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Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.

Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.

IntroductionTwice-daily radiation with concurrent chemotherapy is recognized as the standard of care for the treatment of limited stage small-cell lung carcinoma (SCLC), but its utilization in this setting is unclear. The objective of this study was to analyze modern patterns of treatment for limited stage SCLC and the impact on survival utilizing the National Cancer Database.MethodsBetween 1999 and 2012, there were 25,045 patients diagnosed with nonmetastatic SCLC who met the selection criteria, of whom 22,626 had survival data. Those receiving 45 Gy in 1.5 Gy fractions twice-daily (BID) were compared with those receiving 45 to 72 Gy in 1.8 or 2.0 Gy fractions. Overall survival was analyzed via Kaplan–Meier analysis and compared using the log-rank test. Multivariate Cox regression analysis was used to identify covariates associated with survival.ResultsThe utilization of BID radiation overall was 11.3%. Treatment at an academic center was associated with a higher likelihood of receiving BID treatment (odds ratio: 2.29, 95% confidence interval [CI]: 1.95–2.69; p < 0.001). Median survival was 22.1, 17.2, 18.3, 19.2, and 19.5 months for patients receiving 45 Gy BID, 45 Gy once-daily, 46 to 59.4 Gy once-daily, 60 to 61.2 Gy once-daily, and 62 to 72 Gy once-daily, respectively (p < 0.001 for all pairwise comparisons to BID). On multivariate analysis, treatment at an academic center (hazard ratio: 0.88, 95% CI: 0.83–0.93; p < 0.001) and receipt of BID radiation (hazard ratio: 0.92, 95% CI: 0.86–0.98; p = 0.008) were associated with improved survival.ConclusionsThe adoption of BID radiation remains very limited, but is more commonly utilized in the academic setting. In this hospital-based study, BID fractionation was associated with improved survival over once-daily fractionation, even at doses ≥60 Gy.

Angiosarcoma (AS) of the breast is a rare malignancy most commonly encountered as a secondary malignancy after the treatment of breast cancer with or without adjuvant radiation. The prognosis for secondary AS is poor, with reported five-year overall survival rates ranging from 10%-43%. The establishment of local control is vital to prognosis, yet patients often die with locally progressive disease. Multiple local therapies have been employed including surgery alone, surgery followed by radiation, and concurrent radiation and hyperthermia. Here, we report a case of secondary AS that occurred after breast conserving therapy and adjuvant radiation for ductal carcinoma in situ (DCIS). After initial surgical excision and subsequent local recurrence, our patient was treated with a novel treatment intensification strategy including neoadjuvant, accelerated hyperfractionated radiation with concurrent hyperthermia, followed by total mastectomy and flap reconstruction. The final pathologic evaluation demonstrated a near-complete response to induction thermoradiotherapy.

Purpose: The purpose of this phase II study was to prospectively determine the efficacy of preoperative chemoradiation with a hyperfractionated (Hfx) RT boost to 61.8 Gy in locally advanced rectal cancer. Methods: Eligibility stipulated that the primary lesion had to be either T4; or T3 and >4 cm or 40% of the bowel circumference. Radiation (RT) consisted of 45 Gy to the pelvis (1.8 Gy per fraction) followed by 1.2 Gy twice daily (to the gross tumor volume) to a total RT dose of 61.8 Gy. There was 5-FU infused at 1 g/m 2 /24 hours for 4 days during the 1st and 6th weeks of RT (concurrent with the Hfx boost). Surgical resection was planned 4 to 6 weeks later. Adjuvant chemotherapy (bolus 5-FU/leucovorin) was scheduled for 4 cycles at 28-day intervals. Results: There were 22 patients, ages 22 to 81 years (median, 64) enrolled in the study. Of the 20 patients evaluable for response, 10 (50%) had evidence of clinical downstaging and 5 patients (25%) had ≥90% fibrosis in the resected specimen. With a median f/u of 40 months (7-158), the 4 years actuarial rate for all patients (n = 22) of OS was 64%, of DFS 62%, and of LC 84%. 3/21 patients (14%) had positive margins, all of whom developed a local failure (P < 0.001). Conclusion: This regimen of high dose preoperative chemoRT with a Hfx RT boost (to 61.8 Gy) in patients with bulky, locally advanced rectal cancer results in clinical downstaging in half of the patients with significant fibrosis in the operative specimen.

Purpose The cytoprotective drug amifostine (Ethyol) protects rats from oral mucositis resulting from a single dose of γ-irradiation. We expanded earlier studies to determine whether multiple doses of amifostine protect against fractionated or hyperfractionated radiation and whether the active metabolite of amifostine (WR-1065) accumulates in tissues upon repeated administration. Methods and materials Rats received amifostine daily for 5 days in conjunction with a 1-week fractionated radiation schedule and were evaluated for oral mucositis. Rats also received amifostine before the am or pm exposure or b.i.d. in conjunction with hyperfractionated radiation. To determine the pharmacokinetics of WR-1065 after repeated dosing, amifostine was given 5 days a week for 1 or 3 weeks, and rat tissue and plasma were collected at intervals during and after treatment and analyzed for WR-1065. Results Amifostine protected rats from mucositis resulting from fractionated or hyperfractionated radiation. When the number of days of amifostine administration was reduced, protection was diminished. A dose of 100 mg/kg given in the morning or 2 doses at 50 mg/kg provided the best protection against hyperfractionated radiation. WR-1065 did not accumulate in tissues or tumor upon repeated administration. Conclusions Amifostine prevented radiation-induced mucositis in a rat model; protection was dose and schedule dependent.

From 1986 to 1991, 13 patients at Northwestern Memorial Hospital were entered onto a pilot study designed to test the feasibility of treating children with medulloblastoma (11 patients) or primitive neuroectodermal tumors of the cerebral hemispheres (2 patients) with hyperfractionated craniospinal radiotherapy (HFxRT). Follow-up times ranged from 10 to 96 months with a median of 53 months. The patients were prospectively divided among three treatment arms depending on prior treatment history, if any, and degree of surgical resection. The 3 patients in group I had undergone gross total resection of the primary site, receiving 64.8 Gy to the primary site and 31.2 Gy directed to the craniospinal axis (CSA). Of these 3 patients, patient 1 had residual disease in the thoracic spine at T-10. The 8 patients in group II, who had gross residual disease remaining at the primary site, received 72 Gy to the primary site and 34 Gy to the CSA. Five of these eight patients in group II also received 8-in-1 chemotherapy. The 2 patients in group III had already failed chemotherapy and were then treated with 60 Gy to the primary site and 26 Gy to the CSA. Of the 11 patients in groups I and II, 7 of the 11 (64%) have never recurred. Two of the three group-I patients have not recurred, and 5 of the 7 group-II patients have not recurred. In addition, patient 7 (group II) remains alive after salvage with bone marrow transplant, following a local failure bordering the tentorium. Unfortunately, neither of the group-III patients could be salvaged with HFxRT. Acute/subacute toxicities included 7 cases of external auditory canal or skin desquamation, 2 cases of postradiation somnolence, and 1 case each of poor wound healing and neutropenia. Chronic toxicities included hypothyroidism in 2 patients and growth problems in 2 patients. Neuropsychologic complications affected only the 3 youngest patients in the study. Three patients developed neurologic sequelae attributed to radiation, including 1 with progressive urinary incontinence, 1 who developed a transient ischemic attack, and 1 who became progressively ataxic. Our research, although based on a small number of patients, suggests that hyperfractionated radiation therapy to craniospinal access is feasible and that the survival results are favorable. This treatment strategy should be further explored in a phase-III randomized trial.

Primary malignant melanoma of the nasal cavity and paranasal sinuses is an uncommon disease, accounting for only 0.5-2% of all malignant melanomas. The primary treatment has been surgery. The frequency of local recurrence is high and recurrence is also the major determinant of treatment failure. Here we report on six patients with locally advanced disease, four of whom were too advanced for surgery, who were treated with accelerated hyperfractionated radiation in combination with cis-platinum. Three of four patients treated for local recurrent disease achieved a local cure and died of disseminated disease after 9-21 months. One patient given preoperative cisplatin and radiation is still alive with no evidence of disease 34 months after the completion of treatment. The present protocol may be a useful approach to obtain local control with the possibility of long-term cure.

5519 Background: Cetuximab is commonly used in combination with either chemotherapy or radiation in the treatment of HNC, although the optimal way to integrate cetuximab with concurrent chemoradiat...

7557 Background: Concurrent chemoradiotherapy (CRT) is standard treatment for stage III NSCLC, although the management of resectable patients (pts) remains controversial. We report an open-label phase I/II trial of the epidermal growth factor receptor inhibitor E added to perioperative CRT for resectable stage III NSCLC pts, followed by maintenance (m) E. Methods: Eligible pts had stage IIIA/B NSCLC, PS 0–1, and were resectable as determined by a thoracic surgeon. Pts received weekly P (50 mg/m2), and C (AUC 2) with daily oral E for 28 days concurrent with twice daily thoracic radiation (1.5 Gy/fraction) to 30 Gy, followed by restaging. Non-progressors underwent resection followed by the same CRT regimen and 2 years of mE (150mg). The primary endpoint of the phase I portion was the maximum tolerated dose (MTD) of E given with CRT; and for the phase II was safety and tolerability. Secondary endpoints were pathologic complete response (pCR) rate, pathologic downstaging of mediastinal nodes, progression free survival (PFS), and overall survival (OS). Results: 9 pts were enrolled in the phase I trial. The MTD of E was150mg, which was the phase II dose used. 25 pts were treated in the phase II component: median age 60, 92% stage IIIA, 64% female, 72% PS 0, 64% adenocarcinoma, and 16% never smokers. The median duration of mE was 5.5 months, with the most common reason for discontinuation being pt preference. There was no grade 4 toxicity. Grade 3 toxicity seen in >5% of pts: rash (12%), diarrhea (9%), nausea (9%), and encephalopathy (6%). The most common toxicities during mE: grade 1/2 diarrhea (72%), rash (61%), fatigue (56%), nausea (22%), and dry eyes (17%).1 pt (4%) had a pCR after neoadjuvant CRT, and 46% were downstaged to pN0–1 at surgery. At a median follow-up of 36.5 mos the median PFS is 41.8 mos (95% CI 9.3-not yet reached). The median OS has not been reached. 3 year survival is 69%. Pts downstaged to pN0–1 vs those with persistent pN2–3 had a median PFS of 41.8 vs 18.1 mos (p=0.11). Conclusions: Perioperative P, C, and E given concurrently with HFRT was well tolerated and showed promising efficacy, while compliance was poor with maintenance E. [Table: see text]

7529 Purpose: This analysis was conducted to address the potential antitumor effect of amifostine (AM) in NSCLC patients enrolled on RTOG-9801. The long-term survival results of RTOG-9801 are presented here. Methods: 243 patients (pts) with stage II/IIIAB NSCLC received induction paclitaxel (P) 225 mg/m2IV days 1, 22 and carboplatin (C) AUC 6 days 1, 22 and then concurrent weekly P (50 mg/m2) and C (AUC 2) and HRT (69.6 Gy at 1.2 Gy BID). Pts were randomly assigned to AM 500 mg IV 4x/week or no-AM during chemoradiation. Treatment differences for overall and disease-free survival (OS & DFS) were analyzed with the log-rank test; Gray's test was used for time to progression (TTP). Results: 118 pts were randomly assigned to receive AM and 121 to no-AM (4 pts were ineligible). The median follow-up for pts still alive is 52.3 months (mo) for the AM-arm and 58.3 mo for the no-AM arm (16.6 vs 17.9 for all pts). There are no significant differences in OS, DFS or TTP between arms. The median survival, 3-yr, and 5-yr OS are 17.1 mo, 27% and 17% (AM-arm) vs 18.4 mo, 28% and 16% (no-AM arm) (p=0.97). Grade 3/4/5 late-RT toxicities are similar (11%/3%/2% AM-arm vs 14%/4%/2% no-AM arm). Conclusion: While an earlier publication reported that amifostine did not reduce objective measures of severe esophagitis in RTOG-9801, patient-reported outcome analyses suggested a possible advantage to AM with decreased pain and swallowing symptoms (J Clin Oncol 23:2145–2154, 2005). This long-term follow-up analysis on survival shows no evidence of tumor radioprotection due to amifostine. The promising 5-yr OS suggests that induction paclitaxel/carboplatin (P/C) followed by concurrent RT and weekly low-dose P/C is comparable to other regimens using cisplatin doublets at higher dosages every 3–4 weeks. Research supported by NCI and Medimmune Oncology. No significant financial relationships to disclose.

14004 Background: Gemcitabine (GEM) is recognized as an effective chemotherapeutic agent for non-curative pancreatic cancer and has an activity for radiosensitizer. Although preoperative chemoradiation therapy (preCRT) with GEM is one of the promising adjuvant therapies for potentially curative pancreatic cancer, the clinical significance of the treatment remains to obscure. Methods: Potentially resectable pancreatic cancer patients were recruited in this study from September 2001 through August 2004. Patients were randomly divided into preCRT group and a control group. Patients in preCRT group received GEM (400 mg/m2 or 800 mg/m2 on day 1 and 7) and concomitant accelerated hyperfractionated irradiation (1.5 Gy ×2/day, 5 days/weeks, total dose 30Gy or 36 Gy). After 3–4 weeks’ rest of the preCRT, patients were re-evaluated for resectability. Patients who underwent R0 resection did not received any postoperative adjuvant treatment until recurrence. Results: There were 23 patients in preCRT group and were 19 patients in control group. After re-evaluation, 4 patients (17%) were considered as unresectable due to the progressed disease. 19 patients (83%) in preCRT group and 19 patients (100%) in control group underwent laparotomy. Sixteen patients (70%) in preCRT group and 17 patients (89%) in control group underwent R0 resection. Median survival times were 17.6 months in preCRT group and 16.7 months in control group, respectively (p=0.65). Among patients underwent R0 resection, one and three-years survival rate were 81.2% and 27.1% in preCRT group, while these were 70.6% and 15.4% in the control group (p=0.26). Local recurrence was observed in 4 (25%) of 16 patients who underwent R0 resection in preCRT group and in 7 (41%) of 17 patients who underwent R0 resection in control group, while recurrence at distant organs (liver, lung, peritoneum, bone) were observed in 8 patients (50%) of preCRT group and 8 patients (47%) in control group. Conclusions: Although the preoperative chemoradiation therapy with GEM and accelerated hyperfractionated radiation for potentially curative pancreatic cancer is likely to be promising against local recurrence after R0 resection, survival benefit of the therapy was unsatisfactory. No significant financial relationships to disclose.

5563 Background: Intraarterial cisplatin and hyperfractionated radiation (HYPERADPLAT) is an accepted therapy for Stage III and IV head and neck cancer. We present long-term follow-up of patients with OP and OC cancer treated with HYPERADPLAT at a single institution. Methods: 44 patients with Stage III-IV squamous cell carcinomas of the OP or OC were treated with the HYPERRADPLAT regimen consisting of external beam radiotherapy (76.8–81.6 Gy) delivered in 1.2 Gy BID fractions with intraarterial cisplatin (150 mg/m2) administered when patients had reached 60 Gy. Tumor response, disease free survival (DFS), overall survival (OS), and toxicity were assessed for all patients according to NCI CCT criteria. Results: Of 44 patients, 21 had tumors of the base of tongue, 14-tonsil, 4-floor of mouth, and 5-other. Eighty eight percent of patients had T4 tumors and 7% had T3 tumors. Complete tumor response was observed in 86% of patients and 14% had a partial response. Lymph node metastases were present in 84% of patients with 78% of node positive patients having a complete nodal response and 19% with a partial response to treatment. Three-year DFS was 55% and OS was 45%. Locoregional recurrence was noted in 30% of patients and 16% had distant failure. Overall recurrence was noted in 47% of patients with a median time to recurrence of 8 months (range 4–55 months). Median weight loss during treatment was 9% of initial body weight and 28 patients required a feeding tube within 6 months of starting treatment. Grade 3 mucositis was noted in 68% of patients and 3 patients developed Grade 4 toxicity (2 mucosal, 1 hematologic). Conclusions: HYPERRADPLAT results in excellent tumor control that is well tolerated with minimal Grade 4 toxicity in patients with advanced poor prognosis cancers of the OP and OC. These results compare favorably with historically reported control rates and response for patients with a significantly high percentage of T4 tumors of the oropharynx and oral cavity. No significant financial relationships to disclose.

The purpose was to study the effect of pre-operative radiotherapy on the strength of colon anastomosis, constructed of one irradiated and non-irradiated segment, as well as the difference between a conventional and a hyperfractionated radiation treatment. Groups of 15 animals were treated with conventional (2.0 Gy/day to total doses of 40.0, 60.0 or 80.0 Gy) or hyper-fractionated (1.6 Gy, 2×/day to total doses of 41.6,60.8 or 80.0 Gy) radiotherapy and compared to control and sham treated groups. The strength of the colon anastomosis (constructed the day after ending the radiotherapy) was measured by a bursting experiment. End results were bursting pressure (BP) and bursting wall-tension (BWT). There was no significant difference in BP or BWT between the irradiated animals and the control groups. We conclude that high-dose pre-operative radiotherapy to one end of a colon anastomosis does not affect its anastomotic strength.

Prognostic criteria were developed to select children with high-risk brainstem gliomas for experimental treatment with hyperfractionated radiation. Patients were required to have (a) tumors confined primarily to the brainstem; (b) positive findings in two of three groups of neurologic signs (cranial nerve deficits and long-tract and cerebellar signs), and (c) symptom duration of less than 6 months. The 18-month survival of only 1 of 33 evaluable patients suggests that these criteria did in fact select tumors of poor prognosis. Such noninvasive predictors provide a valuable means of selecting for experimental treatment those children who would not be expected to benefit from standard therapies for malignant brainstem tumors. These criteria do not require routine biopsy for prognostic purposes, and avoid exposing the children to unnecessary risk.