Shauna L. Hillman

Phase III Comparison of Twice-Daily Split-Course Irradiation Versus Once-Daily Irradiation for Patients With Limited Stage Small-Cell Lung Carcinoma

PURPOSE Because small-cell lung cancer is a rapidly proliferating tumor, it was hypothesized that it may be more responsive to thoracic irradiation (TI) given twice-daily than once-daily. This hypothesis was tested in a phase III trial. PATIENTS AND METHODS Patients with limited-stage small-cell lung cancer were entered onto a phase III trial, and all patients initially received three cycles of etoposide (130 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). Subsequently, patients who did not have progression to a distant site (other than brain) were randomized to twice-daily thoracic irradiation (TDTI) versus once-daily thoracic irradiation (ODTI) given concomitantly with two additional cycles of etoposide (100 mg/m(2) x 3) and cisplatin (30 mg/m(2) x 3). The irradiation doses were TDTI, 48 Gy in 32 fractions, with a 2.5-week break after the initial 24 Gy, and ODTI, 50.4 Gy in 28 fractions. After thoracic irradiation, the patients received a sixth cycle of etoposide/cisplatin, followed by prophylactic cranial irradiation (30 Gy/15 fractions) if they had a complete response. RESULTS Of 311 assessable patients enrolled in the trial, 262 underwent randomization to TDTI or ODTI. There were no differences between the two treatments with respect to local-only progression rates, overall progression rates, or overall survival. The patients who received TDTI had greater esophagitis (> or = grade 3) than those who received ODTI (12.3% v 5.3%; P =.05). Although patients received thoracic irradiation encompassing the postchemotherapy volumes, only seven of 90 local failures were out of the portal of irradiation. CONCLUSION When TI is delayed until the fourth cycle of chemotherapy, TDTI does not result in improvement in local control or survival compared with ODTI.

A prognostic model for advanced stage nonsmall cell lung cancer: Pooled analysis of north central cancer treatment group trials

A pooled analysis was performed to examine the impact of pretreatment factors on overall survival (OS) and time to progression (TTP) in patients with advanced‐stage nonsmall cell lung cancer (NSCLC) and to construct a prediction equation for OS using pretreatment factors.

Segmentectomy Versus Wedge Resection for Non-Small Cell Lung Cancer in High-Risk Operable Patients

BACKGROUND Patients with early-stage lung cancer and limited pulmonary reserve may not be appropriate candidates for lobectomy. In these situations, sublobar resection (wedge or segmentectomy) is generally performed. Many physicians believe that segmentectomy is superior because it allows for an improved parenchymal margin and nodal sampling. METHODS We performed an analysis using operative and pathology reports collected as part of planned data collection for American College of Surgeons Surgical Oncology Group (ACOSG) Z4032. This was a prospective trial in which patients with clinical stage I lung cancer and limited pulmonary function were randomized to sublobar resection with or without brachytherapy. The operative approach (video-assisted thoracic surgery [VATS] vs thoracotomy), extent of resection, and degree of lymph node evaluation were at the discretion of the individual surgeon. The primary aim of this analysis was to compare the parenchymal margin achieved between segmentectomy and wedge resection. Secondary aims included the extent of nodal staging and whether the operative approach (VATS vs open) had an effect on margin status and nodal evaluation. RESULTS Among 210 patients, 135 (64%) underwent a VATS approach and 75 (36%) a thoracotomy. A segmentectomy was performed in 57 patients (27%) and a wedge resection in 153 patients (73%). There were no significant differences in the degree of nodal upstaging, stations sampled, or parenchymal margin obtained between VATS and thoracotomy. However, significant differences were observed between patients who underwent a segmentectomy and those who underwent a wedge resection with regard to parenchymal margin (1.5 cm vs 0.8 cm, p = 0.0001), nodal upstaging (9% vs 1%, p = 0.006), and nodal stations sampled (3 vs 1, p < 0.0001) . Notably, 41% of patients treated by wedge resection had no nodes sampled at the time of operation compared with 2% of those who underwent segmentectomy (p < 0.0001). CONCLUSIONS In ACOSG Z4032, wedge resection, regardless of the approach, was associated with a smaller parenchymal margin and a lower yield of lymph nodes and rate of nodal upstaging when compared with segmentectomy.

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.

Evaluation of the Value of Attribution in the Interpretation of Adverse Event Data: A North Central Cancer Treatment Group and American College of Surgeons Oncology Group Investigation

PURPOSE In March 1998, Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AEs) to study drug. We investigate whether attribution adds value to the interpretation of AE data. PATIENTS AND METHODS Patients in the placebo arm of two phase III trials-North Central Cancer Treatment Group Trial 97-24-51 (carboxyamino-triazole v placebo in advanced non-small-cell lung cancer) and American College of Surgeons Oncology Group Trial Z9001 (imatinib mesylate v placebo after resection of primary gastrointestinal stromal tumors)-were studied. Attribution was categorized as unrelated (not related or unlikely) and related (possible, probable, or definite). RESULTS In total, 398 patients (84 from Trial 97-24-51 and 314 from Trial Z9001) and 7,736 AEs were included; 47% and 50% of the placebo-arm AEs, respectively, were reported as related. When the same AE was reported in the same patient on multiple visits, the attribution category changed at least once 36% and 31% of the time. AE type and sex (Trial Z9001) and AE type and performance status (Trial 97-24-51) were associated with a higher likelihood of AEs being deemed related. CONCLUSION Nearly 50% of AEs were reported as attributed to study drug on the placebo arm of two randomized clinical trials. These data provide strong evidence that AE attribution is difficult to determine, unreliable, and of questionable value in interpreting AE data in randomized clinical trials.

A Front-Line Window of Opportunity Phase 2 Study of Sorafenib in Patients With Advanced Nonsmall Cell Lung Cancer: North Central Cancer Treatment Group Study N0326

The current study was conducted to assess the efficacy and toxicity of sorafenib as front‐line therapy in patients with stage IIIB (pleural effusion) or IV nonsmall cell lung cancer (NSCLC).

Endpoints in phase II trials for advanced non-small cell lung cancer.

Introduction: We investigated the relationships between progression-free survival (PFS), response, confirmed response, and failure-free survival (FFS) with overall survival (OS) to assess their suitability as primary endpoints in phase II trials for advanced non-small cell lung cancer. Methods: Individual data of 284 patients from four phase II trials were pooled. Progression status and response were modeled as time dependent variables in a multivariable (adjusted for baseline age, gender, stage, and performance status) Cox proportional hazards model for OS, stratified by trial. Subsequently, Cox proportional hazards models were used to assess the impact of PFS, response, confirmed response, and FFS on subsequent survival, using landmark analysis at 8, 12, 16, 20, and 24 weeks. Model discrimination was evaluated using the concordance index (c-index). Results: The overall median OS, PFS, and FFS were 9.6, 3.7, and 2.8 months, and the response and confirmed response rates were 21 and 15%, respectively. Both progression status and response as time dependent covariates were significantly associated with OS (p < 0.0001; p = 0.009). PFS and FFS at 12 weeks significantly predicted for subsequent survival with the strongest c-index and hazard ratio combination in landmark analyses (hazard ratio, c-index: PFS: 0.39, 0.67; FFS: 0.37, 0.67). The c-indices for response and confirmed response were low (0.59–0.60), indicating their inability to sufficiently discriminate subsequent patient survival outcomes. Conclusions: FFS or PFS at 12 weeks is a stronger predictor of subsequent patient survival compared with tumor response and should be routinely used as endpoints in phase II trials for advanced non-small cell lung cancer.

A phase II study of the dolastatin 15 analogue LU 103793 in the treatment of advanced non-small-cell lung cancer.

A phase II study of the dolastatin 15 analog LU 103793 was conducted by the North Central Cancer Treatment Group in patients with advanced non–small-cell lung cancer (SCLC). Previously untreated patients received this agent at a dosage of 2.5 mg/m2 as a 5-minute intravenous infusion for 5 consecutive days every 3 weeks. Between September 1997 and July 1998, 17 patients were accrued in this study. Forty-two treatment cycles were administered with relatively modest toxicity. No responses were seen. This agent appears to be inactive in the treatment of advanced non-SCLC.

Evaluation of the Optimal Number of Lesions Needed for Tumor Evaluation Using the Response Evaluation Criteria in Solid Tumors: A North Central Cancer Treatment Group Investigation

PURPOSE In February 2000, the criteria for measuring tumor shrinkage as an indicator of antitumor activity were redefined by the Response Evaluation Criteria in Solid Tumors (RECIST). This resulted in simplifying bidimensional to unidimensional measurement of lesions. Under RECIST, all lesions, up to 10, must be measured. Scanning and measuring multiple lesions is costly, time-consuming, and a disincentive to participation in clinical trials. We investigated whether fewer than 10 lesions can be measured without compromising the accuracy of assessing a regimens activity. PATIENTS AND METHODS Thirty-two North Central Cancer Treatment Group trials including 2,374 patients were analyzed. Twelve studies were conducted before RECIST; 20 were conducted post-RECIST. Agreement between objective status by cycle, confirmed response, overall response rate, and time to progression (TTP) was evaluated based on all 10 versus the largest one through five lesions. Results The median number of lesions reported on RECIST trials did not differ from pre-RECIST trials (median = 2.0). One lesion at baseline was reported in 49% of patients, two lesions in 28% of patients, three lesions in 12% of patients, four lesions in 6% of patients, and five lesions in 5% of patients in post-RECIST trials. Utilizing the largest two lesions produced excellent concordance with that using all lesions for all end points. In no trial did the overall response rate differ by more than 3% when two versus all lesions were considered. Evaluating more than two lesions did not significantly improve agreement. CONCLUSION Based on these trials, the assessment of more than two lesions did not alter the conclusions regarding a treatments efficacy as judged by response rate or TTP.