Oral pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study.

BACKGROUND: Fibrosis is a common side effect after treatment with ionizing radiation. Several methods to ameliorate debilitating fibrosis have been employed but without consistent results. The goal of this pilot study is to determine if Pirfenidone, a novel regulator of cytokine gene expression, has the potential to ameliorate established radiation-induced fibrosis. METHODS: Open label, prospective pilot study of 800 mg three times/day, orally administered Pirfenidone was administered to enrolled patients who were had completed radiation therapy and who had established radiation-induced fibrosis. Range of motion (ROM) was assessed using standard measures, and subjective measures of pain, fatigue, disability and global health were measured every three months. RESULTS: Seven patients were enrolled of whom 3 had ROM assessments of 1 site and 2 had ROM assessments of 2 sites. Of these assessments, 6 revealed increased ROM during drug intervention while 1 revealed a decreased ROM. There was an overall improvement in the mental composite score of the SF36 while physical composite score was decreased and the vitality score was unchanged. Two patients were removed from the study because of syncopal episodes. CONCLUSION: Several patients experienced improved function of at least 25% and reported subjective improvement. Pirfenidone may benefit patients with radiation-induced fibrosis and is worthy of a larger well controlled trial.

Pretransplant pulmonary function tests predict risk of mortality following fractionated total body irradiation and allogeneic peripheral blood stem cell transplant.

PURPOSE: To determine the value of pulmonary function tests (PFTs) done before peripheral blood stem cell transplant (PBSCT) in predicting mortality after total body irradiation (TBI) performed with or without dose reduction to the lung. METHODS AND MATERIALS: From 1997 to 2004, 146 consecutive patients with hematologic malignancies received fractionated TBI before PBSCT. With regimen A (n=85), patients were treated without lung dose reduction to 13.6 gray (Gy). In regimen B (n=35), total body dose was decreased to 12 Gy (1.5 Gy twice per day for 4 days) and lung dose was limited to 9 Gy by use of lung shielding. In regimen C (n=26), lung dose was reduced to 6 Gy. All patients received PFTs before treatment, 90 days after treatment, and annually. RESULTS: Median follow-up was 44 months (range, 12-90 months). Sixty-one patients had combined ventilation/diffusion capacity deficits defined as both a forced expiratory volume in the first second (FEV1) and a diffusion capacity of carbon dioxide (DLCO)<100% predicted. In this group, there was a 20% improvement in one-year overall survival with lung dose reduction (70 vs. 50%, log-rank test p=0.042). CONCLUSION: Among those with combined ventilation/diffusion capacity deficits, lung dose reduction during TBI significantly improved survival.

Ectopic Cushing's syndrome caused by an esthesioneuroblastoma.

OBJECTIVE: To report a case of florid Cushing's hormone (ACTH) secretion related to the presence of an esthesioneuroblastoma (ENB). METHODS: We present clinical, laboratory, and pathologic findings in a 36-year-old Caucasian man presenting with Cushing's syndrome. Results of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and somatostatin receptor scintigraphy are presented, along with tumor pathology findings. RESULTS: After initial biochemical studies suggestive of ectopic Cushing's syndrome, CT of the chest and abdomen revealed multiple cavitated pulmonary lesions, an ischiorectal mass, and bilateral adrenal hyperplasia. MRI of the pituitary gland revealed normal findings. Both PET scanning with [18 F]-flurodeoxyglucose (FDG) and somatostatin receptor scintigraphy with 111 indium-penetetreotide (Octreoscan) revealed strong tracer uptake in the ethmoid region. CT and MRI of the sinuses and brain subsequently localized a 5-cm mass in the ethmoid sinuses with intracranial extension. On biopsy, pathology results were consistent with a diagnosis of ENB, and immunohistochemical analysis revealed that tumor cells were strongly positive for ACTH, synaptophysin, and S-100, providing definitive diagnosis of ACTH-producing ENB. Hypercortisolemia was initially controlled by metyrapone, then by external beam radiation therapy (RT). CONCLUSION: This case illustrates the usefulness of nuclear imaging in the diagnosis of ENB, and the importance of prompt control of hypercortisolemia in Cushing's syndrome.

Pentoxifylline in the treatment of radiation-induced fibrosis.

PURPOSE: Fibrotic sequelae remain the most important dose-limiting toxicity of radiation therapy to soft tissue. Functionally, this is reflected in loss of range of motion and muscle strength and the development of limb edema and pain. Tumor necrosis factor alpha and fibroblast growth factor 2 (FGF2), which are abnormally elevated in irradiated tissues, may mediate radiation fibrovascular injury. PATIENTS AND METHODS: In an open label drug trial, we studied the effects of pentoxifylline (400 mg orally tid for 8 weeks) on 30 patients who displayed late, radiation-induced fibrosis at 1 to 29 years posttreatment (40 to 84 Gy). The primary outcome measurement was change in physical impairments thought to be secondary to radiation, including active and passive range of motion (AROM and PROM), muscle strength, limb edema, and pain. Plasma levels of cytokines (tumor necrosis factor alpha and FGF2) also were measured. Twenty-seven patients completed baseline and 8-week assessments, and 24 patients completed baseline, 8-week, and 16-week assessments. RESULTS: After 8 weeks of pentoxifylline intervention, 20 of 23 patients with impaired AROM and 19 of 22 with impaired PROM improved; 11 of 19 patients with muscle weakness showed improved motor strength; five of seven patients with edema had decreased limb girth; and nine of 20 patients had decreased pain. Pretreatment FGF2 levels dropped from an average of 44.9 pg/mL to 24.0 pg/mL after 8 weeks of treatment. CONCLUSION: Patients receiving pentoxifylline demonstrated improved AROM, PROM, and muscle strength and decreased limb edema and pain. Reversal of these delayed radiation effects was associated with a decrease in circulating FGF2.

Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial.

BACKGROUND: Between 1979-1987, the National Cancer Institute conducted a randomized, prospective study of mastectomy (MT) versus breast conservation therapy (BCT) in the treatment of patients with early-stage breast carcinoma. After a median potential follow-up of 18.4 years, the authors present the updated results. METHODS: After informed consent was obtained from each patient, 237 evaluable women with clinical AJCC Stage I and Stage II breast carcinoma were enrolled on an institutionally reviewed protocol and randomly assigned to undergo modified radical MT (116 patients) or BCT (121 patients), which was comprised of lumpectomy, axillary lymph node dissection, and radiation therapy. Negative surgical margins in the lumpectomy arm were not required. The 237 randomized patients were followed for a median potential follow-up of 18.4 years. The primary endpoints were overall survival and disease-free survival. RESULTS: At a median follow-up of 18.4 years, there was no detectable difference with regard to overall survival between patients treated with MT and those treated with BCT (58% vs. 54%; P = 0.67 overall). Twenty-seven women in the BCT arm (22%) experienced an in-breast event. After censoring in-breast events in the BCT arm that were salvaged successfully by MT, disease-free survival also was found to be statistically similar (67% in the MT arm vs. 63% in the BCT arm; P = 0.64 overall). There was no statistically significant difference with regard to contralateral breast carcinoma between the two treatment arms (P = 0.70). CONCLUSIONS: After nearly 20 years of follow-up, there was no detectable difference in overall survival or disease-free survival in patients with early-stage breast carcinoma who were treated with MT compared with those treated with BCT. For BCT patients, long-term in-breast failures continued to occur throughout the duration of follow-up. There was no statistically significant difference in the incidence of contralateral breast carcinoma between the two treatment groups.

Juxtathyroidal neck soft tissue angiosarcoma presenting as an undifferentiated thyroid carcinoma.

Angiosarcoma is a malignant growth of endothelial origin, uncommon in the head and neck. We present the case of a 38-year-old woman with long-standing goiter who presented with a rapidly growing 6.0-cm neck mass. Fine-needle aspiration biopsy of the tumor showed features of "undifferentiated thyroid carcinoma (ThyrCa)." Total thyroidectomy resulted in extirpation of all gross disease. Pathology revealed a high-grade angiosarcoma of the neck invading the thyroid gland, coexisting with papillary ThyrCa (follicular variant) in the contralateral lobe. Aggressive external electron beam radiotherapy was initiated for local control. Despite the absence of systemic dissemination initially, bulky neck recurrences, and pulmonary metastases developed rapidly, leading to the patient's demise on postoperative day 41. Autopsy showed metastatic disease involving most organs. This case illustrates that neck angiosarcomas need to be considered in the differential diagnosis of "poorly differentiated" thyroid malignancies. These soft tissue neck tumors may complicate postoperative management due to their bleeding tendency and aggressive infiltrative behavior, and carry a dismal prognosis because of the rapidity of development of local recurrence and distant metastases.