title: Long-term normal tissue effects of intraoperative electron radiation therapy (IOERT): late sequelae, tumor recurrence, and second malignancies.
abstract: OBJECTIVE
  To evaluate long-term survivors treated with intraoperative electron radiation therapy (IOERT) as a component, with particular emphasis on analyzing late normal tissue toxicity, second malignancies, and patterns of delayed tumor recurrence.
  
  
  METHODS
  From September 1984 to December 1991, 739 patients were treated with IOERT. One hundred ninety-five patients were alive at least 5 years after IOERT (26%). Patient information regarding late complications related symptoms, incidence of second tumors, and delayed relapses were analyzed. Normal tissue changes were categorized by a modified LENT/SOMA scale (Grade 0-1, Grade 2, and Grade 3-4). Risk of late toxicity was grouped by type and number of cancer treatment modalities employed in each patient: surgery + IOERT alone (17 patients, 9%); IOERT + external radiotherapy +/- chemosensibilization (90 patients, 46%); IOERT +/- external radiotherapy +/- neoadjuvant chemotherapy (+/- previous radiotherapy) (88 patients, 45%). Biologic effective doses (BED) were calculated for alpha/beta = 3.5 for late fibrosis.
  
  
  RESULTS
  With a mean follow-up time of the surviving patients of 94 months (range: 55-162 months), 99 patients (51%) had Grade 0-1 toxicity, 52 (27%) had Grade 2, and 44 patients (23%) presented Grade 3-4 late normal tissue complications. Risk groups by treatment intensity did correlate with severity of observed toxicity (p < 0.001). BED estimations did not correlate with late normal tissue damage. The tumor type with higher toxicity scores was bone sarcoma (28/46, 60%), in which the estimated BED = 100.5 Gy. Peripheral neuropathy was the dominant IOERT-specific toxicity present in 24 patients (12%). Second malignancies were identified in 8 patients (4%), none inside the IOERT field (3 questionable to be marginal to the external beam radiotherapy volume). In 36 patients (18%), recurrence of the originally treated tumor was detected, including 11 (7%) local relapses.
  
  
  CONCLUSIONS
  The incidence of late normal tissue complications (50%) and severity (23%) is significant in a cohort of patients surviving more the 5 years after IOERT. The understanding of the contribution of IOERT to late tissue damage requires specific analysis. Peripheral neuropathy is a characteristic finding in IOERT trials. Second malignancies inside the IOERT field were not identified during the study period. The risk of recurrences, including local failures, requires an intensive follow-up of long-term survivors from IOERT trials.
authors.affiliation: Department of Oncology, Clínica Universitaria, Universidad de Navarra, Pamplona, Spain. azinovic@unav.es
authors.forename: I
authors.initials: I
authors.lastname: Azinovic
authors.forename: F A
authors.initials: FA
authors.lastname: Calvo
authors.forename: F
authors.initials: F
authors.lastname: Puebla
authors.forename: J
authors.initials: J
authors.lastname: Aristu
authors.forename: R
authors.initials: R
authors.lastname: Martínez-Monge
mesh_terms: D003131:Combined Modality Therapy; D004583:Electrons / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007432:Intraoperative Period; D008297:Male; D009369:Neoplasms / Q000532:radiotherapy* / Q000601:surgery; D016609:Neoplasms, Second Primary / Q000453:epidemiology*; D010523:Peripheral Nervous System Diseases / Q000453:epidemiology* / Q000209:etiology / Q000473:pathology; D011832:Radiation Injuries / Q000453:epidemiology* / Q000473:pathology; D011879:Radiotherapy Dosage; D012008:Recurrence; D012062:Relative Biological Effectiveness; D017741:Survivors