Phase I study and biomarker analysis of lapatinib and concurrent radiation for locally advanced breast cancer.

PURPOSE: This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways. METHODS: Eligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry. RESULTS: Doses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per response evaluation criteria in solid tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation. CONCLUSIONS: The combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen.

The impact of local and regional disease extent on overall survival in patients with advanced stage IIIB/IV non-small cell lung carcinoma.

PURPOSE: Patients with advanced stage IIIB or stage IV non-small cell lung carcinoma are typically treated with initial platinum-based chemotherapy. A variety of factors (eg, performance status, gender, age, histology, weight loss, and smoking history) are generally accepted as predictors of overall survival. Because uncontrolled pulmonary disease constitutes a major cause of death in these patients, we hypothesized that clinical and radiographic factors related to intrathoracic disease at diagnosis may be prognostically significant in addition to conventional factors. The results have implications regarding the selection of patients for whom palliative thoracic radiation therapy may be of most benefit. METHODS AND MATERIALS: We conducted a pooled analysis of 189 patients enrolled at a single institution into 9 prospective phase II and III clinical trials involving first-line, platinum-based chemotherapy. Baseline clinical and radiographic characteristics before trial enrollment were analyzed as possible predictors for subsequent overall survival. To assess the relationship between anatomic location and volume of disease within the thorax and its effect on survival, the pre-enrollment computed tomography images were also analyzed by contouring central and peripheral intrapulmonary disease. RESULTS: On univariate survival analysis, multiple pulmonary-related factors were significantly associated with worse overall survival, including pulmonary symptoms at presentation (P=.0046), total volume of intrathoracic disease (P=.0006), and evidence of obstruction of major bronchi or vessels on prechemotherapy computed tomography (P<.0001). When partitioned into central and peripheral volumes, central (P<.0001) but not peripheral (P=.74) disease was associated with worse survival. On multivariate analysis with known factors, pulmonary symptoms (hazard ratio, 1.46; P=.042), central disease volume (hazard ratio, 1.47; P=.042), and bronchial/vascular compression (hazard ratio, 1.54; P=.022) remained significant. CONCLUSIONS: Patients with bulky central disease, bronchial/vascular compression, and/or pulmonary symptoms exhibited worse overall survival after first-line, platinum-based chemotherapy. A subset of these patients may be studied to determine whether early, planned palliative thoracic radiation could also be of benefit.

Challenges scoring radiation pneumonitis in patients irradiated for lung cancer.

BACKGROUND AND PURPOSE: To quantify uncertainties in scoring radiation pneumonitis. MATERIALS AND METHODS: Records of 434 patients irradiated for lung cancer from 2000 to 2010 were retrospectively reviewed; IRB-approved study. From these, 121 received ≥ 60 Gy for non-small cell lung cancer (NSCLC) with ≥ 6 months follow-up. Patients where the physicians were uncertain of the diagnosis due to confounding factors were deemed "hard to score". Subgroups were defined based on lung dosimetric parameters, and frequencies in different subgroups were compared via Fisher's exact test. RESULTS: 21/121 of patients were considered to have pneumonitis; median follow 17 months. Of these, 10/21 were "hard to score"; reasons including acute COPD exacerbation, infection, and tumor progression. "Hard to score" pneumonitis was slightly more common in patients with a COPD history (15%) vs. without COPD (4%) (p=0.05); and with a pre-RT FEV1<1.7 L (16%) vs. ≥1.7 L (4%) (p=0.09). Rates of "unambiguous" pneumonitis trended to be non-significantly slightly higher in patients higher mean lung doses, V5, and V30. CONCLUSION: Radiation pneumonitis occurred in 17% of patients undergoing RT for NSCLC; with diagnostic uncertainty in 48% of these. Poor pre-RT pulmonary function increases the rate of "hard to score" pneumonitis. Dosimetric parameters are slightly better related to "unambiguous" than "hard to score" pneumonitis, as expected.

Predicting the need for palliative thoracic radiation after first-line chemotherapy for advanced nonsmall cell lung carcinoma.

BACKGROUND: The objective of this secondary analysis was to identify patients with selected stage IIIB/IV nonsmall cell lung carcinoma and good performance status who were at high risk for requiring subsequent palliative thoracic radiotherapy after initial treatment with first-line chemotherapy. METHODS: The authors conducted a pooled analysis of patients at a single institution who enrolled onto 10 prospective phase 2 and 3 clinical trials that involved first-line, platinum-based chemotherapy. Baseline lung-related characteristics before trial enrollment were analyzed as possible prognostic factors for freedom from pulmonary events (defined either as subsequent thoracic radiation or as a new collapsed lung, which is an indication for thoracic radiation). RESULTS: Of 244 consecutive patients who were reviewed, 42 patients received a palliative course of thoracic radiation, 40 exhibited evidence of new lobar collapse on follow-up chest imaging, and 14 received thoracic radiation for lobar collapse. On univariable analysis, pulmonary symptoms (P = .043) or pneumonia at presentation (P = .0001), increasing size of hilar disease (P < .0001), and evidence of obstruction of major bronchi or vessels (P = .0003) were associated with subsequent pulmonary events. On multivariable analysis, hilar disease measuring >3 cm (hazard ratio, 1.8; P = .003) and prechemotherapy pneumonia (hazard ratio, 2.1; P = .009) were associated with pulmonary events; patients who had both risk factors or hilar disease >5 cm in greatest dimension exhibited a >50% risk of subsequent events. CONCLUSIONS: Patients with bulky hilar disease and a history of pneumonia at presentation were at high risk for requiring palliative thoracic radiation. The authors propose studying these patients to determine whether early thoracic radiation may be beneficial by preserving quality of life and performance status.

Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: a phase II trial.

PURPOSE: Trastuzumab (Herceptin), an anti-human epidermal growth factor receptor 2 (HER2) antibody, has been shown to be an effective radiosensitizer in preclinical studies. The present Phase II trial evaluated trastuzumab plus radiotherapy in patients with HER2-positive, chemotherapy-refractory, locally advanced or locoregionally recurrent breast cancer. METHODS AND MATERIALS: Eligible patients had measurable disease, normal cardiac function, and biopsy-confirmed residual HER2-positive disease. Patients received weekly trastuzumab (2 mg/kg intravenously), concurrent with radiotherapy (50 Gy) to the breast and regional lymph nodes for 5 weeks. If feasible, surgery followed radiotherapy. The primary endpoint was safety, and the secondary endpoint was efficacy (pathologic response and interval to symptomatic local progression). RESULTS: Of the 19 patients enrolled, 7 were ineligible and received radiotherapy alone and 12 received therapy per protocol. Of these 12 patients, 11 had a Stage T4 diagnosis. Grade 3 toxicities included skin (n = 2) and lymphopenia (n = 1). One patient experienced delayed wound healing after surgery. No patients developed symptomatic cardiac dysfunction. Of the 7 patients who had undergone mastectomy, 3 (43%) had a substantial pathologic response (complete response or microscopic residual disease), significantly more than a comparison cohort (2 of 38 or 5%, p = .02). The median interval to symptomatic local progression was not reached. The median overall survival was 39 months. CONCLUSION: This is the first prospective trial providing evidence for a radiosensitizing effect of trastuzumab in breast cancer. The combination of trastuzumab and radiotherapy was well tolerated.

Late complications of high-dose (>/=66 Gy) thoracic conformal radiation therapy in combined modality trials in unresectable stage III non-small cell lung cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: High-dose thoracic conformal radiotherapy is feasible and results in promising survival outcomes. Late complications occur in a minority of patients.

Long-term follow-up of a phase I/II trial of dose escalating three-dimensional conformal thoracic radiation therapy with induction and concurrent carboplatin and paclitaxel in unresectable stage IIIA/B non-small cell lung cancer.

BACKGROUND: We conducted a modified phase I/II trial investigating the incorporation of three-dimensional conformal thoracic radiation therapy (TCRT) into the treatment paradigm of induction and concurrent carboplatin and paclitaxel in patients with unresectable stage IIIA/B non-small cell lung cancer. METHODS: Patients received 2 cycles of induction carboplatin (area under the curve of 6) and paclitaxel (225 mg/m) on days 1, and 22. On day 43 concurrent TCRT and weekly x6 of carboplatin (area under the curve = 2) and paclitaxel (45 mg/m) was initiated. The TCRT dose was escalated from 60 to 74 Gy in 4 cohorts (60, 66, 70, and 74 Gy), and the 74 Gy cohort was expanded into a phase II trial. RESULTS: Sixty-two patients were enrolled; the median age 57 years (range, 36-82), 39 were male (63%), 61 (98%) had a performance status of 0 or 1, 28 (45%) had stage IIIA disease, 21 (34%) had >5% weight loss, and the median forced expiratory volume 1 = 2.10 liters (range, 1.02-3.75). With a median follow-up for survivors of approximately 9 years (range, 7-11 years) the median progression-free survival, time to tumor progression, and overall survival (OS) (with 95% confidence intervals) were 10 (8.5-17), 15 (9-50), and 25 months (18-37), respectively. The 5-year progression-free survival and OS rates were 21% (12-32%) and 27% (17-39%), respectively. The 10-year OS rate was 14% (7-25%). CONCLUSION: The long term survival rate compares favorably to other treatment approaches for stage III non-small cell lung cancer.

Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB non-small cell lung cancer.

INTRODUCTION: Combined modality therapy is a standard therapy for patients with unresectable stage III non-small cell lung cancer (NSCLC). Gefitinib is active in advanced NSCLC, and in preclinical models, it potentiates the activity of radiation therapy. We investigate the tolerability of gefitinib in combined modality therapy in combination with three-dimensional thoracic conformal radiation therapy (3-dimensional TCRT). METHODS: Stage III patients with a good performance status were treated with induction chemotherapy (carboplatin area under the curve [AUC] of 5, irinotecan 100 mg/m(2), and paclitaxel 175 mg/m(2) days 1 and 22) with pegfilgrastim support followed by concurrent chemotherapy (carboplatin AUC 2, and paclitaxel 45 mg/m(2) weekly) and gefitinib 250 mg daily beginning on day 43 with 3-dimensional TCRT to 74 Gy. RESULTS: Between March 2004 and January 2006, 23 patients received treatment on the trial: median age 62 years (range 44-82), 52% female, 61% stage IIIA, 61% performance status 0, 17% > or =5% weight loss, and 91% underwent positron emission tomography staging. Induction chemotherapy with pegfilgrastim support was well tolerated and active (partial response rate, 24%; stable disease, 76%; and early progression, 0%). Twenty-one patients initiated the concurrent chemoradiation, and 20 patients completed therapy to 74 Gy. The primary toxicities of concurrent chemoradiation were grade 3 esophagitis (19.5%) and cardiac arrhythmia (atrial fibrillation) (9.5%). The median progression-free survival and overall survival were 9 months (95% confidence intervals [CI]: 7-13 months) and 16 months (95% CI: 10-20 months), respectively. CONCLUSIONS: Treatment with induction chemotherapy and gefitinib concurrent with 3-dimensional TCRT has an acceptable toxicity and tolerability, but the survival results were disappointing.

Post-chemotherapy gross tumor volume is predictive of survival in patients with stage III non-small cell lung cancer treated with combined modality therapy.

PURPOSE: To evaluate the influence of clinical covariates, particularly pre-chemotherapy gross tumor volume (GTV), post-chemotherapy GTV, on overall survival in the treatment of stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: We retrospectively analyzed 102 patients who were enrolled on three consecutive clinical trials, which employed the treatment paradigm of two cycles of induction chemotherapy followed by thoracic radiation therapy. The pre-chemotherapy GTV, post-chemotherapy GTV, change in GTV, histology, disease stage, performance status, age, race, treatment with concurrent chemoradiotherapy versus radiotherapy alone were evaluated to determine their impact on overall survival. The log10 of the GTV was used to normalize the data and thereby reduce the impact of exceptionally large values. RESULTS: Both the log10 of the post-chemotherapy GTV and Eastern Cooperative Oncology Group (ECOG) performance status covariates were highly prognostic for overall survival (p = 0.006 and p = 0.008, respectively). Disease stage (at diagnosis) was also significant (p = 0.048). The log10 pre-chemotherapy GTV covariate was borderline significant (p = 0.067). The strongest prognostic model was the two-covariate model, which contained the log10 post-chemotherapy GTV and ECOG performance status covariates, (model chi2 of 18.67, with p = 0.001 for each covariate). CONCLUSIONS: The log10 post-chemotherapy GTV has significant prognostic survival value when the strategy of induction chemotherapy is employed in the treatment on stage III NSCLC. ECOG performance status and stage were also significant prognostic factors for survival.

Comparison of three concomitant boost techniques for early-stage breast cancer.

PURPOSE: Whole breast radiotherapy (RT) followed by a tumor bed boost typically spans 5-6 weeks of treatment. Interest is growing in RT regimens, such as concomitant boost, that decrease overall treatment time, lessening the time/cost burden to patients and facilities. METHODS AND MATERIALS: Computed tomography (CT) scans from 20 cases were selected for this retrospective, dosimetric study to compare three different techniques of concomitant boost delivery: (1) standard tangents plus an electron boost, (2) intensity-modulated RT (IMRT) tangents using custom compensators plus an electron boost, and (3) IMRT tangents plus a conformal photon boost. The equivalent uniform dose model was used to compare the plans. RESULTS: The average breast equivalent uniform dose value for the three techniques (standard, IMRT plus electrons, and IMRT plus photons) was 48.6, 47.9, and 48.3, respectively. The plans using IMRT more closely approximated the prescribed dose of 46 Gy to the whole breast. The breast volume receiving >110% of the dose was less with the IMRT tangents than with standard RT (p = 0.037), but no significant difference in the maximal dose or other evaluated parameters was noted. CONCLUSION: Although the IMRT techniques delivered the prescribed dose with better dose uniformity, the small improvement seen did not support a goal of improved resource use.

American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome.

BACKGROUND: Response to neoadjuvant chemotherapy is used as an intermediate endpoint for breast cancer relapse and survival. Most breast cancer response classification systems use pathologic complete response, either alone or in conjunction with clinical assessments, to categorize response. We examined the ability of the revised 2003 American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system, which considers both the number of involved axillary lymph nodes and the extent of tumor in the breast to predict patient survival after neoadjuvant chemotherapy for breast cancer. METHODS: We assessed the pathologic stage of residual tumor in 132 patients with nonmetastatic breast cancer after they had undergone neoadjuvant chemotherapy and examined the association between AJCC TNM stage and subsequent distant disease-free survival and overall survival. All statistical tests were two-sided. RESULTS: At a median follow-up of 5 years, pathologic stage in the surgical specimens after neoadjuvant chemotherapy using the revised AJCC system was strongly associated with both distant disease-free survival and overall survival. A higher pathologic stage of residual tumor after neoadjuvant chemotherapy was associated with a statistically significant lower rate of distant disease-free survival (stage 0: 95%, stage I: 84%, stage II: 72%, and stage III: 47%; Ptrend < .001). The 5-year distant disease-free survival for patients with residual stage IIIC tumors was only 18% (95% CI = 0% to 36%). CONCLUSION: Classification of residual tumor in the breast and axillary surgical specimens after neoadjuvant chemotherapy using the revised AJCC TNM system is useful for predicting distant relapse and survival.

Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer.

PURPOSE: We employed meta-analytic techniques to evaluate early (E) versus late (L) timing of thoracic radiation therapy (RT) in limited-stage small-cell lung cancer (LS-SCLC). In addition, we assessed the impact of radiation fractionation and chemotherapeutic regimen on timing. METHODS: Randomized trials published after 1985 addressing timing of RT relative to chemotherapy in LS-SCLC were included. Trials were analyzed by risk ratio (RR), risk difference, and number-needed-to-treat methods. RESULTS: Overall survival (OS) RRs for all studies were 1.17 at 2 years (95% CI, 1.02 to 1.35; P = .03) and 1.13 at 3 years (95% CI, 0.92 to 1.39; P = .2), indicating a significantly increased 2-year survival for ERT versus LRT patients and suggestive of a similar trend at 3 years. Subset analysis of studies using hyperfractionated RT revealed OS RR for ERT versus LRT of 1.44 (95% CI, 1.17 to 1.77; P = .001) and 1.39 (95% CI, 1.02 to 1.90; P = .04) at 2 and 3 years, respectively, indicating a survival benefit of ERT versus LRT. Studies using once-daily fractionation showed no difference in 2- and 3-year OS RRs for ERT compared with LRT. Studies using platinum-based chemotherapy had OS RRs of 1.30 (95% CI, 1.10 to 1.53; P = .002) and 1.35 (95% CI, 1.07 to 1.70; P = .01) at 2 and 3 years, respectively, favoring ERT. Studies using nonplatinum-based chemotherapy regimens had nonsignificant differences in OS. CONCLUSION: A small but significant improvement in 2-year OS for ERT versus LRT in LS-SCLC was observed, similar to the benefit of adding RT to chemotherapy or prophylactic cranial irradiation. A greater difference was evident for hyperfractionated RT and platinum-based chemotherapy.

Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial.

PURPOSE: Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non-small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival. PATIENTS AND METHODS: Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m(2), and paclitaxel 175 mg/m(2) days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTV(I)) and boost clinical target volume (CTV(B)), respectively. The CTV(I) received 40 to 50 Gy; the CTV(B) received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose. RESULTS: Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% > or = 5% weight loss). Induction CIP was well tolerated (with filgrastim support) and active (partial response rate, 46.2%; stable disease, 53.8%; and early progression, 0%). The TCRT dose was escalated from 78 to 90 Gy without dose-limiting toxicity. The primary acute toxicity was esophagitis (16%, all grade 3). Late toxicity consisted of grade 2 esophageal stricture (n = 3), bronchial stenosis (n = 2), and fatal hemoptysis (n = 2). The overall response rate was 60%, with a median survival time and 1-year survival probability of 24 months and 0.73 (95% CI, 0.55 to 0.89), respectively. CONCLUSION Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.

Seeking a home for a PET, part 1: Defining the appropriate place for positron emission tomography imaging in the diagnosis of pulmonary nodules or masses.

There is a growing experience with positron emission tomography (PET) in patients with pulmonary nodules or masses. As PET imaging becomes more widely available, it is important to thoughtfully define when application of this technology is warranted. Review of the literature to date suggests that PET imaging for diagnosis of pulmonary lesions is most useful in patients who have a low or intermediate risk of lung cancer as determined by an evaluation of symptoms, risk factors, and radiographic appearance. There is little role for PET in diagnosis in patients with a very low or a high risk of lung cancer, and there is little role in patients with lesions < 1 cm in diameter, or lesions suspected to be an infection, a bronchioloalveolar carcinoma, or a typical carcinoid tumor.

Seeking a home for a PET, part 2: Defining the appropriate place for positron emission tomography imaging in the staging of patients with suspected lung cancer.

In patients who have a high likelihood of having lung cancer, there is little role for positron emission tomography (PET) imaging for diagnosis of the primary lesion. The primary impact of PET imaging is in extrathoracic staging, but it should not replace a clinical evaluation by a physician experienced in lung cancer. PET imaging is most useful for confirmation of the presumed extrathoracic stage in patients with intermediate stages of lung cancer. The role of PET imaging is limited in patients with strong clinical signs of metastatic disease, or in patients with a clinical stage I lung cancer and a negative clinical evaluation. With regard to intrathoracic staging, PET imaging has a definite role in communities in which mediastinoscopy is not available, whereas the impact is limited in institutions in which invasive mediastinal staging is available. The data suggest that a positive PET result in the mediastinum should be confirmed by biopsy. A mediastinoscopy is also reasonable in patients with clinical stage III lung cancer who have no mediastinal PET uptake. It is unclear and controversial whether a biopsy is needed in patients with clinical stage II lung cancer who have no PET uptake in the mediastinum.

High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial.

PURPOSE: We completed a Phase I/II clinical trial (Lineberger Comprehensive Cancer Center 9603), in which we treated 62 Stage IIIA/IIIB inoperable non-small-cell lung cancer (NSCLC) patients with two cycles of induction carboplatin/paclitaxel chemotherapy, followed by concurrent weekly carboplatin/paclitaxel with radiation doses escalated from 60 to 74 Gy. The median survival of 24 months, 3-year survival rate of 38%, and the high dose of radiation used justified a critical analysis of the technical and clinical components of this trial. METHODS AND MATERIALS: Between 1996 and 1999, 62 sequential patients with inoperable Stage IIIA/IIIB NSCLC were enrolled and treated with two cycles of induction carboplatin (area under the concentration curve = 6 using the Calvert equation) and paclitaxel (225 mg/m(2)), followed by an escalating radiation dose of 60-74 Gy with concurrent carboplatin weekly (area under the concentration curve = 2) and paclitaxel weekly (45 mg/m(2)). The goals of the trial were to determine whether 74 Gy of radiation could be safely delivered under these circumstances and whether patients could potentially benefit in terms of survival. The radiation treatment plans for all 62 patients were reviewed to determine the prechemotherapy and postchemotherapy tumor volume, as well as the dose-volume histograms of the normal lung and esophagus. RESULTS: Of the 62 patients who entered the trial, 48 completed the entire course of treatment. At last follow-up, 20 patients were alive (crude survival rate 32%). With a median follow-up of 43 months, the median survival was 24 months. The survival rate was 50% at 2 years and 38% at 3 years. Cox regression analysis showed that survival was best predicted by whether the patient had received radiotherapy (finished the trial), performance status, disease stage, and log postchemotherapy tumor volume. The 3-year survival rate for the 48 patients finishing the trial was 45%. Eight patients (13%) suffered locoregional relapse as the only site of failure. Only 1 patient had Grade 2 radiation pneumonitis. Five patients (8%) had Radiation Therapy Oncology Group Grade 3 or 4 esophagitis; 40 (65%) had a Grade 1 or 2 esophagitis. Esophageal toxicity could be predicted by the length of esophagus receiving 40 or 60 Gy. CONCLUSION: Radiation doses of 74 Gy, when given under the guidelines of the Lineberger Comprehensive Cancer Center 9603, appear to be safe and may possibly contribute to increased survival in patients with inoperable Stage IIIA/IIIB NSCLC.