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.

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.

The efficacy of electromagnetic navigation to assist with computed tomography-guided percutaneous thermal ablation of lung tumors.

OBJECTIVE: Electromagnetic (EM) navigation is increasingly used to assist with bronchoscopic interventions such as biopsy or fiducial placement. Electromagnetic navigation can also be a useful adjunct to computed tomography (CT)-guided thermal ablation and biopsy of lung tumors. This study compares procedures carried out using an EM navigation system (Veran Medical Technologies Inc, St Louis, MO) with procedures using CT fluoroscopy only. METHODS: Over a 23-month period, 17 patients scheduled for thermal ablation were prospectively enrolled in this study. The mean age was 72 years (range, 60-84 years). Seven patients were women. Patients were randomized to EM navigation (n = 7) or CT fluoroscopy alone (n = 10). In some cases, additional ablation or biopsies were performed with or without EM navigation depending on the randomization arm. All procedures were performed under general anesthesia either by a thoracic surgeon or a radiologist. RESULTS: A total of 23 procedures were performed in 17 patients: 20 were ablation procedures and 3 were biopsies. Fourteen were performed for non-small cell lung cancer, and 9 for pulmonary metastases from other organs. Despite randomization, patients receiving EM navigation had a trend for smaller tumors (mean diameter, 1.45 vs 2.90 cm; P = 0.06). For thermal ablation procedures, the time to complete intervention was significantly less when EM navigation was used (mean, 7.6 vs 19 minutes; P = 0.022). Although not statistically significant, there were fewer skin punctures (mean, 1 vs 1.25; P = 0.082), fewer adjustments (mean, 5.6 vs 11.8; P = 0.203), less CT fluoroscopy time (mean, 21.3 vs 34.3 seconds; P = 0.345), and fewer CT scans (mean, 7 vs 15; P = 0.204) whenever EM navigation was used. CONCLUSIONS: Electromagnetic navigation reduces the time to successfully place an ablation probe in a target tumor. Further study is required to determine whether EM navigation may also reduce the number of adjustments, skin punctures, and CT scans as well as decrease CT fluoroscopy time.

Endoscopic fundoplication for the treatment of gastroesophageal reflux disease: initial experience.

OBJECTIVE: Transoral incisionless fundoplication (TIF) is a promising approach for gastroesophageal reflux disease (GERD) that may decrease morbidity compared with conventional antireflux procedures. We report our initial experience with this minimally invasive approach. METHODS: Over a 24-month period, 46 patients (mean age, 49 years; 50% female) underwent 48 TIF procedures. All procedures were performed under general anesthesia. Two surgeons participated in all cases; one served as the endoscopist, and the other performed the partial fundoplication. Heartburn severity was measured using the GERD health-related quality of life (GERD-HRQL) instrument (best score = 0, worst score = 45), which includes an additional question assessing overall satisfaction. RESULTS: Preoperatively, 33 (72%) of 46 patients had small (<3 cm) hiatal hernias, and none had undergone any previous antireflux procedures. Preoperative workup included manometry and barium esophagogram, with pH testing reserved for patients with atypical symptoms or typical symptoms and a lack of response to proton-pump inhibitors. The mean procedure time was 83 minutes (range, 36-180 minutes). The mean procedure time decreased after the first 5 cases from 122 to 78 minutes (P = .001). Mean length of stay was 1.3 days. One patient was readmitted with aspiration pneumonia. Three patients had minor complications (1 had minor bleeding from a suture site and 2 had urinary retention). There were no perioperative deaths. Mean follow-up was 140 days. The mean GERD-HRQL scores improved significantly (23 vs 7; P < .001). There were 22 patients with follow-up greater than 90 days (mean follow-up, 240 days). GERD-HRQL scores remained significantly improved for these patients (23 vs 8; P = .001). Four patients from the entire group (8.6%) had no improvement, in 3 instances due to breakdown of the wrap. Two patients were treated with repeat endoscopic fundoplication and 1 was treated with laparoscopic Nissen fundoplication, and all had a significant improvement in symptoms after reoperation. CONCLUSIONS: TIF is effective at short-term follow-up and safe for patients with GERD. However, long-term follow-up and randomized trials are required to assess the efficacy and durability of this approach compared with conventional surgical repair.

Role of surgery following induction therapy for stage III non-small cell lung cancer.

Over the last 30 years neoadjuvant treatment of stage IIIA non-small cell lung cancer (NSCLC) followed by surgical resection for stage IIIB disease has significantly improved the overall results of treatment for patients with stage III NSCLC as well as for those with locally invasive tumors. Different chemotherapy regimens have been used, although in most studies some combination of drugs that include cisplatin is the standard. Radiation when given as part of the induction protocol appears to offer a higher rate of resection and complete resection, and higher doses of radiation are associated with better nodal downstaging. Resection in patients with persistent N2 disease and pneumonectomy following induction therapy remain controversial. Resection in patients with persistent N2 disease and pneumonectomy following induction therapy remain controversial.

Thirty- and ninety-day outcomes after sublobar resection with and without brachytherapy for non-small cell lung cancer: results from a multicenter phase III study.

OBJECTIVE: Sublobar resection (SR) is commonly used for patients considered high risk for lobectomy. Nonoperative therapies are increasingly being reported for patients with similar risk because of perceived lower morbidity. We report 30- and 90-day adverse events (AEs) from American College of Surgeons Oncology Group Z4032, a multicenter phase III study for high-risk patients with stage I non-small cell lung cancer. METHODS: Data from 222 evaluable patients randomized to SR (n = 114) or SR with brachytherapy (n = 108) are reported. AEs were recorded using the Common Terminology Criteria for Adverse Events, Version 3.0, at 30 and 90 days after surgery. Risk factors (age, percent baseline carbon monoxide diffusion in the lung [DLCO%], percent forced expiratory volume in 1 second [FEV1%], upper lobe vs lower lobe resections, performance status, surgery approach, video-assisted thoracic surgery vs open and extent, and wedge vs segmentectomy) were analyzed using a multivariable logistic model for their impact on the incidence of grade 3 or higher (G3+) AEs. Respiratory AEs were also specifically analyzed. RESULTS: Median age, FEV1%, and DLCO% were similar in the 2 treatment groups. There was no difference in the location of resection (upper vs lower lobe) or the use of segmental or wedge resections. There were no differences between the groups with respect to "respiratory" G3+ AEs (30 days: 14.9% vs 19.4%, P = .35; 0-90 days: 19.3% vs 25%, P = .31) and "any" G3+ AEs (30 days: 25.4% vs 30.6%, P = .37; 0-90 days: 29.8% vs 37%, P = .25). Further analysis combined the 2 groups. Mortality occurred in 3 patients (1.4%) by 30 days and in 6 patients (2.7%) by 90 days. Four of the 6 deaths were thought to be due to surgery. When considered as continuous variables, FEV1% was associated with "any" G3+ AE at days 0 to 30 (P = .03; odds ratio [OR] = 0.98) and days 0 to 90 (P = .05; OR = 0.98), and DLCO% was associated with "respiratory" G3+ AE at days 0 to 30 (P = .03; OR = 0.97) and days 0 to 90 (P = .05; OR = 0.98). Segmental resection was associated with a higher incidence of any G3+ AE compared with wedge resection at days 0 to 30 (40.3% vs 22.7%; OR = 2.56; P < .01) and days 0 to 90 (41.5% vs 29.7%; OR = 1.96; P = .04). The median FEV1% was 50%, and the median DLCO% was 46%. By using these median values as potential cutpoints, only a DLCO% of less than 46% was significantly associated with an increased risk of "respiratory" and "any" G3+ AE for days 0 to 30 and 0 to 90. CONCLUSIONS: In a multicenter setting, SR with brachytherapy was not associated with increased morbidity compared with SR alone. SR/SR with brachytherapy can be performed safely in high-risk patients with non-small cell lung cancer with low 30- and 90-day mortality and acceptable morbidity. Segmental resection was associated with increased "any" G3+ AE, and DLCO% less than 46% was associated with "any" G3+ AE and "respiratory" G3+ AE at both 30 and 90 days.

The impact of adjuvant brachytherapy with sublobar resection on pulmonary function and dyspnea in high-risk patients with operable disease: preliminary results from the American College of Surgeons Oncology Group Z4032 trial.

BACKGROUND: Z4032 was a randomized study conducted by the American College of Surgeons Oncology Group comparing sublobar resection alone versus sublobar resection with brachytherapy for high-risk operable patients with non-small cell lung cancer (NSCLC). This evaluates early impact of adjuvant brachytherapy on pulmonary function tests, dyspnea, and perioperative (30-day) respiratory complications in this impaired patient population. METHODS: Eligible patients with stage I NSCLC tumors 3 cm or smaller were randomly allocated to undergo sublobar resection with (SRB group) or without (SR group) brachytherapy. Outcomes measured included the percentage predicted forced expiratory volume in 1 second (FEV1%), percentage predicted carbon monoxide diffusion capacity (DLCO%), and dyspnea score per the University of California San Diego Shortness of Breath Questionnaire. Pulmonary morbidity was assessed per the Common Terminology Criteria for Adverse Events version 3.0. Outcomes were measured at baseline and 3 months. A 10% change in pulmonary function test or 10-point change in dyspnea score was deemed clinically meaningful. RESULTS: Z4032 permanently closed to patient accrual in January 2010 at 224 patients. At 3-month follow-up, pulmonary function data are currently available for 148 (74 SR and 74 SRB) patients described in this report. There were no differences in baseline characteristics between arms. In the SR arm, 9 patients (12%) reported grade 3 respiratory adverse events, compared with 12 (16%) in the SRB arm (P = .49). There was no significant change in percentage change in DLCO% or dyspnea score from baseline to 3 months within either arm. In the case of FEV1%, percentage change from baseline to 3 months was significant within the SR arm (P = .03), with patients reporting improvement in FEV1% at month 3. Multivariable regression analysis (adjusted for baseline values) showed no significant impact of treatment arm, tumor location (upper vs other lobe), or surgical approach (video-assisted thoracoscopic surgery vs thoracotomy) on 3-month FEV1%, DLCO%, and dyspnea score. There was no significant difference in incidence of clinically meaningful (10% pulmonary function or 10-point dyspnea score change) change between arms. Twenty-two percent of patients with lower-lobe tumors and 9% with upper-lobe tumors demonstrated 10% decline in FEV1% (odds ratio, 2.79; 95 confidence interval, 1.07-7.25; P = .04). CONCLUSIONS: Adjuvant intraoperative brachytherapy in conjunction with sublobar resection did not significantly worsen pulmonary function or dyspnea at 3 months in a high-risk population with NSCLC, nor was it associated with increased perioperative pulmonary adverse events. Lower-lobe resection was the only factor significantly associated with clinically meaningful decline in FEV1%.

Impact of neoadjuvant chemoradiotherapy followed by surgical resection on node-negative T3 and T4 non-small cell lung cancer.

OBJECTIVE: This study examined the impact of neoadjuvant chemotherapy and concurrent high-dose radiation therapy on survival in patients with node-negative T3 and T4 non-small cell lung cancer. METHODS: A total of 110 consecutive patients underwent surgical resection for invasive T3N0M0 (94 patients) and T4N0M0 (16 patients) non-small cell lung cancer between 1979 and 2008. Forty-seven patients received neoadjuvant chemotherapy and concurrent high-dose (5940 cGy) radiation therapy before resection (Chemo-RT group). Sixty-three patients underwent surgical resection without receiving induction chemoradiotherapy (Surg group), of whom 21 received neoadjuvant radiation, 19 received adjuvant radiation, 17 received surgery alone, 2 received adjuvant chemotherapy, 2 received adjuvant chemoradiotherapy, and 2 received brachytherapy. Survival of the Chemo-RT and Surg groups was compared using both crude and adjusted Cox proportional hazards models. RESULTS: The 5-year, 10-year, and median survivals were 61%, 50%, and 90 months, respectively, in the Chemo-RT group versus 22%, 14%, and 22 months, respectively, in the Surg group. Subjects in the Surg group had an increased risk of death (hazard ratio, 2.60; 95% confidence interval, 1.62-4.18; P = .0001) compared with the Chemo-RT group. After adjustment for potential confounding variables of age, sex, tumor size, tumor location, type of operation, and decade of care, subjects in the Surg group remained at increased risk of death (hazard ratio, 2.81; 95% confidence interval, 1.45-5.44, P = .002) compared with the Chemo-RT group. CONCLUSIONS: Aggressive treatment of node-negative invasive T3 and T4 NSCLC with induction chemoradiotherapy may significantly prolong survival. This approach should be evaluated in a prospective multicenter national trial.

Location as an important predictor of lymph node involvement for pulmonary adenocarcinoma.

BACKGROUND: Increasing data implicate histologic grade and radiographic appearance along with tumor size as key prognostic indicators for pulmonary adenocarcinoma. The impact of tumor location on prognosis has not been examined. METHODS: The records of 530 consecutive patients with pulmonary adenocarcinoma pathologically staged between June 1979 and July 2002 were reviewed. All patients had a preoperative computed tomographic scan of the chest and underwent surgical staging by mediastinoscopy, lymph node sampling, or lymph node dissection. Patients with bronchioalveolar cell carcinoma were excluded. Peripheral tumors were compared with central tumors with regard to stage and survival. A tumor was considered to be central if visualized within the inner third of the lung field or seen bronchoscopically. Patients with T1 cancers were further analyzed on the basis of tumor size. Survival was determined by the Kaplan-Meier analysis and comparisons were made by the log-rank method. RESULTS: Central tumors were more advanced and demonstrated a significantly (P < .0001) poorer survival than peripheral tumors (median 18 vs 39 months). Sixty percent of patients with central tumors had stage III or stage IV disease compared with 25% of those with peripheral tumors. Central T1 tumors, however, demonstrated a 50% incidence of lymph node involvement. Although the incidence of lymph node metastases increased incrementally with the size of peripheral T1 tumors, it remained 50% for central T1 tumors irrespective of size. CONCLUSION: Tumor location for pulmonary adenocarcinoma should be considered when planning therapy. Central tumors have a high incidence of lymph node metastases (regardless of size) and a poorer prognosis.

Pneumonectomy after high-dose radiation and concurrent chemotherapy for nonsmall cell lung cancer.

BACKGROUND: Pneumonectomy after high-dose radiotherapy and concurrent chemotherapy has been associated with high operative mortality. Therefore, most induction protocols limit radiation to 5,000 cGy or less. Additionally, the safety of right pneumonectomy after induction therapy has been questioned. The feasibility of pneumonectomy after high-dose radiotherapy and concurrent chemotherapy is reviewed. METHODS: From 1990 to 2005, 30 patients with locally advanced nonsmall-cell lung cancer underwent pneumonectomy after 5,940 cGy of radiation and two cycles of etoposide and cisplatin. To minimize postpneumonectomy pulmonary edema, patients were treated with a protocol that included fluid restriction and 48 hours of mechanical ventilation. Morbidity, mortality, and survival were examined. RESULTS: There were 18 right and 12 left pneumonectomies. Death occurred in 4 patients (13.3%) but in only 1 (5.6%) after right pneumonectomy. Causes of death included aspiration, bronchopleural fistula, pneumonia, and massive pulmonary embolus. Major morbidity occurred in 5 (pneumonia in 2 and aspiration in 3). Median hospital stay was 9 days (range, 2 to 45), and intensive care unit stay was 2 days (range, 2 to 35). Median overall survival was 22 months with a 5-year survival of 33%. Patients surviving operation had a median survival of 33 months and a 5-year survival of 38%. CONCLUSIONS: The mortality rate after pneumonectomy after high-dose radiation and concurrent chemotherapy is relatively high but results in significant survival. The mortality rate is not increased after right-sided operations. Pneumonectomy should continue to be offered to patients with advanced locoregional disease after induction high-dose radiotherapy and concurrent chemotherapy when a complete resection cannot be carried out with a lesser procedure.

Limited resection for non-small cell lung cancer: observed local control with implantation of I-125 brachytherapy seeds.

BACKGROUND: Limited resection for lung cancer has been associated with a relatively high incidence of local recurrence. This retrospective study evaluates the impact of implanting radioactive iodine-125 (125I) seeds along the resection margin in these patients. METHODS: Thirty-three patients with lung cancer who were not candidates for lobectomy or pneumonectomy underwent a limited resection of 35 primary non-small cell lung cancers. 125I brachytherapy seeds were implanted along the resection margin to reduce the risk of local recurrence. Survival using the Kaplan-Meier method and sites of recurrence were documented. Follow-up ranged from 20 to 98 months (median, 51 months). RESULTS: The 5-year survival was 47% for all patients. For patients with T1N0 tumors, it was 67%, and for patients with T2N0 tumors, it was 39%. However, the cancer-specific survivals were 77% and 53% for patients with T1N0 and T2N0 tumors, respectfully. Ten patients experienced recurrence, with two local (at the resection margin) and six regional recurrences (five mediastinum, one chest wall). Both local recurrences and one regional recurrence occurred in the 19 patients with T1N0 tumors. CONCLUSIONS: 125I seed implantation along the resected margin for compromised patients undergoing limited resection of lung cancer results in a relatively low incidence of local recurrence and may prolong survival.