Thoracic Conformal Radiation Therapy Research Articles

P2.02-029 Concomitant ChemoRadiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Phase II Study from the Galician Lung Cancer Group

Concomitant platinum-based ChemoRadiotherapy (CT-RT) is the recommended treatment for unresectable locally advanced Non-Small Cell Lung Cancer (NSCLC). We conducted a phase II study to evaluate the efficacy and safety of concomitant CT-RT with cisplatin (C) and intravenous and oral vinorelbine (V) and thoracic radiotherapy. 31 chemo-naive patients with histologically confirmed inoperable locally advanced NSCLC, stage IIIA (T4 or N2)/IIIB, PS 0-1 and adequate lung function (FEV1 > 1.1, V20 < 30%) were included in concomitant CT-RT with: C 80 mg/m2 day 1 and intravenous V 25 mg/m2 day 1 and oral V 25 mg/m2 day 8 for three cycles, during conformal thoracic radiotherapy (66 Gys, 180 cGy/day). The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), response rate (RR) and toxicity. Median follow-up: 18,1 months. The patients characteristics were: mean age 59,6 years (44-75); male/female: 26/5; ECOG PS 0/1: 5/26; adeno/squamous/large cell carcinoma: 15/12/4; stage IIIA 16 patients and stage IIIB 15 patients. 28 patients were evaluable for response (3 patients in treatment) and 31 for toxicity. RR: 3 CR, 18 PR (RR 75%; 95% CI: 59-91), 5 SD (17.8%) and 2 PD (7.2%). The median PFS was 12 months (95% CI:6-18) and median OS was 28 months (95% CI:21-34). The PFS at 1/3 years were 47%/20% and the OS at 1/3 years were 77%/45%. Main toxicities (NCI-CTC 4.0) per patient in CT-RT (89 cycles of chemotherapy, 2.9 per patient; mean doses RT: 65,4 Gys) grade 1-2/3-4 (%) were: neutropenia 32/22.5; anemia 39/10; thrombocytopenia 13/0; nausea/vomiting 31/3; fatigue 29/0; esophagitis 39/6 and pneumonitis 16/0; hospitalizations was necessary in 9 patients: febrile neutropenia in 3 patients and grade 3 esophagitis in 2 patients. Concomitant CT-RT with Cisplatin and intravenous and oral Vinorelbine during thoracic radiotherapy is a feasible treatment option for inoperable locally advanced stage III NSCLC, showing good clinical efficacy and tolerability with acceptable long-term survival.

Gefitinib Combined With Standard Chemoradiotherapy in EGFR-Mutant Locally Advanced Non–Small-Cell Lung Cancer: The LOGIK0902/OLCSG0905 Intergroup Study Protocol

Herein, we describe an ongoing phase II trial in patients with locally advanced non–small-cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR). Patients with chemotherapy-naive locally advanced disease with active EGFR mutations will receive the induction treatment, specified as gefitinib monotherapy (250 mg/body) for 8 weeks. Patients whose disease has not progressed during the induction therapy will receive cisplatin and docetaxel (40 mg/m2) on days 1, 8, 29, and 36, and concurrent 3-dimensional conformal thoracic radiotherapy with a single daily fraction of 2 Gy, for 5 consecutive days each week to provide a total dose of 60 Gy. The primary end point is overall survival at 24 months. A target sample size of 21 evaluable patients is considered sufficient to validate an expected rate of 85%, and 60% would be the lower limit of interest, with 80% power and a 1-sided α of 5%. Secondary end points include toxicity, response rate, and overall survival. This study will clarify whether tyrosine kinase inhibitors targeted to EGFR can produce a maximal effect in selected NSCLC patients with the relevant driver mutation, even in the locally advanced setting.

Efficacy of 3D conformal thoracic radiotherapy for extensive-stage small-cell lung cancer: A retrospective study.

The aim of the present study was to evaluate the effect of 3-dimensional conformal thoracic radiotherapy (TRT) on extensive-stage small-cell lung cancer (ES-SCLC). A total of 165 patients with ES-SCLC were enrolled in the present study, including 82 patients receiving chemotherapy combined with TRT (the ChT/TRT group) and 83 patients receiving chemotherapy alone (the ChT group). The overall survival (OS) and progression-free survival (PFS) rates were compared between the ChT/TRT and ChT groups, and the prognostic factors for OS rate were identified. It was found that the patients had a median OS time of 15 months, and 2- and 5-year OS rates of 31.5 and 2.4%, respectively. The 2- and 5-year OS rates were 35.3 and 2.4% in the ChT/TRT group, and 14.5 and 2.4% in the ChT group, respectively (P<0.05). The 1- and 2-year PFS rates were 35.4 and 6.0% in the ChT/TRT group, and 20.5 and 6.0% in the ChT group, respectively (P<0.05). The median PFS was 11 months in the 20 patients receiving TRT at 45 Gy/30 fractions twice daily, and 9 months in the 22 patients receiving TRT at 60 Gy/30 fractions daily (P=0.043). Multivariate analysis revealed that receiving ≥4 cycles of chemotherapy (P=0.001) and TRT (P=0.008) were favorable prognostic factors for OS. It was concluded that the addition of TRT improves the OS and PFS rates of patients with ES-SCLC, and TRT administration at 45 Gy/30 fractions twice daily is feasible and tolerable for the treatment of ES-SCLC. Thus, TRT and receiving ≥4 cycles of chemotherapy are independent, favorable prognostic factors for OS in patients with ES-SCLC.

Prognostic Factors and Survival in Non-Small Cell Lung Cancer Patients Treated with Chemoradiotherapy.

BACKGROUND:According to the literature, performance status, stage-tumor dimension and nodal status, weight loss, were the most important prognostic factors for survival in patients with locally advanced non-small cell lung cancer.AIM:To evaluate the treatment results and the prognostic variables in our patients treated with sequential and concurrent chemoradiotherapy.MATERIAL AND METHODS:In the study 85 patients were randomly assigned to one of the two treatment arms. In the sequential arm, 45 patients had previously received sequential chemotherapy with 4 cycles of and etoposide followed by conformal radiotherapy (RT). In the second concurrent group, 40 patients received concomitant chemotherapy of cisplatine and etoposide and conformal RT, followed by two cycles of consolidation chemotherapy of carboplatine and etoposide. We described all phases of the conformal three dimensional (3-D) RT.RESULTS:From October 2005 to March 2008, 93 patients were enrolled. Eight patients were not eligible, seven had stage IV and one patient had pleural effusion. They were all initially considered to have stage IIIB disease. The median survival was 13 months for the patients in the sequential arm and 19 months for those in the concurrent treatment arm. The differences were statistically significant (log-rank test p=0.0039). The disease-free survival was 9 months in the sequential arm and 16 months in the concurrent treatment group. The differences were statistically significant (log-rank test p=0.0023). We found that the following prognostic factors significantly influenced the survival in lung cancer patients treated with conservative method: - age, p<0.05; - performant status, p<0.001; - weight loss, p<0.001; tumor dimension, p<0.05; and - nodal involvement, p<0.05.CONCLUSION:In our study, the dose-limiting toxicity, esophagitis was reduced by performing conformal radiotherapy. Conformal thoracic radiotherapy and new radiotherapy technics, such as respiratory gated radiotherapy, allow dose escalating and may probably improve survival and local control in lung cancer patients.

Comparative Effectiveness of Intensity-Modulated Versus 3D Conformal Radiation Therapy Among Medicare Patients with Stage III Lung Cancer

The clinical benefit of intensity-modulated radiation therapy (IMRT) compared to 3D conformal radiation (3D-RT) has not been well established for locally advanced non-small-cell lung cancer (NSCLC). Using SEER-Medicare, we identified Medicare beneficiaries diagnosed with stage III NSCLC who received potentially curative (≥ 25 fractions) thoracic IMRT or 3D-RT from 2002-2009. Overall survival and number of hospital days within 90 days of radiation were analyzed using Cox proportional hazard and negative binomial regression models, respectively. Propensity score adjustment was used to control for clinical and demographic variables associated with outcomes. IMRT comprised an increasing proportion of conformal thoracic radiation for NSCLC, rising from 3.0% in 2002 to 26.8% in 2009. Use of IMRT varied significantly by year of diagnosis, facility type, and geographic region and was more likely to be used among patients receiving chemotherapy or with higher comorbidity scores. Among patients receiving potentially curative treatment, there was no difference in overall survival (propensity adj HR .99, p = 0.83) or number of hospital days in the 90 days following radiation start (propensity adj HR 1.15, p = 0.23). When radiation is used to treat locally advanced NSCLC, IMRT is increasingly preferred to 3D-RT. However, among patients receiving potentially curative radiation there was no significant difference in overall survival or time spent hospitalized following treatment.

Role of thoracic conformal radiotherapy in patients with extensive-stage small cell lung cancer

Objective To evaluate the role of thoracic three-dimensional conformal radiotherapy (3DCRT) in patients with extensive-stage small cell lung cancer (ES-SCLC).Methods A total of 171 patients with ES-SCLC admitted from 2004 to 2009 were included in the study.Eighty-six patients received thoracic 3DCRT and systemic chemotherapy (CT),while 85 patients received systemic CT alone.3DCRT was delivered at 1.5 Gy/fraction twice daily or 2.0 Gy/fraction once daily,with a total dose ranging from 40 to 62 Gy.The CT regimen consisted of carboplatin/cisplatin and etoposide.The survival time and survival rate were calculated by the Kaplan-Meier method,and the log-rank test was used for univariate prognostic analysis;the Cox model was used for multivariate prognostic analysis.Results The follow-up rate was 100％.The median overall survival (OS) time and the 2-and 5-year OS rates were 15 months,31.5％,and 2.4％,respectively,for all patients;they were 18 months,35.3％,and 2.4％,respectively,for the CT/3DCRT group,versus 12 months,14.5％,and 2.4％ for the CT group (P =0.023).The median progression-free survival (PFS) time and the 1-and 2-year PFS rates were 8 months,27.5％,and 2.4％,respectively,for all patients;they were 9 months,35.4％,and 6.0％,respectively,for the CT/3DCRT group,versus 6 months,20.5％,and 6.0％ for the CT group (P =0.004).In the CT/3DCRT group,the 22 patients who received 45 Gy at 1.5 Gy/fraction twice daily had a median PFS time of 11 months,versus 9 months for the 26 patients who received 60 Gy at 2.0 Gy/fraction once daily (P =0.037).Multivariate analysis revealed that receiving ≥ 4 cycles of CT (P =0.001) and 3DCRT (P =0.008) were favorable prognostic factors for OS.Conclusions Thoracic 3DCRT can improve the OS and PFS in patients with EDSCLC,and it has good efficacy when delivered with a total dose of 45 Gy at 1.5 Gy/fraction twice daily.Thoracic 3DCRT and receiving ≥4 cycles of CT are independent favorable prognostic factors for OS. Key words: Lung neoplasms/radiotherapy; Radiotherapy, three-dimensional conformal; Radiotherapy, hyperfraction; Prognosis

Concurrent chemoradiation (CChRT) with bi-weekly docetaxel and cisplatin and thoracic radiotherapy for stage III non-small cell lung cancer (NSCLC): A phase II study from the Galician Lung Cancer Group.

7549 Background: CChRT is recommended as the evidence-based approach for the management of patients (p) with locally advanced stage III NSCLC and a good performance status, although a clearly superior regimen has not been identified. The aim of our study was to evaluate the effectiveness and toxicities of CChRT with bi-weekly docetaxel (D) and cisplatin (C) and thoracic radiotherapy. Methods: 50 p with histologically confirmed inoperable locally advanced NSCLC, stage IIIAN2/IIIB (no pleural T4), PS 0-1 and adequate lung function (FEV1 &gt; 1.1, V20 &lt; 25%) were included: one cycle of D 75 mg/m2 on day 1 and C 40 mg/m2 days 1-2 followed at 21 days by CChRT with bi-weekly D 40 mg/m2 and C 40 mg/m2 for four courses, during conformal thoracic radiotherapy (66 Gys, 180 cGy/day). The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), response rate (RR) and toxicity. Median follow-up: 14,5 months. Results: The p characteristics were: mean age 59,1 years (34-75); male/female 44/6; squamous/adeno/large cell carcinoma: 52%/34%/14%; stage IIIAN2 14 p (28%) and stage IIIB 36 p (72%). All p were evaluable for response and toxicity. RR: 4 CR, 36 PR (RR 80%; 95% CI:69-91), 4 SD (8%) and 6 PD (12%). The median PFS was 13 months (95% CI:8-18) and median OS was 19 months (95% CI:14-24). The PFS and OS at 1/2 years were 52%/30% and 79%/40% respectively. A total of 50 cycles of D-C induction chemotherapy were given; main toxicities (NCI-CTC 3.0) per p Grade (g) 1-2/3-4 (%) were as follows: neutropenia 2/16; anemia 12/0; nausea/vomiting 28/2; diarrhea 22/4; there were two episodes of febrile neutropenia. Main toxicities per p in CChRT (D-C doses: 192, 3.8 per p; mean doses RT: 64,6 Gys) were g1-2/3 (%): neutropenia 28/6; anemia 60/0; esophagitis 52/4 and pneumonitis 34/0; there were four episodes of hospitalization: febrile neutropenia, 2 p and g3 esophagitis, 2 p. Conclusions: CChRT with bi-weekly docetaxel and cisplatin and thoracic radiotherapy is a feasible treatment option for inoperable locally advanced stage III NSCLC, showing good clinical efficacy and tolerability with acceptable long-term survival.

Dose-Escalation Study of Three-Dimensional Conformal Thoracic Radiotherapy With Concurrent S-1 and Cisplatin for Inoperable Stage III Non–Small-Cell Lung Cancer

PurposeTo determine the recommended dose (RD) in concurrent conformal radiotherapy with S-1 and cisplatin chemotherapy for inoperable stage III non–small-cell lung cancer. Patients and MethodsEligible patients with inoperable stage III non–small-cell lung cancer, age ≥ 20 years, performance status 0-1 received 4 cycles of intravenous cisplatin (60 mg/m2, day 1) and oral S-1 (80, 100, or 120 mg based on body surface area, days 1-14) repeated every 4 weeks. Radiation doses were 66, 70, and 74 Gy for arms 1, 2, and 3, respectively. ResultsA total of 24 patients were enrolled in our study, including 6 in arm 1, 6 in arm 2, and 12 in arm 3. The patients consisted of 14 men and 10 women, with a median age of 63 years (range, 44-73 years). The median follow-up was 27.3 months (range, 8.5-42.6 months) for all patients and 33.9 months (range, 15.2-42.6 months) for those still alive. Grade 3 febrile neutropenia, lung toxicities, and heart toxicities occurred in 2, 2, and 2 patients, respectively. Dose-limiting toxicity occurred in 2, none, and 1 patient in arms 1, 2, and 3, respectively. The median survival was not reached, and the 2-year survival rate was 70% (95% CI, 51%-89%). Two-year local relapse-free survival and distant metastasis–free survival were 74% (95% CI, 56%-92%) and 45% (95% CI, 25%-65%), respectively. ConclusionsHigh-dose radiotherapy with S-1 and cisplatin is feasible, and 74 Gy was determined as the recommended dose.

Incorporating Bevacizumab and Erlotinib in the Combined-Modality Treatment of Stage III Non–Small-Cell Lung Cancer: Results of a Phase I/II Trial

Bevacizumab and erlotinib have been shown to improve survival in stage IV non-small-cell lung cancer (NSCLC). This phase I/II trial was designed to incorporate these agents with induction and concurrent chemoradiotherapy in stage III NSCLC. Patients received induction chemotherapy (carboplatin area under the curve [AUC] 6, paclitaxel 225 mg/m(2), and bevacizumab 15 mg/kg on days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly with bevacizumab 10 mg/kg every other week for four doses) and thoracic conformal radiation therapy (TCRT) to 74 Gy. In the phase I portion, cohort 1 received no erlotinib, whereas cohorts 2 and 3 received erlotinib at 100 and 150 mg, respectively, Tuesday through Friday, during TCRT. Consolidation therapy with erlotinib (150 mg daily) and bevacizumab (15 mg/kg every 3 weeks) was planned 3 to 6 weeks later for six cycles. Forty-five eligible patients were enrolled. The objective response rates to induction and overall treatment were 39% (95% CI, 24% to 55%) and 60% (95% CI, 44% to 75%), respectively. The median progression-free and overall survival times were 10.2 months (95% CI, 8.4 to 18.3 months) and 18.4 months (95% CI, 13.4 to 31.7 months), respectively. The principal toxicity was esophagitis (29% grade 3 or 4 esophagitis, with one patient with grade 3 tracheoesophageal fistula), which was often prolonged. Consolidation therapy with bevacizumab and erlotinib was not feasible. The use of bevacizumab and erlotinib as administered in this trial is not recommended given the lack of an efficacy signal and the substantial risk of esophageal toxicity.

Cancers bronchiques non à petites cellules : facteurs prédictifs de survenue de pneumopathie radique

PurposeTo evaluate the predictors of acute radiation pneumonitis after conformal thoracic radiotherapy in the treatment of locally advanced non-small cell lung cancer. Patients and methodsForty-seven consecutive patients were treated with conformal thoracic irradiation for locally advanced non-small cell lung cancer and retrospectively analysed. The mean total dose of radiotherapy was 65Gy with respiratory gating in 19 cases. Neoadjuvant and concomitant chemotherapy was performed in 33 patients (70%) and 41 patients (87%) respectively. ResultsEleven patients (23%) had an acute radiation pneumonitis, resulting in death for one patient. In univariate analysis, age, sex, pretherapeutic value of forced expiratory volume, non-gated radiotherapy and type of concomitant chemotherapy did not appear as contributing factors in contrast to the administration of neoadjuvant gemcitabine (P=0.03). The occurrence of acute radiation pneumonitis was significantly associated with non-tumour lung volumes irradiated to 13Gy (V13, P=0.04), 20Gy (V20, P=0.02) and 25Gy (V25, P=0.006), the mean lung dose (P=0.008) and lung normal tissue complication probability (P=0.004). In multivariate logistic regression analysis, the occurrence of acute radiation pneumonitis was significantly associated with age above 75 years (odds ratio [OR]=16.72 ; P=0.02) and with administration of neoadjuvant gemcitabine (OR=18.08, P=0.04). ConclusionAcute radiation pneumonitis is a common acute side effect of the conformal thoracic radiotherapy of locally advanced non-small cell lung cancer, requiring close post-treatment follow-up, particularly for elderly patients. The use of gemcitabine before radiation should be avoided. The benefits and risks of conformal thoracic radiotherapy must be carefully analyzed in view of the dosimetric parameters obtained.

A phase II trial of induction gefitinib monotherapy followed by cisplatin-docetaxel and concurrent thoracic irradiation in patients with EGFR-mutant locally advanced non-small-cell lung cancer (LA-NSCLC): LOGIK0902/OLCSG0905 intergroup trial.

7045 Background: We previously reported efficacy and safety of cisplatin-docetaxel and concurrent thoracic radiotherapy (TRT) for LA-NSCLC (Segawa Y and Kiura K. JCO 2010). However, its cure rate remains unsatisfied, and further improvement in the treatment outcome is strongly warranted. Recently, systemic chemotherapy has been individualized by intensive anti-cancer researches through the discovery of certain molecular targets in the metastatic NSCLC. Especially, gefitinib, EGFR tyrosine kinase inhibitor, is quite active and now one of the standard chemotherapy for untreated metastatic EGFR-mutant NSCLC (Maemondo M and Inoue A. NEJM 2010). Even in the locally advanced setting, approximately 30% of Japanese NSCLC patients possess EGFR-mutant tumors. Given all of these backgrounds, investigation on the role of adding gefitinib monotherapy to the standard concurrent chemoradiotherapy might cause a new paradigm shift in this setting. Methods: Patients have to meet the following eligibility criteria: LA-NSCLC; active tumor EGFR mutations (exons 19 and 21) but without 790M; measurable lesions; performance status (PS) of 0 or 1; age &lt; 75 years; and V20 ≤ 35%. The primary endpoint is set as 2-year progression-free survival (PFS) rate; assuming that 75% in eligible patients would indicate potential usefulness, whereas 60% would be the lower limit of interest (α = 0.05, ß = 0.20), the estimated accrual number is 46 patients. The secondary endpoint includes toxicity, response rate and overall survival. Patients will receive the induction treatment, specified as gefitinib monotherapy (250 mg/body) for 8 weeks. Patients who have not progressed during the induction therapy will receive cisplatin and docetaxel (40 mg/m2; days 1, 8, 29, 36, each) and concurrent three-dimensional conformal TRT (2-Gy, single, daily fractions for 5 consecutive days each week to provide a total dose of 60 Gy). Enrollment began in 2010, and will complete by 2015. UMIN registration number of 000005086.

Randomized phase II trial comparing two schedules of thoracic radiotherapy (TRT) in limited disease small-cell lung cancer (LD SCLC).

7027 Background: Concurrent chemotherapy and TRT is standard therapy for SCLC if all lesions can be included in a radiotherapy field (LD). Several schedules of TRT are used. One study showed that two fractions a day improved local control and overall survival (OS), but this schedule has not been compared to a commonly used 3 wks schedule. Methods: Eligible pts had LD SCLC and PS 0-2. Pleural fluid was accepted if negative cytology. Pts received 4 cycles of PE (cisplatin 75 mg/m2 IV day 1 and etoposide 100 mg/m2 IV day 1-3 q 3 wks) and were randomly assigned to 3 wks of 3D conformal TRT [A] 42 Gy (2.8 Gy x 1/day) or [B] 45 Gy (1.5 Gy x 2/day). TRT started 3-4 wks after the first PE. All responders received prophylactic cranial irradiation (PCI) 2 Gy x 15 ≤ 6 wks after last PE. Pts reported health related quality of life (HRQoL) on EORTC QLQ C30 + LC13. Primary endpoint: 1-year local failure. Secondary: OS, toxicity and HRQoL (dysphagia and dyspnea; a difference ≥ 10 points was considered significant). 75 pts were required in each arm to show a 30% improvement of local disease control with α=.05 and β=.8. Results: 159 eligible pts were enrolled at 18 sites in Norway May 05 – Jan 11 (A: 85, B: 74). Median age 60 (40-85); 52% men, 84 % PS 0-1, 11% pleural fluid. Mean no. of PE-cycles was 3.8, 97% completed TRT, 82 % PCI (no difference between arms). Response rates were similar (A: 92%, B: 94%; p=.8), but more pts on Arm B had CR (A: 13%, B: 35%; p=.01). There was no difference in local failure as first site of progression at 1 year (A: 17%, B: 12%; p=.4) or 1-year PFS (A: 44%, B: 50% ; p=.4). There was similar grade 3-4 esofagitis (A: 33%, B: 37 %; p=.7) and pneumonitis (A: 6 %, B: 7 %; p=.9). 2 pts (1 on each arm) died from pneumonitis. Pts in Arm B reported more dysphagia (A: 64 points, B: 73 points), but not more dyspnea (A: 29 points, B: 28 points). 1-year OS was similar (A: 77%, B: 76%; p=.9). Currently, 2-year survival among those followed ≥ 2 years (n=130) favors Arm B (A: 40%, B: 55%; p=.09) and so far (all pts followed ≥ 1-year; 103 events) median OS favors Arm B (A: 18.7 mos, B: 26.6 mos; p=.34). Conclusions: Twice daily TRT resulted in more CRs, slightly more dysphagia, similar 1-year local control and 1-year PFS. There are indications of improved 2-year and median OS in this arm.

Phase I/II trial of bevacizumab (B) and erlotinib (E) with induction (IND) and concurrent (CON) carboplatin (Cb)/paclitaxel (P) and 74 Gy of thoracic conformal radiotherapy (TCRT) in stage III non-small cell lung cancer (NSCLC).

7016 Background: Agents which target the epidermal growth factor receptor (EGFR) and inhibit angiogenesis have been shown to improve overall survival (OS) in advanced NSCLC and have radiosensitizing properties Methods: Patients (pts) received Cb (AUC=6), P (225 mg/m2) and B (15 mg/kg) on days 1 and 22. On day 43 patients received Cb (AUC=2) and P (45 mg/m2) weekly x 7 weeks (wks) with TCRT to 74 Gy; cohort 1 (n=5) received B 10 mg/kg q 2 wks, cohort 2 (n=5) and cohort 3 (n=5) both received B 10 mg/kg q 2 wks as well E at 100 mg and 150 mg Tuesday-Friday each week of concurrent therapy. After completion of concurrent therapy pts received consolidation therapy (CT) with B+ E for 6 cycles. All histologies were eligible; an early stopping rule for pulmonary hemorrhage (PH) was included for the squamous (SQ) pts. The primary end-point was 1-year progression free survival (PFS). Results: 45 patients eligible patients were accrued; median age 61 yrs (range 34 to 74), 33 non-SQ and 12 SQ; 29 stage IIIA and 16 stage IIIB; 33 pts PS 0 and 12 PS of 1. Cohort 2 was expanded to the phase II trial. CT was determined to not be feasible and SQ cohort was closed due to PH. Grade ≥ 3 toxicity observed with IND therapy was neutropenia (42%) and grade 3 hypertension (2%). Grade ≥ 3 toxicities observed with CON were esophagitis (29%), pneumonitis (2%); neutropenia (13%), hgb (7%), thrombocytopenia (7%); one trachoesphogeal fistula was observed. In SQ cohort 3 of 12 patients experienced PH; 1 grade 3, 2 grade 5. 33 pts have experienced disease progression or death; the 1-year PFS rate observed was 44% (95% CI, 29-58%), median PFS was 10 months (95% CI, 8-22). 27 pts have died, and the median follow-up for survivors is 37 months (range 5-54); median OS was 19 months (95% CI, 13 to 33). The median OS observed in the non-SQ and SQ cohorts was 19 and 17 months, respectively. Conclusions: The PFS and OS with the addition of B+E to CbP with 74 Gy TCRT appears similar to previous experience with CbP alone with 74 Gy TCRT.

Pulmonary Toxicity in Stage III Non-Small Cell Lung Cancer Patients Treated With High-Dose (74 Gy) 3-Dimensional Conformal Thoracic Radiotherapy and Concurrent Chemotherapy Following Induction Chemotherapy: A Secondary Analysis of Cancer and Leukemia Group B (CALGB) Trial 30105

Cancer and Leukemia Group B (CALGB) 30105 tested two different concurrent chemoradiotherapy platforms with high-dose (74 Gy) three-dimensional conformal radiotherapy (3D-CRT) after two cycles of induction chemotherapy for Stage IIIA/IIIB non-small cell lung cancer (NSCLC) patients to determine if either could achieve a primary endpoint of >18-month median survival. Final results of 30105 demonstrated that induction carboplatin and gemcitabine and concurrent gemcitabine 3D-CRT was not feasible because of treatment-related toxicity. However, induction and concurrent carboplatin/paclitaxel with 74 Gy 3D-CRT had a median survival of 24 months, and is the basis for the experimental arm in CALGB 30610/RTOG 0617/N0628. We conducted a secondary analysis of all patients to determine predictors of treatment-related pulmonary toxicity. Patient, tumor, and treatment-related variables were analyzed to determine their relation with treatment-related pulmonary toxicity. Older age, higher N stage, larger planning target volume (PTV)1, smaller total lung volume/PTV1 ratio, larger V20, and larger mean lung dose were associated with increasing pulmonary toxicity on univariate analysis. Multivariate analysis confirmed that V20 and nodal stage as well as treatment with concurrent gemcitabine were associated with treatment-related toxicity. A high-risk group comprising patients with N3 disease and V20 >38% was associated with 80% of Grades 3-5 pulmonary toxicity cases. Elevated V20 and N3 disease status are important predictors of treatment related pulmonary toxicity in patients treated with high-dose 3D-CRT and concurrent chemotherapy. Further studies may use these metrics in considering patients for these treatments.

Phase II Trial of Induction Gemcitabine and Carboplatin Followed by Conformal Thoracic Radiation to 74 Gy with Weekly Paclitaxel and Carboplatin in Unresectable Stage III Non-small Cell Lung Cancer

The survival for patients with locally advanced, unresectable non-small cell lung cancer receiving standard of care concomitant chemoradiation remains disappointingly low. A reduction in both local and distant recurrence is needed to improve patients' outcome. Performing molecular studies on serially collected tumor specimens may result in a better selection of therapeutic options. We conducted a phase II single-institution trial of two cycles of induction chemotherapy with gemcitabine and carboplatin followed by high-dose conformal radiation concomitant with weekly paclitaxel and carboplatin in 39 patients. The trial required a dedicated tumor biopsy before treatment initiation. In addition, tumor biopsies were requested, if safely feasible, before initiation of chemoradiation and 2 months after completion all therapy. Induction chemotherapy was well tolerated, and 38 patients proceeded with chemoradiation. The mean delivered radiation dose was 70.2 Gy, 23 patients received the full dose of 74 Gy, and 19 patients completed all treatment on schedule without dose reductions or delays. Median overall and progression-free survivals were 22.7 and 14.3 months, respectively. A total of 82 procedures, including 46 transthoracic core needle biopsies, were performed. Thirteen patients had all three serial tumor biopsies. Three of these procedures resulted in complications that required an intervention; all for the treatment of a biopsy-induced pneumothorax. We conclude that induction gemcitabine/carboplatin followed by concurrent paclitaxel/carboplatin with conformal radiation to 74 Gy is safe and tolerable with promising efficacy. We demonstrated that dedicated and serial tumor collections are safe, feasible, and acceptable for patients with non-small cell lung cancer.

Pulmonary Toxicity in Stage III Non-Small Cell Lung Cancer Patients Treated With High-Dose (74 Gy) 3-Dimensional Conformal Thoracic Radiotherapy and Concurrent Chemotherapy Following Induction Chemotherapy: A Secondary Analysis of Cancer and Leukemia Group B (CALGB) Trial 30105

Pulmonary Toxicity in Stage III Non-Small Cell Lung Cancer Patients Treated With High-Dose (74 Gy) 3-Dimensional Conformal Thoracic Radiotherapy and Concurrent Chemotherapy Following Induction Chemotherapy: A Secondary Analysis of Cancer and Leukemia Group B (CALGB) Trial 30105

A Phase I Study of Gefitinib with Concurrent Dose-Escalated Weekly Docetaxel and Conformal Three-Dimensional Thoracic Radiation Followed by Consolidative Docetaxel and Maintenance Gefitinib for Patients with Stage III Non-small Cell Lung Cancer

Concurrent radiation and chemotherapy is the standard of care for good performance status patients with stage III non-small cell lung cancer. Locoregional control remains a significant factor relating to poor outcome. Preclinical and early clinical data suggest that docetaxel and gefitinib have radiosensitizing activity. This study sought to define the maximum tolerated dose of weekly docetaxel that could be given with daily gefitinib and concurrent thoracic radiation therapy. Patients with histologically confirmed, inoperable stage III non-small cell lung cancer and good performance status (Eastern Cooperative Oncology Group 0-1) were eligible for this study. Patients received three-dimensional conformal thoracic radiation to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. Sixteen patients were enrolled on the study between December 2003 and April 2007 with the following characteristics: median age, 64 years (range 43-79 years); M/F: 9/7; and performance status 0/1, 1/15. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2, resulting in a maximum tolerated dose of 20 mg/m2/wk. Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The overall response rate was 46%, and the median survival for all patients was 21 months. Concurrent thoracic radiation with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2.

Incorporation of bevacizumab (B) and erlotinib (Er) with induction (Ind) and concurrent (Conc) carboplatin (Cb)/paclitaxel (P) and 74 Gy of thoracic radiotherapy in stage III non-small cell lung cancer (NSCLC)

7528 Background: Therapies directed at both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways have been shown to improve survival in NSCLC and also have radiosensitizing properties. Methods: Pts receive Ind Cb (AUC 6), P (225 mg/m2) and B (15 mg/kg) on d1 and 22. PET scans are done pre- and post-I. On day 43, pts receive weekly Cb (AUC 2 x 7) and P (45 mg/m2 x 7) with 74 Gy (2 Gy/d) of thoracic conformal radiotherapy (TCRT). Cohort I (n=5) received B at 10 mg/kg q2wks during C therapy. Cohorts II and III (both n=5) received the same dose of B as in cohort I but also received Er at 100 mg and 150 mg po Tuesday - Friday of each week of C therapy, respectively. The primary endpoint is PFS at 1 year. All histologies are allowed including squamous (SQ) (an early stopping rule is in place for pulmonary hemorrhagic (PH) complications in SQ pts). Results: Thus far, 31 eligible PS 0–1 pts have been accrued (med age 62 yrs, range 41–74, 19 non- squamous, 12 SQ, 63% IIIA, 37% IIIB). Ind CbP + B has been well tolerated (1 gr 3 hypertension). No PH during Ind has been seen (including the 12 SQ cell pts). Response after Ind, 37% PR, 59% SD, 4% PD. Tumor volumes and PET SUVs have significantly decreased comparing pre- and post-Ind studies (p=0.0001 and p=0.0002, respectively). Cohort II has been expanded as the phase II regimen. To date, 25 of 26 (96%) pts have achieved the dose of 74 Gy (1 pt stopped at 60 Gy due to ILD). During Conc therapy, the principal toxicity has been esophagitis (53.8% gr 2, 19.2% gr 3). One grade 3 PH occurred in 1 SQ pt. One gr 5 late (&gt; 2 mos after treatment) PH occurred in a SQ pt. Overall response rate following treatment - 68.2% (95% CI, 45–86%). The PFS at 1 year is 58% (95% CI, 34–76%) with an estmated 1-year overall survival rate of 79% (95% CI, 53–92%) which compares favorably to our historical experience. Conclusions: Preliminarily, we conclude that 1) Incorporation of B and E into this treatment paradigm appears feasible, 2) Esophagitis remains the primary toxicity, 3) Phase II accrual continues but early analysis of survival appears promising. Further details regarding the TCRT parameters and toxicity will be presented. [Table: see text]

Late Complications of High-Dose (≥66 Gy) Thoracic Conformal Radiation Therapy in Combined Modality Trials in Unresectable Stage III Non-small Cell Lung Cancer

Late Complications of High-Dose (≥66 Gy) Thoracic Conformal Radiation Therapy in Combined Modality Trials in Unresectable Stage III Non-small Cell Lung Cancer

Late Complications of High-Dose (≥66 Gy) Thoracic Conformal Radiation Therapy in Combined Modality Trials in Unresectable Stage III Non-small Cell Lung Cancer

Combined modality treatment is the standard of care for patients (pts) with unresectable stage III non-small cell lung cancer. Dose escalation of radiotherapy is one strategy used to improve locoregional control and survival, but it increases the risk of both early and late treatment related toxicities. From May 1996 to August 2004, a total of 112 stage III non-small cell lung cancer pts were treated on 4 phase I/II or phase II trials to assess the safety and feasibility of high-dose (60-90 Gy) thoracic conformal radiotherapy. Patients who received >/=66 Gy (n = 88) were included in an analysis of late complications. Late complications were defined as complications that developed or persisted >/=90 days postradiotherapy. The classic lung toxicities of radiation pneumonitis and fibrosis were not included in this analysis. Of the 88 patients included in this analysis of late complications, 21 patients (24%) developed a late complication and a total of 28 late complications were observed. The late complications were: pulmonary (n = 5; bronchial stenosis [n = 3] and fatal pulmonary hemoptysis [n = 2]), esophageal (n = 6), cardiac (n = 9), osseous (n = 6), and second primary tumor (n = 2). The median survival for all patients enrolled on the 4 trials (with 95% confidence interval [CI]) was 24.7 months (18.1-30.4 months), and the 5-year overall survival (with 95% CI) was 24% (16-32%). Data to assess for radiographic evidence of local progression were available for 99 patients, and the rate of local progression was 43% (95% CI 34-53%). High-dose thoracic conformal radiotherapy is feasible and results in promising survival outcomes. Late complications occur in a minority of patients.