Angelina D. Tan

Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (Alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer.

PURPOSE A major concern with sublobar resection (SR) for non-small-cell lung cancer (NSCLC) is high local recurrence (LR). Adjuvant brachytherapy may reduce LR This multicenter randomized trial compares SR to SR with brachytherapy (SRB). PATIENTS AND METHODS High-risk operable patients with NSCLC ≤ 3 cm were randomly assigned to SR or SRB. The primary end point was time to LR, where LR included recurrence at the staple line (local progression), in the primary tumor lobe away from the staple line, and in ipsilateral hilar nodes. The trial was designed to have a 90% power to detect a hazard ratio (HR) of 0.315 in favor of SRB, using a one-sided type I error rate of 0.05 with a sample size of 100 eligible patients in each arm. RESULTS Two hundred twenty-four patients were randomly assigned; 222 patients were evaluable for intent-to-treat analysis. Median age was 71 years (range, 49 to 87 years). No differences were found in baseline characteristics. Median follow-up time was 4.38 years (range, 0.04 to 5.59 years). There was no difference in time to LR (HR, 1.01; 95% CI, 0.51 to 1.98; log-rank P = .98) or in the types of LR. Local progression occurred in only 17 (7.7%) of 222 patients. In patients with potentially compromised margins (margin < 1 cm, margin-to-tumor ratio < 1, positive staple line cytology, wedge resection, nodule size > 2.0 cm), SRB did not reduce LR, although trends favored the SRB arm. This was most marked in 14 patients with positive staple line cytology (HR, 0.22; P = .24). Three-year overall survival rates were similar for patients in the SR (71%) and SRB (71%) arms (P = .97). CONCLUSION Brachytherapy did not reduce LR after SR. This finding may have been related to closer attention to parenchymal margins by surgeons participating in this study.

Radiofrequency ablation of stage IA non–small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial

This study evaluated the 2‐year overall survival rate, adverse event rate, local control rate, and impact on pulmonary function tests for medically inoperable patients with stage IA non–small cell lung cancer (NSCLC) undergoing computed tomography (CT)–guided radiofrequency ablation (RFA) in a prospective, multicenter trial.

Pretreatment Quality of Life Is an Independent Prognostic Factor for Overall Survival in Patients with Advanced Stage Non-small Cell Lung Cancer

Hypothesis: We conducted this pooled analysis to assess the prognostic value of pretreatment Quality of Life (QOL) assessments on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Methods: Four hundred twenty patients with advanced NSCLC (stages IIIB with pleural effusion and IV) from six North Central Cancer Treatment Group trials were included in this study. QOL assessments included the single-item Uniscale (355 patients), Lung Cancer Symptom Scale (217 patients), and Functional Assessment of Cancer Therapy-Lung (197 patients). QOL scores were transformed to a 0 to 100 scale with higher scores representing better status and categorized using the sample median or clinically deficient score (CDS, ≤50 versus >50). Cox proportional hazards models stratified by study were used to evaluate the prognostic importance of QOL on OS alone and in the presence of other prognostic factors such as performance status, age, gender, body mass index, and laboratory parameters. Results: Pretreatment QOL accessed by Uniscale was significantly associated with OS univariately (p < 0.0001). Uniscale (p < 0.0001; hazard ratio = 1.6 for the sample median and 2.0 for the CDS categorization) and body mass index were the only significant predictors of OS multivariately. The median survival of patients who had a Uniscale score less than or equal to the CDS (≤50) was 5.7 versus 11.1 months for the >50 group; and 7.8 versus 13 months for the less than or equal to sample median (≤83) group and >83 group, respectively. The Lung Cancer Symptom Scale and the Functional Assessment of Cancer Therapy-Lung total scores were not significant predictors of OS. Conclusions: Pretreatment QOL measured by Uniscale is a significant and an independent prognostic factor for OS, and QOL should be routinely integrated as a stratification factor in advanced NSCLC trials.

Phase I Trial of Sirolimus Combined with Radiation and Cisplatin in Non-small Cell Lung Cancer

Purpose: The safety and tolerability of sirolimus combined with thoracic radiation and cisplatin was evaluated in patients with lung cancer. In parallel, the effects of sirolimus were studied in a murine model of radiation pneumonitis. Materials and Methods: The phase I trial evaluated standard three-dimensional conformal thoracic radiation therapy (60 Gy) and weekly cisplatin (25 mg/m2 IV) in combination with escalating doses of oral sirolimus. Sirolimus drug levels and inhibition of mTOR signaling to ribosomal S6 protein were assessed in blood. The effects of sirolimus administered during and after whole thoracic radiation of C57BL6/J mice were evaluated by monitoring mouse breathing rates and survival. Results: Seven patients with stage III lung cancer were accrued to the clinical study. None of the four patients treated with 2 mg/day sirolimus developed dose-limiting toxicities. Three patients were treated with 5 mg/day sirolimus, and one patient at this dose level had dose-limiting toxicity of grade 3 dysphagia. However, the maximally tolerated dose of sirolumus in this regimen was not defined because the study was terminated prematurely because of loss of funding. In the mouse experiments, concomitant sirolimus treatment was not associated with an increase in radiation-associated morbidity or mortality. Conclusions: Combination therapy with sirolimus, radiation, and cisplatin was well tolerated in patients.

Analysis of longitudinal quality-of-life data in high-risk operable patients with lung cancer: Results from the ACOSOG Z4032 (Alliance) multicenter randomized trial

BACKGROUND Prior studies have suggested that low baseline quality-of-life (QOL) scores predict worse survival in patients undergoing lung cancer surgery. However, these studies involved average-risk patients undergoing lobectomy. We report QOL results from a multicenter trial, American College of Surgeons Oncology Group Z4032, which randomized high-risk operable patients to sublobar resection (SR), or SR with brachytherapy, and included longitudinal QOL assessments. METHODS Global QOL, using the 36-item Short-Form Health Survey (SF36), and the dyspnea score from the University of California, San Diego Shortness of Breath Questionnaire (SOBQ) scale, was measured at baseline, 3, 12, and 24 months. SF36 physical component summary (PCS) and mental component summary (MCS) scores were standardized and adjusted for age and gender normals, with scores <50 indicating below-average health status. SOBQ scores were transformed to a 0-100 (poor-excellent) scale. Aims were to: (1) determine the impact of baseline scores on recurrence-free survival, overall survival, and 30-day adverse events (AEs); and (2) identify subgroups (surgical approach, resection type. tumor location, tumor size, respiratory function) with a ≥ 10-point decline or improvement in QOL after SR. RESULTS Two hundred twelve eligible patients were included. There were no significant differences in baseline QOL scores between arms. Median baseline PCS, MCS, and SOBQ scores were 42.7, 51.1, and 70.8, respectively. There were no differences in grade-3+ AEs, overall survival, or recurrence-free survival in patients with baseline scores ≤ median versus > median values, except for a significantly worse overall survival for patients with baseline SOBQ scores ≤ median value. There were no significant differences between the study arms in percentage change of QOL scores from baseline to 3, 12, or 24 months. Further comparison combining the 2 arms demonstrated a higher percentage of patients with a ≥ 10-point decline in SOBQ scores with segmentectomy compared with wedge resection (40.5% vs 21.9%, P = .03) at 12 months, with thoracotomy versus video-assisted thoracic surgery (VATS) (38.8% vs 20.4%, P = .03) at 12 months, and T1b versus T1a tumors (46.9% vs 23.5%, P = .020) at 24 months. A ≥ 10-point improvement in PCS score was seen at 3 months with VATS versus thoracotomy (16.5% vs 3.6%, P = .02). CONCLUSIONS In high-risk operable patients, poor baseline QOL scores were not predictive for worse overall or recurrence-free survival, or for higher risk for AEs following SR. VATS was associated with improvement in physical function at 3 months, and improved dyspnea scores at 12 months, lending support for the preferential use of VATS when SR is undertaken.

A Nomogram to Predict Recurrence and Survival of High-Risk Patients Undergoing Sublobar Resection for Lung Cancer: An Analysis of a Multicenter Prospective Study (ACOSOG Z4032)

BACKGROUND Individualized prediction of outcomes may help with therapy decisions for patients with non-small cell lung cancer. We developed a nomogram by analyzing 17 clinical factors and outcomes from a randomized study of sublobar resection for non-small cell lung cancer in high-risk operable patients. The study compared sublobar resection alone with sublobar resection with brachytherapy. There were no differences in primary and secondary outcomes between the study arms, and they were therefore combined for this analysis. METHODS The clinical factors of interest (considered as continuous variables) were assessed in a univariate Cox proportional hazards model for significance at the 0.10 level for their impact on overall survival (OS), local recurrence-free survival (LRFS), and any recurrence-free survival (RFS). The final multivariable model was developed using a stepwise model selection. RESULTS Of 212 patients, 173 had complete data on all 17 risk factors. Median follow-up was 4.94 years (range, 0.04 to 6.22). The 5-year OS, LRFS, and RFS were 58.4%, 53.2%, and 47.4%, respectively. Age, baseline percent diffusing capacity of lung for carbon monoxide, and maximum tumor diameter were significant predictors for OS, LRFS, and RFS in the multivariable model. Nomograms were subsequently developed for predicting 5-year OS, LRFS, and RFS. CONCLUSIONS Age, baseline percent diffusing capacity of lung for carbon monoxide, and maximum tumor diameter significantly predicted outcomes after sublobar resection. Such nomograms may be helpful for treatment planning in early stage non-small cell lung cancer and to guide future studies.

A new scoring system for predicting survival in patients with non-small cell lung cancer

This analysis was performed to create a scoring system to estimate the survival of patients with non‐small cell lung cancer (NSCLC). Data from 1274 NSCLC patients were analyzed to create and validate a scoring system. Univariate (UV) and multivariate (MV) Cox models were used to evaluate the prognostic importance of each baseline factor. Prognostic factors that were significant on both UV and MV analyses were used to develop the score. These included quality of life, age, performance status, primary tumor diameter, nodal status, distant metastases, and smoking cessation. The score for each factor was determined by dividing the 5‐year survival rate (%) by 10 and summing these scores to form a total score. MV models and the score were validated using bootstrapping with 1000 iterations from the original samples. The score for each prognostic factor ranged from 1 to 7 points with higher scores reflective of better survival. Total scores (sum of the scores from each independent prognostic factor) of 32–37 correlated with a 5‐year survival of 8.3% (95% CI = 0–17.1%), 38–43 correlated with a 5‐year survival of 20% (95% CI = 13–27%), 44–47 correlated with a 5‐year survival of 48.3% (95% CI = 41.5–55.2%), 48–49 correlated to a 5‐year survival of 72.1% (95% CI = 65.6–78.6%), and 50–52 correlated to a 5‐year survival of 84.7% (95% CI = 79.6–89.8%). The bootstrap method confirmed the reliability of the score. Prognostic factors significantly associated with survival on both UV and MV analyses were used to construct a valid scoring system that can be used to predict survival of NSCLC patients. Optimally, this score could be used when counseling patients, and designing future trials.

Long-Term Results of a Trial of Concurrent Chemotherapy and Escalating Doses of Radiation for Unresectable Non–Small Cell Lung Cancer: NCCTG N0028 (Alliance)

Introduction This phase I/II trial was designed to determine the maximally tolerated dose of thoracic radiotherapy as part of a combined modality approach. This report includes the long‐term outcomes of patients treated on this study. The phase II portion was never completed, as RTOG‐0617 opened before it was concluded. Methods In this study, the maximally tolerated dose was defined as 74 Gy of radiation in 37 fractions. Twenty‐five patients with unresectable NSCLC were treated with 2‐Gy daily fractions and concurrent weekly carboplatin and paclitaxel. Of these patients, 20 had stage III disease and five had stage I or II disease. Results Patients were followed until death or for a minimum of 5 years in the case of survivors. The median and 5‐year survivals were 42.5 months and 20% for all patients, 52.9 months and 40% in patients with stages I or II disease, and 39.8 months and 15% in patients with stage III disease. Conclusions The median survival of the stage III patients was quite favorable. We believe that this may have been due to a robust central review program of radiotherapy plans before treatment, ensuring compliance with protocol guidelines along with very low exposure of the heart to radiotherapy. Further improvements in 5‐year survival will likely require research on both systemic therapy and thoracic radiotherapy. Potential therapeutic modalities that may aid in these efforts include immunotherapy, targeted therapy, improved imaging, adaptive radiotherapy, simultaneous integrated boost techniques, novel dose fractionation regimens, and charged particle therapy.