Gary W. Chmielewski

Outcomes After Stereotactic Lung Radiotherapy or Wedge Resection for Stage I Non–Small-Cell Lung Cancer

PURPOSE To compare outcomes between lung stereotactic radiotherapy (SBRT) and wedge resection for stage I non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS One hundred twenty-four patients with T1-2N0 NSCLC underwent wedge resection (n = 69) or image-guided lung SBRT (n = 58) from February 2003 through August 2008. All were ineligible for anatomic lobectomy; of those receiving SBRT, 95% were medically inoperable, with 5% refusing surgery. Mean forced expiratory volume in 1 second and diffusing capacity of lung for carbon monoxide were 1.39 L and 12.0 mL/min/mmHg for wedge versus 1.31 L and 10.14 mL/min/mmHg for SBRT (P = not significant). Mean Charlson comorbidity index and median age were 3 and 74 years for wedge versus 4 and 78 years for SBRT (P < .01, P = .04). SBRT was volumetrically prescribed as 48 (T1) or 60 (T2) Gy in four to five fractions. Results Median potential follow-up is 2.5 years. At 30 months, no significant differences were identified in regional recurrence (RR), locoregional recurrence (LRR), distant metastasis (DM), or freedom from any failure (FFF) between the two groups (P > .16). SBRT reduced the risk of local recurrence (LR), 4% versus 20% for wedge (P = .07). Overall survival (OS) was higher with wedge but cause-specific survival (CSS) was identical. Results excluding synchronous primaries, nonbiopsied tumors, or pathologic T4 disease (wedge satellite lesion) showed reduced LR (5% v 24%, P = .05), RR (0% v 18%, P = .07), and LRR (5% v 29%, P = .03) with SBRT. There were no differences in DM, FFF, or CSS, but OS was higher with wedge. CONCLUSION Both lung SBRT and wedge resection are reasonable treatment options for stage I NSCLC patients ineligible for anatomic lobectomy. SBRT reduced LR, RR, and LRR. In this nonrandomized population of patients selected for surgery versus SBRT (medically inoperable) at physician discretion, OS was higher in surgical patients. SBRT and surgery, however, had identical CSS.

Durability and Predictors of Successful Radiofrequency Ablation for Barrett's Esophagus

BACKGROUND & AIMS After radiofrequency ablation (RFA), patients may experience recurrence of Barretts esophagus (BE) after complete eradication of intestinal metaplasia (CEIM). Rates and predictors of recurrence after successful eradication have been poorly described. METHODS We used the US RFA Registry, a nationwide registry of BE patients receiving RFA, to determine rates and factors that predicted recurrence of intestinal metaplasia (IM). We assessed recurrence by Kaplan-Meier analysis for the overall cohort and by worst pretreatment histology. Characteristics associated with recurrence were included in a logistic regression model to identify independent predictors. RESULTS Among 5521 patients, 3728 had biopsies 12 months or more after initiation of RFA. Of these, 3169 (85%) achieved CEIM, and 1634 (30%) met inclusion criteria. The average follow-up period was 2.4 years after CEIM. IM recurred in 334 (20%) and was nondysplastic or indefinite for dysplasia in 86% (287 of 334); the average length of recurrent BE was 0.6 cm. In Kaplan-Meier analysis, more advanced pretreatment histology was associated with an increased yearly recurrence rate. Compared with patients without recurrence, patients with recurrence were more likely, based on bivariate analysis, to be older, have longer BE segments, be non-Caucasian, have dysplastic BE before treatment, and require more treatment sessions. In multivariate analysis, the likelihood for recurrence was associated with increasing age and BE length, and non-Caucasian race. CONCLUSIONS BE recurred in 20% of patients followed up for an average of 2.4 years after CEIM. Most recurrences were short segments and were nondysplastic or indefinite for dysplasia. Older age, non-Caucasian race, and increasing length of BE length were all risk factors. These risk factors should be considered when planning post-RFA surveillance intervals.

Evaluation of the safety and pharmacokinetics of the multi-targeted receptor tyrosine kinase inhibitor sunitinib during embryo–fetal development in rats and rabbits

BACKGROUND Angiogenesis plays a key role in embryo-fetal development and, based on nonclinical safety data, the majority of vascular endothelial growth factor (VEGF)-targeted antiangiogenic agents used in cancer therapy are not recommended during pregnancy. We investigated the effects of sunitinib (an oral inhibitor of multiple receptor tyrosine kinases [RTKs] including VEGF-receptors) on embryo-fetal development. METHODS Presumed-pregnant Sprague-Dawley rats and New Zealand White rabbits received repeated daily oral doses of sunitinib (0-30 mg/kg/day), during the major period of organogenesis. Clinical/physical examinations were performed throughout the gestation phase, and blood samples were collected to determine systemic exposure. Necropsy (including uterine examination) was performed on all animals and fetal morphology was examined. RESULTS The no-observed-adverse-effect level was 1-5 mg/kg/day for maternal toxicity and 3 mg/kg/day for developmental toxicity in rats; 1 and 0.5 mg/kg/day, respectively, in rabbits. Embryo-fetal toxicity included decreases in the number of live fetuses and increases in the numbers of resorptions and post-implantation/complete litter losses; these were observed at doses of > or =5 mg/kg/day in rats and 5 mg/kg/day in rabbits. Malformations included fetal skeletal malformations (generally thoracic/lumbar vertebral alterations) in rats and cleft lip/palate in rabbits. These developmental effects were observed at approximately 5.5- (rats) and approximately 0.3-times (rabbits) the human systemic exposure at the approved sunitinib dose (50 mg/day). CONCLUSIONS Similar effects have been reported with the prototype monoclonal antibody bevacizumab. As is typically observed for potent inhibitors of RTKs involved in angiogenesis, sunitinib was associated with embryo-fetal developmental toxicity in rats and rabbits at clinically relevant dose levels.

Wedge resection margin distances and residual adenocarcinoma in lobectomy specimens.

We studied 31 T1 N0 M0 peripheral adenocarcinomas diagnosed by wedge resection and treated by lobectomy. Factors recorded were pleural surface-based, gross cut-surface, and microscopic margin distances; morphologic features of the adenocarcinomas; microscopic extension distance of beyond gross perimeter of neoplasm; and presence of residual adenocarcinoma in the lobectomy specimen. All staple-line margins in the wedge and lobectomy specimens underwent complete histologic examination. The mean pleural surface-based, gross cut-surface, and microscopic margin distances in wedge resections were 13.1, 4.1, and 2.3 mm, respectively. The mean microscopic wedge resection margin distance was 11 mm smaller than the pleural surface-based measured margin. The mean microscopic lepidic growth beyond the gross perimeter of the neoplasm was 7.4 mm. Fourteen lobectomy specimens (45%) included adenocarcinoma. The mean microscopic wedge resection specimen margin distances in cases with and without residual adenocarcinoma in the lobectomy specimens were 0.7 and 2.4 mm, respectively (P < .001). Incomplete excision may contribute to higher locoregional recurrence rates following limited resection surgery. Two processes affected wedge resection margin distances: stapling-induced parenchymal stretching, resulting in overestimation of pleural surface-based distances, and microscopic extension of adenocarcinoma beyond the gross perimeter of the neoplasm.

Age, tumor size, type of surgery, and gender predict survival in early stage (stage I and II) non-small cell lung cancer after surgical resection

BACKGROUND Even after presumably curative resection the 5-year survival rates are only 60-80% in stage I and 40-50% in stage II NSCLC. Purpose of the present study was the identification of independent clinico-pathological predictors of their survival. METHODS A retrospective review of 519 consecutive subjects who had undergone attempted curative resection for stage I or II NSCLC was performed. Patients who had received any adjuvant or neo-adjuvant chemo- or radiation therapy were excluded. Primary outcome measure was the duration of overall survival. RESULTS Median survival was 7.25 years for stage IA, 5.71 years for stage IB and 3.85 years for stage IIB. In univariate analysis, six variables were significantly associated (p-value<0.05) with poorer survival: older age, larger size of the tumor, male gender, surgery other than lobectomy, squamous histology and later stages (stage IB and IIB). In multivariate analysis, age (Hazard ratio=1.06 per year increase in age; p<0.0001), larger tumor size (Hazard ratio=1.54 per doubling of tumor size; p<0.0001), type of surgery (Hazard ratio=1.50 for surgery other than lobectomy; p=0.036), and gender (Hazard ratio=1.45 for male gender; p=0.039) were the predictors of overall survival. CONCLUSIONS In surgically treated early stage (I and II) NSCLC patients, age, tumor size, type of surgery, and gender are the important predictors of survival.

Incidence of Esophageal Adenocarcinoma and Causes of Mortality After Radiofrequency Ablation of Barrett’s Esophagus

BACKGROUND & AIMS Radiofrequency ablation (RFA) is commonly used to treat Barretts esophagus (BE). We assessed the incidence of esophageal adenocarcinoma (EAC) after RFA, factors associated with the development of EAC, and EAC-specific and all-cause mortality. METHODS We collected data for outcomes of patients who underwent RFA for BE from July 2007 through July 2011 from US multicenter RFA Patient Registry. Patients were followed until July 2014. Kaplan-Meier curves of EAC incidence were stratified by baseline histology. Crude EAC incidence and mortality (all-cause and EAC-specific) were calculated, and adjusted all-cause mortality was assessed. Logistic regression models were constructed to assess predictors of EAC and all-cause mortality. RESULTS Among 4982 patients, 100 (2%) developed EAC (7.8/1000 person-years [PY]) and 9 patients (0.2%) died of EAC (0.7/1000 PY) in a mean 2.7 ± 1.6 years. The incidence of EAC in nondysplastic BE was 0.5/1000 PY. Overall, 157 patients (3%) died during follow-up (all-cause mortality, 11.2/1000 PY). On multivariate logistic regression, baseline BE length (odds ratio, 1.1/ cm) and baseline histology (odds ratios, 5.8 and 50.3 for low-grade dysplasia and high-grade dysplasia [HGD] respectively) predicted EAC incidence. Among 9 EAC deaths, 6 (67%) had baseline HGD, and 3 (33%) had baseline intramucosal EAC. The most common causes of death were cardiovascular (15%) and extraesophageal cancers (15%). No deaths were associated with RFA. CONCLUSIONS Based on analysis of a multicenter registry of patients who underwent RFA of BE, less than 1% died from EAC. The incidence of EAC was markedly lower in this study than in other studies of disease progression, with the greatest absolute benefit observed in patients with HGD.

RAPID DISEASE PROGRESSION WITH DELAY IN TREATMENT OF NON-SMALL-CELL LUNG CANCER

PURPOSE To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. RESULTS Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. CONCLUSIONS With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.

Introduction: The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography–based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography–based screening and promote its rapid implementation. Methods: We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules. Results: Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2R&agr;, stromal cell-derived factor-1&agr;+&bgr;, tumor necrosis factor &agr;, and macrophage inflammatory protein 1 &agr;. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%. Conclusion: We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.

Radiographic and metabolic response rates following image-guided stereotactic radiotherapy for lung tumors

PURPOSE To evaluate radiographic and metabolic response after stereotactic body radiotherapy (SBRT) for early lung tumors. MATERIALS AND METHODS Thirty-nine tumors were treated prospectively with SBRT (dose=48-60 Gy, 4-5 Fx). Thirty-six cases were primary NSCLC (T1N0=67%; T2N0=25%); three cases were solitary metastases. Patients were followed using CT and PET at 6, 16, and 52 weeks post-SBRT, with CT follow-up thereafter. RECIST and EORTC criteria were used to evaluate CT and PET responses. RESULTS At median follow-up of 9 months (0.4-26), RECIST complete response (CR), partial response (PR), and stable disease (SD) rates were 3%, 43%, 54% at 6 weeks; 15%, 38%, 46% at 16 weeks; 27%, 64%, 9% at 52 weeks. Mean baseline tumor volume was reduced by 46%, 70%, 87%, and 96%, respectively at 6, 16, 52, and 72 weeks. Mean baseline maximum standardized uptake value (SUV) was 8.3 (1.1-20.3) and reduced to 3.4, 3.0, and 3.7 at 6, 16, and 52 weeks after SBRT. EORTC metabolic CR/PR, SD, and progressive disease rates were 67%, 22%, 11% at 6 weeks; 86%, 10%, 3% at 16 weeks; 95%, 5%, 0% at 52 weeks. CONCLUSIONS SBRT yields excellent RECIST and EORTC based response. Metabolic response is rapid however radiographic response occurs even after 1-year post treatment.

The Safe Transition from Open to Thoracoscopic Lobectomy: A 5-Year Experience

BACKGROUND We hypothesized that established thoracic surgeons without formal minimally invasive training can learn thoracoscopic lobectomy without compromising patient safety or outcome. METHODS Data were retrospectively collected on patients who underwent pulmonary lobectomy at a single health system between August 1, 2003, and April 1, 2008. Age, sex, pulmonary function tests, preoperative and postoperative stages, pathologic diagnosis, anatomic resection, extent of lymph node sampling, surgical technique and duration, complications, blood loss, transfusion requirement, chest tube duration, length of hospital stay, 30-day readmission, and mortality rate were examined. The percentage of patients who underwent thoracoscopic lobectomy and their outcomes were then compared among three chronologic cohorts. RESULTS Three hundred sixty-four patients underwent pulmonary lobectomy (239 open; 99 thoracoscopic; 26 thoracoscopic converted to open). Baseline characteristics, staging, pathologic diagnosis, and anatomic resections were similar in the early, middle, and late cohorts. The percentage of thoracoscopic lobectomies increased from 16% to 49%, whereas open lobectomy decreased from 81% to 42% (p < 0.0001). The complication rate remained constant with the exception of air leaks lasting more than 7 days (9% versus 10% versus 2%; p = 0.02). Hospital length of stay (6 versus 5 versus 4 days; p < 0.0001) and chest tube duration (4 versus 3 versus 3 days; p < 0.0001) decreased and operative duration increased as more thoracoscopic lobectomies were performed. Blood loss, transfusion requirement, 30-day readmission, and 1-year survival were not significantly different among chronologic cohorts. CONCLUSIONS Established thoracic surgeons can safely incorporate thoracoscopic lobectomy with no increase in morbidity or mortality.