to 75 patients with tumors [24,25]. Moreover, we added dexamethasone to these two >3 cm and only 12% developed LRR, nearly all patients regimens as an antiemetic drug, and to reduce the risk of (96%) underwent conservative surgery with satisfactory radiation neumonitis. Despite the recent knowledge of cosmetic results . In contrast, in the present study the Page 5 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:24 http://www.ro-journal.com/content/4/1/24 all patients underwent mastectomy, which likely contrib- tive RT with or without concurrent CT, and reported at uted to the lower LRR (1%) observed in this study. multivariate analysis that the CCRTh group exhibited a statistically lower recurrence rate with significantly higher There are few reports of CCRTh in LABC. Additional expe- grade 2 acute skin toxicity in the concurrent group (21.2 rience in treatment type is available for early stage breast vs. 11.2% of the RT-only group; p < 0.0001) . A phase carcinoma [31-33]. A retrospective study analyzed 38 III study compared concurrent or sequential adjuvant CRT patients from five institutional trials with inoperable loco- after conservative surgery for early-stage breast cancer, regional disease after primary chemotherapy completion reporting no significant difference for DFS or LRR-free sur- and pre-operative RT treatment, reporting a 5-years DFS of vival; nevertheless in the node-positive subgroup, the 5- only 35% and a 5-year LRR of 27% for surgically treated year LRR-free survival was statistically better in the concur- patients. In our study we report longer survival and pro- rent arm (97% in concurrent vs. 91% in sequential; p = gression-free rates among a larger cohort of patients. Dif- 0.02) corresponding 39% decreased risk for LRR . ferences between our results and those of the previously mentioned study could be due to differences in the In our study, on multivariate analysis, ER negative tumors patient populations (our study did not include stage IV were associated with higher pCR rates, and poorly differ- patients, while 24% of patient in the other study had N3 entiated tumors showed a trend for higher pCR rates. A disease) and our use of CCRTh with radiosensitizing study of 399 pre-operative CT-treated patients with LABC agents (mitomycin C (5 mg/m ), 5-fluorouracil (500 mg/ reported that negative ER- and PgR expression and grade m ), and dexamethasone (16 mg) or cisplatin (30 mg/ 3 are associated with high pCR rates . Two other stud- 2 2 m ), gemcitabine (100 mg/m ), and dexamethasone (16 ies reported similar results concerning the association of mg) weekly for six total courses) during RT. absent hormonal receptors (12 times more likely to achieve a pCR) and high histological grade with major The success of RT depends on increasing malignant-cell pCR rate to neoadjuvant CT in patients with LABC [9,37]. sensitivity to radiation-induced cell kill coupled with a Response rates of neoadjuvant CT in LABC are between 5 reduction in metastasis phenotypes of these cells. Radia- and 8.7% with anthracycline-based CT, taxane-containing tion damage to cells and tissues involve generation of regimens, or navelbine-containing regimens [9,37,38]. In reactive oxygen species and reactive nitrogen species fol- our study, using CCRTh, we found superior pRCB (42%) lowed by alterations in lipids, DNA, and proteins, which and pCR (29.5%) than in other series. A phase II study eventually lead to cellular dysfunction or cell death. Alter- reported similar results to ours, for example, a 27% pCR ations in lipid membrane due to peroxidative damage rate employing pre-operative CCRTh for breast cancer, in may form a potential initiator of radiosensitizing effects which CT was based on 5-FU and vinorelbine regimens. in combination with drugs acting through modulation of Therefore, similar to our results, these authors found three membrane associated events involved in apoptosis induc- pCR-associated factors: histological grade 3; absence of tion and increasing oxidative damage or by synchronizing hormonal receptors, and high mitotic index . Tumour cells to a radiosensitive phase of the cell cycle thus causing response to pre-operative CT correlates with outcomes enhanced killing . This is the rationale for utilizing and could identify patients with CT-sensitive micrometas- radiosensitizing agents, and could explain the good path- tases . We found no association between pCR and DFS. ological response and LRR rates of our study. Nonetheless, A possible explanation is that tumor response to CCRTh this treatment type could increase toxicity as a result of cell does not reflect sensitivity systemically, but only locally. damage and apoptosis, but this event was presented in our study patients with the following acceptable profile: grade A previous report clearly describes the surgical complica- 1–2 neutropenia in 32.2%; grade 1–2 anemia in 5.2%, tions of CCRTh-treated patients at our Institution. Three and grade 3 radioepithelitis in 22.4% of patients. This tox- hundred sixty patients were enrolled in this report, of icity is consistent with other retrospective analyses on whom 46% developed wound complications, 17% surgi- CCRTh, but in patients with early breast carcinoma cal site infection, and 16.9% developed necrosis. The [32,33]. For example, a retrospective analysis of 106 authors found that radiotherapy-induced skin toxicity patients with early disease treated with CCRTh after breast comprises a risk factor for development of major wound conservative surgery (adjuvant CCRTh) reported grade 3 complications. These elevated wound complications may radioepithelitis in 20% of patients. Furthermore, when be explained by radiotherapy effects on tissue healing, authors compared sequential CT and RT with CCRTh, the decrease of vascularity, and induction of tissue-hypoxia latter treatment was superior for 10-year local control (92 and fibrosis, producing necrosis and ulceration . In our vs. 83%); however, in this report there were at least four analysis, we only included 112 of these 360 patients, different CCRTh schedules; therefore, it is difficult to con- because they achieved selection criteria for our analysis. clude which of the four comprises the better treatment Despite that our series has the larger reported number of regime . Another retrospective study compared 485 CCRTh-treated patients and that treatment was homoge- patients treated with conservative surgery and post-opera- neous (only two regimens of radiosensitizing CT), it Page 6 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:24 http://www.ro-journal.com/content/4/1/24 mark N: Preoperative chemotherapy: updates of National entertains the limitation of being a retrospective analysis Surgical Adjuvant Breast and Bowel Project Protocols B-18 and patient selection was based on clinical response and B-27. J Clin Oncol 2008, 26:778-785. according to the attending physician. 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Bollet MA, Sigal-Zafrani B, Gambotti L, Extra JM, Meunier M, Nos C, available free of charge to the entire biomedical community Dendale R, Campana F, Kirova YM, Dieras V, Fourquet A: Patholog- ical response to preoperative concurrent chemo-radiother- peer reviewed and published immediately upon acceptance apy for breast cancer: results of a phase II study. Eur J Cancer cited in PubMed and archived on PubMed Central 2006, 42:2286-2295. yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 8 of 8 (page number not for citation purposes)
Radiation Oncology – Springer Journals
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