title: Impact of Sequencing Radiation Therapy and Chemotherapy on Long-Term Local Toxicity for Early Breast Cancer: Results of a Randomized Study at 15-Year Follow-Up.
abstract: To compare long-term late local toxicity after either concomitant or sequential chemoradiation therapy after breast-conserving surgery.
  
  
  
  From 1997 to 2002, women aged 18 to 75 years who underwent breast-conserving surgery and axillary dissection for early breast cancer and in whom CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy was planned were randomized between concomitant and sequential radiation therapy. Radiation therapy was delivered to the whole breast through tangential fields to 50 Gy in 20 fractions over a period of 4 weeks, followed by an electron boost. Surviving patients were tentatively contacted and examined between March and September 2014. Patients in whom progressive disease had developed or who had undergone further breast surgery were excluded. Local toxicity (fibrosis, telangiectasia, and breast atrophy or retraction) was scored blindly to the treatment received. A logistic regression was run to investigate the effect of treatment sequence after correction for several patient-, treatment-, and tumor-related covariates on selected endpoints. The median time to cross-sectional analysis was 15.7 years (range, 12.0-17.8 years).
  
  
  
  Of 206 patients randomized, 154 (74.8%) were potentially eligible. Of these, 43 (27.9%) refused participation and 4 (2.6%) had been lost to follow-up, and for 5 (3.2%), we could not restore planning data; thus, the final number of analyzed patients was 102. No grade 4 toxicity had been observed, whereas the number of grade 3 toxicity events was low (<8%) for each item, allowing pooling of grade 2 and 3 events for further analysis. Treatment sequence (concomitant vs sequential) was an independent predictor of grade 2 or 3 fibrosis according to both the National Cancer Institute Common Terminology Criteria for Adverse Events (odds ratio [OR], 4.05; 95% confidence interval [CI], 1.34-12.2; P=.013) and the SOMA (Subjective, Objective, Management and Analytic) scale (OR, 3.75; 95% CI, 1.19-11.79; P=.018), as well as grade 2 or 3 breast atrophy or retraction (OR, 3.87; 95% CI, 1.42-10.56; P=.008). No effect on telangiectasia was detected.
  
  
  
  At long-term follow-up, concomitant chemoradiation therapy has a detrimental effect on both fibrosis and retraction with an approximately 4-fold increase in the odds of grade 2 or 3 toxicity.
authors.affiliation: Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Pinnarò
authors.affiliation: Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Farneti
authors.affiliation: Department of Physics, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Strigari
authors.affiliation: Department of Physics, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Landoni
authors.affiliation: Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Marucci
authors.affiliation: Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Petrongari
authors.affiliation: Department of Radiation Oncology, Regina Elena National Cancer Institute, Rome, Italy. Electronic address: sanguineti@ifo.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sanguineti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged