Response to Dabrafenib Plus Trametinib in a Patient With an Uncommon Activating BRAF Mutation: A First in Non-Small Cell Lung Cancer.

Mutations in BRAF are present in 4% of non-small cell lung cancer (NSCLC), of which half are well-characterized activating variants affecting codon 600 (classified as class I). These mutations, most commonly BRAF V600E, have been associated with response to BRAF/MEK-directed small molecule kinase inhibitors. NSCLC with kinase-activating BRAF mutations occurring at other codons (class II variants) represent a substantial portion of BRAF-mutated NSCLC, but use of targeted therapy in these tumors is still under investigation. Class II mutations have been described in other tumor types and have been associated with response to BRAF/MEK-targeted agents, although optimal treatment strategies for these patients are lacking. This report presents a case of a woman with metastatic NSCLC harboring a class II BRAF p.N486_P490del variant who had a sustained clinical response to combination therapy with dabrafenib and trametinib. This first report of the use of BRAF/MEK-targeted therapy for this variant in NSCLC supports consideration of such treatment for tumors with class II BRAF variants.

Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer.

Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non-small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment-while reducing blood flow, volume, and permeability in the overall population-may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.

Neoadjuvant irinotecan, cisplatin, and concurrent radiation therapy with celecoxib for patients with locally advanced esophageal cancer.

BACKGROUND: Patients with locally advanced esophageal cancer who are treated with trimodality therapy have a high recurrence rate. Preclinical evidence suggests that inhibition of cyclooxygenase 2 (COX2) increases the effectiveness of chemoradiation, and observational studies in humans suggest that COX-2 inhibition may reduce esophageal cancer risk. This trial tested the safety and efficacy of combining a COX2 inhibitor, celecoxib, with neoadjuvant irinotecan/cisplatin chemoradiation. METHODS: This single arm phase 2 trial combined irinotecan, cisplatin, and celecoxib with concurrent radiation therapy. Patients with stage IIA-IVA esophageal cancer received weekly cisplatin 30 mg/m(2) plus irinotecan 65 mg/m(2) on weeks 1, 2, 4, and 5 concurrently with 5040 cGy of radiation therapy. Celecoxib 400 mg was taken orally twice daily during chemoradiation, up to 1 week before surgery, and for 6 months following surgery. RESULTS: Forty patients were enrolled with stage IIa (30 %), stage IIb (20 %), stage III (22.5 %), and stage IVA (27.5 %) esophageal or gastroesophageal junction cancer (AJCC, 5th Edition). During chemoradiation, grade 3-4 treatment-related toxicity included dysphagia (20 %), anorexia (17.5 %), dehydration (17.5 %), nausea (15 %), neutropenia (12.5 %), diarrhea (10 %), fatigue (7.5 %), and febrile neutropenia (7.5 %). The pathological complete response rate was 32.5 %. The median progression free survival was 15.7 months and the median overall survival was 34.7 months. 15 % (n = 6) of patients treated on this study developed brain metastases. CONCLUSIONS: The addition of celecoxib to neoadjuvant cisplatin-irinotecan chemoradiation was tolerable; however, overall survival appeared comparable to prior studies using neoadjuvant cisplatin-irinotecan chemoradiation alone. Further studies adding celecoxib to neoadjuvant chemoradiation in esophageal cancer are not warranted. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00137852 , registered August 29, 2005.

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Potential of 18F-FDG PET toward personalized radiotherapy or chemoradiotherapy in lung cancer.

PURPOSE: We investigated the metabolic response of lung cancer to radiotherapy or chemoradiotherapy by (18)F-FDG PET and its utility in guiding timely supplementary therapy. METHODS: Glucose metabolic rate (MRglc) was measured in primary lung cancers during the 3 weeks before, and 10-12 days (S2), 3 months (S3), 6 months (S4), and 12 months (S5) after radiotherapy or chemoradiotherapy. The association between the lowest residual MRglc representing the maximum metabolic response (MRglc-MMR) and tumor control probability (TCP) at 12 months was modeled using logistic regression. RESULTS: We accrued 106 patients, of whom 61 completed the serial (18)F-FDG PET scans. The median values of MRglc at S2, S3 and S4 determined using a simplified kinetic method (SKM) were, respectively, 0.05, 0.06 and 0.07 µmol/min/g for tumors with local control and 0.12, 0.16 and 0.19 µmol/min/g for tumors with local failure, and the maximum standard uptake values (SUVmax) were 1.16, 1.33 and 1.45 for tumors with local control and 2.74, 2.74 and 4.07 for tumors with local failure (p < 0.0001). MRglc-MMR was realized at S2 (MRglc-S2) and the values corresponding to TCP 95 %, 90 % and 50 % were 0.036, 0.050 and 0.134 µmol/min/g using the SKM and 0.70, 0.91 and 1.95 using SUVmax, respectively. Probability cut-off values were generated for a given level of MRglc-S2 based on its predicted TCP, sensitivity and specificity, and MRglc ≤0.071 µmol/min/g and SUVmax ≤1.45 were determined as the optimum cut-off values for predicted TCP 80 %, sensitivity 100 % and specificity 63 %. CONCLUSION: The cut-off values (MRglc ≤0.071 µmol/min/g using the SKM and SUVmax ≤1.45) need to be tested for their utility in identifying patients with a high risk of residual cancer after standard dose radiotherapy or chemoradiotherapy and in guiding a timely supplementary dose of radiation or other means of salvage therapy.

A rapid outcomes ascertainment system improves the quality of prognostic and pharmacogenetic outcomes from observational studies.

PURPOSE: Case-control and observational studies are popular choices for evaluating molecular prognostic/pharmacogenetic outcomes, but data quality is rarely tested. Using clinical trial and epidemiologic methods, we assessed the quality of prognostic and outcomes data obtainable from a large case-control study of lung cancer. METHODS: We developed an explicit algorithm (set of standard operating procedures forming a rapid outcomes ascertainment system) that encompassed multiple tests of quality assurance, and quality of data for a range of prognostic and outcomes variables, in several cancers, across several centers and two countries were assessed. Based on these assessments, the algorithm was revised and physicians' clinical practice changed. We reevaluated the quality of outcomes after these revisions. RESULTS: Development of an algorithm with internal quality controls showed specific patterns of data collection errors, which were fixable. Although the major discrepancy rate in retrospective data collection was low (0.6%) when compared with external validated sources, complete data were found in <50% of patients for treatment response rate, toxicity, and documentation of patient palliative symptoms. Prospective data collection and changes to clinical practice led to significantly improved data quality. Complete data on response rate increased from 45% to 76% (P = 0.01, Fisher's exact test), for toxicity data, from 26% to 56% (P = 0.02), and for palliative symptoms, from 25% to 70% (P < 0.05), in one large lung cancer case-control study. CONCLUSIONS: Observational studies can be a useful source for studying molecular prognostic and pharmacogenetic outcomes. A rapid outcomes ascertainment system with strict ongoing quality control measures is an excellent means of monitoring key variables.

Phase I study of flavopiridol in combination with Paclitaxel and Carboplatin in patients with non-small-cell lung cancer.

PURPOSE: The aim of this study was to evaluate the safety and tolerability of escalating doses of flavopiridol/ paclitaxel/carboplatin in patients with advanced-stage non-small-cell lung cancer (NSCLC) as well as the pharmacokinetics and activity of flavopiridol when used in combination with paclitaxel/carboplatin. PATIENTS AND METHODS: Eligible patients aged 18-75 years with previously untreated stage IIIB/IV NSCLC received paclitaxel 175 mg/m2 over 3 hours followed by carboplatin area under the curve (AUC) 5 over 1 hour and flavopiridol 30-85 mg/m2 over 24 hours every 3 weeks for 3 cycles. RESULTS: Eighteen patients were enrolled at 4 sites in the United States and received flavopiridol 30 mg/m2 (n = 3), 50 mg/m2 (n = 6), 70 mg/m2 (n = 3), or 85 mg/m2 (n = 6). No dose-limiting toxicities (DLTs) occurred at the 50-mg/m2 or 70-mg/m2 dose levels. Two patients treated at the 85-mg/m2 dose level experienced cardiovascular events that did not meet the criteria for DLT but were fatal in 1 case, prompting no further flavopiridol dose escalations and establishment of 70 mg/m2 as the maximum tolerated dose. The most frequently reported adverse events across all dose levels combined were nausea (89%), asthenia (67%), and diarrhea (56%). Flavopiridol concentrations increased rapidly, reached a plateau, and showed a multiphasic decline after the 24-hour infusion. Of 12 patients evaluable for efficacy, 8 achieved a partial response, and 4 had stable disease. CONCLUSION: Flavopiridol in doses

A phase II study of gefitinib in patients with advanced thyroid cancer.

OBJECTIVE: To determine the efficacy of gefitinib in patients with advanced thyroid cancer. DESIGN: In this open-label phase II trial, 27 patients with radioiodine-refractory, locally advanced, or metastatic thyroid cancer were treated with 250 mg of daily gefitinib. Histologic subtypes included papillary (41%), follicular (22%), anaplastic (19%), medullary (15%), and Hürthle cell carcinomas (4%). The primary endpoint was overall response rate. Secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS). MAIN OUTCOMES: There were no objective responses among the 25 patients evaluated. After 3, 6, and 12 months of treatment, 48%, 24%, and 12% of patients had stable disease (SD), respectively. Median PFS and OS were 3.7 and 17.5 months, respectively. Five patients with SD had a decrease in thyroglobulin (Tg) to <90% of baseline that was maintained for at least 3 months. CONCLUSIONS: Although gefitinib therapy did not result in any tumor responses, 32% of patients had reductions in tumor volume that did not meet criteria for partial response rate. Along with falling Tg levels and prolonged SD in a subset of patients, this may indicate biologic activity.

Epidermal growth factor receptor mutation testing in the care of lung cancer patients.

As the literature about epidermal growth factor receptor (EGFR) mutations grows and screening for mutations becomes increasingly integrated into clinical care, it is important to examine how best to do somatic mutational analyses and how best to use the test results in clinical decision making. We began offering mutation screening by comprehensive direct sequence analysis of exons 18 to 24 of the tyrosine kinase domain of EGFR in August 2004 as part of clinical cancer care and protocol therapy at our institutions. All identified potential mutations are confirmed with three to five independent PCRs of the original genomic DNA sample and, if not previously noted in the literature, are compared with the patient's germ-line DNA to ensure the finding is somatic. We formally analyzed the first 100 patients to undergo EGFR sequence analysis and found that testing was feasible and significantly affected the treatment of patients with non-small cell lung cancer (NSCLC). Patients harboring EGFR mutations were significantly more likely to receive recommendations for therapy with EGFR tyrosine kinase inhibitors (i.e., gefitinib or erlotinib) than patients without mutations. However, negative EGFR test results did not prevent physicians from administering these agents to selected patients. Ideally, a standardized technique for mutation testing could be developed, with demonstrated reproducibility and validity. Clinical trials incorporating molecular diagnostics are ongoing to assess the efficacy of EGFR tyrosine kinase inhibitors as first-line therapy for metastatic NSCLC and as adjuvant therapy for early-stage resected NSCLC. It is likely that mutation testing and other molecular analyses will be most useful in these two clinical situations.

Concurrent cisplatin, 5-FU, paclitaxel, and radiation therapy in patients with locally advanced esophageal cancer.

PURPOSE: Phase I-II data regarding neoadjuvant cisplatin, 5-fluorouracil (5-FU), paclitaxel, and radiation (PFT-R) from our institution demonstrated encouraging pathologic complete response (pCR) rates. This article updates our experience with PFT-R, and compares these results to our experience with cisplatin, 5-FU, and radiation therapy (PF-R) in locally advanced esophageal cancer. PATIENTS AND METHODS: We searched the Massachusetts General Hospital cancer registry for esophageal cancer patients treated with radiation therapy and chemotherapy between 1994-2002. Records of patients treated with curative, neoadjuvant therapy were examined for chemotherapeutic regimen. Outcomes of patients treated with PF-R or PFT-R were assessed for response to therapy, toxicity, and survival. RESULTS: A total of 177 patients were treated with neoadjuvant therapy with curative intent; 164 (93%) received PF-R (n=81) or PFT-R (n=83). Median overall survival was 24 months. After a median follow-up of 54 months for surviving patients, 3-year overall survival was 40% with no significant difference between PF-R (39%) and PFT-R (42%). CONCLUSIONS: Our findings failed to demonstrate an improvement in pCR or survival with PFT-R vs. PF-R. These results do not support this regimen of concurrent neoadjuvant PFT-R in esophageal cancer, and suggest that further investigations into alternative regimens and novel agents are warranted.

Effect of chemotherapy for advanced non-small cell lung cancer on patients' quality of life. A randomized controlled trial.

BACKGROUND: Patients with advanced non-small cell lung cancer (NSCLC) do not have curative treatment options; therefore, treatments should prolong survival and improve quality of life (QoL). We compared the effect on QoL of two docetaxel-platinum regimens with vinorelbine-cisplatin. METHODS: QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and the general EuroQol five-dimensional questionnaire (EQ-5D) in 926 chemotherapy-naïve patients with stages IIIB to IV NSCLC. Patients were randomly assigned to receive: docetaxel 75 mg/m2 plus cisplatin 75 mg/m2, every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin 6 mg/ml min, every 3 weeks (DCb); or vinorelbine 25 mg/m2/week plus cisplatin 100 mg/m2, every 4 weeks (VC). RESULTS: Overall, patients treated with either docetaxel-containing regimen had better QoL than VC-treated patients (LCSS global item "QoL today": P=0.064 for DC and P=0.016 for DCb versus VC; EQ-5D global item "health state today": P=0.016 for DC and P<0.001 for DCb versus VC). DC-treated patients experienced improved pain relief compared with VC (P=0.033), whereas pain relief with DCb and VC was similar. Patients treated with either docetaxel regimen had more favorable changes in performance status (P=0.065 for DC and P<0.001 for DCb versus VC) and mean weight loss (0.06 kg, gain of 0.08 kg, and 2.27 kg for DC, DCb, and VC, respectively; P<0.001 for both DC versus VC and DCb versus VC). CONCLUSION: The TAX 326 study shows that docetaxel-platinum regimens relieve symptoms and improve QoL in patients with advanced NSCLC. DCb and DC were superior to VC in all QoL outcomes assessed except for the difference between DC and VC in LCSS "QoL today", which was not significant.

Acquired Resistance to First-Line Afatinib and the Challenges of Prearranged Progression Biopsies.

OBJECTIVES: The mechanisms of acquired resistance to the irreversible EGFR inhibitor afatinib are not well documented. We performed this prospective clinical trial to determine the prevalence of the mutation T790M in afatinib-resistant patients. METHODS: Eligible patients had EGFR mutations; they were tyrosine kinase inhibitor-naive and were treated with afatinib, 40 mg daily. At enrollment, patients consented to a future repeat biopsy at the time of acquired resistance. RESULTS: A total of 24 patients were enrolled. The objective response rate was 58% (95% confidence interval [CI]: 37-78) with a median progression-free survival of 11.4 months (95% CI: 5.9-13.7) and median overall survival of 20.8 months (95% CI: 15.1-40.5). Of the 24 patients enrolled, 23 progressed and only 14 completed repeat biopsy at time of progression, with 11 samples sufficient for molecular analysis. Of those 11 patients, four (36% [95% CI: 10.9-69.2]) harbored T790M. CONCLUSIONS: T790M is likely a common resistance mechanism in patients treated with first-line afatinib. Although repeat biopsies at progression are crucial in elucidating resistance mechanisms, this study suggests that clinical and technical issues often limit their feasibility, highlighting the importance of developing noninvasive tumor-genotyping strategies.

Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma.

PURPOSE: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

Induction docetaxel and carboplatin followed by weekly docetaxel and carboplatin with concurrent radiotherapy, then surgery in stage III non-small cell lung cancer: a Phase I study.

PURPOSE: To determine the maximum-tolerated dose of docetaxel (DOC) in combination with carboplatin (CAR) and thoracic radiotherapy (RT), in the setting of trimodality treatment of patients with stage III non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Thirty-two patients with biopsy-proven stage IIIA (n = 20) or IIIB (n = 12) NSCLC were given two initial cycles of CAR (area under the curve = 6) and DOC (75 mg/m(2)), subsequent RT (54 Gy) with concurrent weekly CAR (area under the curve = 2), and DOC at six dose levels from 10 to 40 mg/m(2), then surgery if the patient's disease was resectable. RESULTS: Three patients did not complete induction computed tomography (CT). Twenty-nine patients received concurrent CT/RT. Fifteen patients were eligible for surgery. Dose-limiting toxicities occurred in 2 patients, at dose levels two (atrial fibrillation) and three (transaminitis). The maximum-tolerated dose, as defined by the protocol, was not reached, although grade 3 and 4 toxicities were encountered at all dose levels. The most common more than or equal to grades 3 toxicities were neutropenia, nausea, vomiting, and fatigue. Four patients (13.3%) responded to induction CT. Ten patients (38.5%) responded to CT/RT. Eight surgical patients (57.1%) were downstaged, including 3 pathologic complete responses. Median relapse free and overall survivals are 8.5 and 12 months. One-year and estimated 2-year survival rates are 56.3 and 34.3%. CONCLUSION: This new regimen for stage III NSCLC of induction CAR/DOC, then weekly CAR/DOC with concurrent RT followed by surgery, can be safely administered and offers encouraging results. DOC at 30 mg/m(2) in combination with CAR and RT is recommended for Phase II study.

Radiation dose escalation in limited-stage small-cell lung cancer.

PURPOSE: To review the treatment outcomes of limited-stage small-cell lung cancer (LS-SCLC) patients treated with > or =50 Gy of radiation at Massachusetts General Hospital (MGH) between 1987 and 2000 and to assess for evidence of a continuation of a radiation dose response. METHODS AND MATERIALS: The MGH cancer registry was searched for SCLC patients treated with radiotherapy between 1987 and 2000. Records of LS-SCLC patients treated with curative intent and radiation doses > or =50 Gy at MGH were reviewed. Surgical patients were excluded. RESULTS: Eighty-four LS-SCLC patients were treated with radiotherapy at MGH between 1987 and 2000. Of the 84 patients, 54 (64%) met the inclusion criteria; 30 patients (56%) in this study died, and 4 (7%) were lost to follow-up. The median follow-up of the surviving patients was 42 months. The median overall survival was 29 months. The 2- and 5-year survival rate was 64% and 47%, respectively. The local control rate at 3 years was 78%. CONCLUSION: The overall survival, local control, and disease-free survival rates for LS-SCLC patients treated with > or =50 Gy of radiation compare favorably with historical data. These findings suggest a continuation of the radiation dose-response curve in LS-SCLC. This further supports the need for appropriately powered, Phase III, prospective randomized trials in radiation dose escalation or radiation dose intensification for LS-SCLC.