PET Imaging and Rate of Pathologic Complete Response in Esophageal Squamous Cell Carcinoma.

BACKGROUND: For locally advanced esophageal squamous cell carcinoma (ESCC), chemoradiation (ChemoRT) followed by surgery offers the best chance of cure, with a 35-50% pathologic complete response (pCR) rate. Given the morbidity of esophagectomy and the possibility of pCR with ChemoRT, a 'watch and wait' strategy has been proposed, particularly for squamous cell carcinoma. The ability to accurately predict which patients will have pCR from ChemoRT is critical in treatment decision making. This study assessed positron emission tomography (PET) in predicting pCR after neoadjuvant ChemoRT for ESCC. METHODS: ESCC patients treated with ChemoRT followed by surgery were identified. Maximum standard uptake value (SUV), metabolic tumor volume, total lesion glycolysis, and first-order textual features of standard deviation, kurtosis and skewness were measured from PET. Univariable and multivariable generalized linear method analyses were performed. A metabolic complete response (mCR) was defined as a post-therapy PET scan with maximum SUV < 4.0. RESULTS: Twenty-seven patients underwent ChemoRT followed by surgery, with overall pCR seen in 11 (41%) patients and radiographic mCR seen in 12 (44%) patients. Final pathology for these 12 patients revealed pCR (ypT0N0M0) in 5 (42%) patients and persistent disease in 7 (58%) patients. Univariate analysis did not reveal PET parameters predictive of pCR. CONCLUSION: Treatment of ESCC with ChemoRT often results in a robust clinical response. Among patients with an mCR after ChemoRT, disease persistence was found in 58%. The inability of PET to predict pCR is important in the context of a 'watch and wait' strategy for ESCC treated with ChemoRT.

Extremity Soft Tissue Sarcoma: A Multi-Institutional Validation of Prognostic Nomograms.

BACKGROUND: Prognostic nomograms for patients with resected extremity soft tissue sarcoma (STS) include the Sarculator and Memorial Sloan Kettering (MSKCC) nomograms. We sought to validate these two nomograms within a large, modern, multi-institutional cohort of resected primary extremity STS patients. METHODS: Resected primary extremity STS patients from 2000 to 2017 were identified across nine high-volume U.S. institutions. Predicted 5- and 10-year overall survival (OS) and distant metastases cumulative incidence (DMCI), and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated with Sarculator and MSKCC nomograms, respectively. Predicted survival probabilities stratified in quintiles were compared in calibration plots to observed survival assessed by Kaplan-Meier estimates. Cumulative incidence was estimated for DMCI. Harrell's concordance index (C-index) assessed discriminative ability of nomograms. RESULTS: A total of 1326 patients underwent resection of primary extremity STS. Common histologies included: undifferentiated pleomorphic sarcoma (35%), fibrosarcoma (13%), and leiomyosarcoma (9%). Median tumor size was 8.0 cm (IQR 4.5-13.0). Tumor grade distribution was: Grade 1 (13%), Grade 2 (9%), Grade 3 (78%). Median OS was 172 months, with estimated 5- and 10-year OS of 70% and 58%. C-indices for 5- and 10-year OS (Sarculator) were 0.72 (95% CI 0.70-0.75) and 0.73 (95% CI 0.70-0.75), and 0.72 (95% CI 0.69-0.75) for 5- and 10-year DMCI. C-indices for 4-, 8-, and 12-year DSS (MSKCC) were 0.71 (95% CI 0.68-0.75). Calibration plots showed good prognostication across all outcomes. CONCLUSIONS: Sarculator and MSKCC nomograms demonstrated good prognostic ability for survival and recurrence outcomes in a modern, multi-institutional validation cohort of resected primary extremity STS patients. External validation of these nomograms supports their ongoing incorporation into clinical practice.

A multi-institutional validation study of prognostic nomograms for retroperitoneal sarcoma.

BACKGROUND AND OBJECTIVES: Prognostic nomograms for patients undergoing resection of retroperitoneal sarcoma (RPS) include the Sarculator and Memorial Sloan Kettering (MSK) sarcoma nomograms. We sought to validate the Sarculator and MSK nomograms within a large, modern multi-institutional cohort of patients with primary RPS undergoing resection. METHODS: Patients who underwent resection of primary RPS between 2000 and 2017 across nine high-volume US institutions were identified. Predicted 7-year disease-free (DFS) and overall survival (OS) and 4-, 8-, and 12-year disease-specific survival (DSS) were calculated from the Sarculator and MSK nomograms, respectively. Nomogram-predicted survival probabilities were stratified in quintiles and compared in calibration plots to observed survival outcomes assessed by Kaplan-Meier estimates. Discriminative ability of nomograms was quantified by Harrell's concordance index (C-index). RESULTS: Five hundred and two patients underwent resection of primary RPS. Histologies included leiomyosarcoma (30%), dedifferentiated liposarcoma (23%), and well-differentiated liposarcoma (15%). Median tumor size was 14.0 cm (interquartile range [IQR], 8.5-21.0 cm). Tumor grade distribution was: Grade 1 (27%), Grade 2 (17%), and Grade 3 (56%). Median DFS was 31.5 months; 7-year DFS was 29%. Median OS was 93.8 months; 7-year OS was 51%. C-indices for 7-year DFS, and OS by the Sarculator nomogram were 0.65 (95% confidence interval [CI]: 0.62-0.69) and 0.69 (95%CI: 0.65-0.73); plots demonstrated good calibration for predicting 7-year outcomes. The C-index for 4-, 8-, and 12-year DSS by the MSK nomogram was 0.71 (95%CI: 0.67-0.75); plots demonstrated similarly good calibration ability. CONCLUSIONS: In a diverse, modern validation cohort of patients with resected primary RPS, both Sarculator and MSK nomograms demonstrated good prognostic ability, supporting their ongoing adoption into clinical practice.

Radiographic Surveillance of Patients with Non-BRCA1/2 Pathogenic Variants.

INTRODUCTION: The National Comprehensive Cancer Network (NCCN) developed clinical practice guidelines for germline pathogenic variants in highly penetrant genes, such as TP53 and PTEN, and in moderately penetrant genes, such as CHEK2, ATM and PALB2. Whether the practice of radiographic surveillance of patients with pathogenic variants in genes other than BRCA1/2 complies with current NCCN guidelines remains unclear. METHODS: Retrospective review of patients identified with pathogenic variants in genes other than BRCA1/2 from 2007 through 2017 to determine if radiographic surveillance was in accordance with NCCN guidelines for mammography and consideration of magnetic resonance imaging (MRI). Exclusions included variants of unknown significance, pathogenic variants not associated with an increased risk of breast cancer, and previous breast cancer diagnosis. RESULTS: After exclusions, 35 patients with pathogenic variants in ATM, CDH1, CHEK2, NBN, PALB2, PTEN, and STK11 genes were reviewed to assess whether radiographic surveillance was in accordance with NCCN guidelines. Guidelines for those with variants in ATM, CHEK2 and NBN includes annual mammography with tomosynthesis and consideration of breast MRI at age 40, variants in CDH1 and PALB2 at age 30, variants in PTEN at age 30-35 or 5-10 years before the earliest family breast cancer, and variants in STK11 at age 25. Of these 35 patients, 11 (31%) received mammography only; 11 (31%) received mammography and MRI, and 13 (37%) received no radiographic surveillance. Two of the 35 (6%) patients who received radiographic surveillance were diagnosed with ductal carcinoma in situ or invasive breast cancer. CONCLUSION: Thirty-one percent of patients with pathogenic variants in genes other than BRCA1/2 received both mammography and MRI. Thirty-seven percent of patients with these highly penetrant and moderately penetrant genes received no radiographic follow-up, clearly demonstrating an opportunity for improvement.

Effect of Surgical Approach on Node Harvest in Gastrectomy: Analysis of the National Cancer Database.

BACKGROUND: Gastrectomy is the cornerstone of treatment for gastric cancer. Recent studies demonstrated significant surgical outcome advantages for patients undergoing minimally invasive versus open gastrectomy. Lymph node harvest is an indicator of adequate surgical resection, and greater harvest is associated with improved staging and patient outcomes. This study evaluated lymph node harvest based on surgical approach. METHODS: Gastric adenocarcinoma patients were identified from NCDB who underwent gastrectomy between 2010 and 2016. Patients were classified by surgical approach into three cohorts: robotic, laparoscopic, or open gastrectomy. Clinical and demographic data were collected. Lymph node harvest was compared with univariate analysis and multivariable generalized linear mixed model. Univariate analysis with propensity matching was also performed to control for differences in patient population across cohorts. RESULTS: We identified 10,690 patients that underwent gastrectomy for gastric adenocarcinoma, with 68% males and median age of 66 (IQR 5774) years. 7161 (67%) underwent open, 2841 (26.6%) laparoscopic, and 688 (6.4%) robotic gastrectomy. Multivariable analysis revealed robotic was associated with a significantly higher median node harvest (18, IQR 1326) compared to laparoscopic (17, IQR 1125) and open gastrectomy (16, IQR 1023). Laparoscopic was also associated with significantly higher node harvest then open gastrectomy. Propensity-matched analysis (6950 patients) showed robotic gastrectomy was still associated with significantly higher node harvest (18, IQR 1226) compared to laparoscopic (17, IQR 1125) and open (17, IQR 1124); however, laparoscopic and open were not significantly different. CONCLUSION: Robotic approach is associated with increased node harvest compared to laparoscopic and open approach in gastrectomy patients.

Swallowing dysfunction after minimally invasive oesophagectomy.

OBJECTIVES: Patients undergoing oesophagectomy frequently experience malnutrition, which in combination with the catabolic effects of surgery can result in loss of muscle mass and function. Safe swallowing requires preservation of muscle mass. Swallowing dysfunction puts postoperative patients at risk for aspiration and pneumonia. Modified Barium Swallow Study (MBSS) enables assessment of postoperative swallowing impairments. The current study assessed incidence and risk factors associated with swallowing dysfunction and restricted diet at discharge in patients after oesophagectomy in a high-volume surgical centre. METHODS: Patients with an MBSS after oesophagectomy were identified between March 2015 to April 2020 at a high-volume surgical centre. Swallowing was quantitatively evaluated on MBSS with the Rosenbek Penetration-Aspiration Scale (PAS). Muscle loss was evaluated clinically with preoperative hand grip strength (HGS). Univariable and multivariable logistic and linear regression analyses were performed. RESULTS: 129 patients (87% male; median age 66 years) underwent oesophagectomy with postoperative MBSS. Univariate analysis revealed older age, preoperative feeding tube, lower preoperative HGS and discharge to non-home were associated with aspiration or penetration on MBSS. Age and preoperative feeding tube remained as independent predictors in the multivariable analysis. Both univariate and multivariable analyses revealed increased age and preoperative feeding tube were associated with diet restrictions at discharge. CONCLUSIONS: Swallowing dysfunction after oesophagectomy is correlated with increased age and need for preoperative enteral feeding tube placement. Further research is needed to understand the relationship between muscle loss and aspiration with the goal of enabling preoperative physiological optimisation and patient selection.

Preoperative Muscle Strength Is a Predictor of Outcomes After Esophagectomy.

BACKGROUND: Sarcopenia, loss of muscle mass and strength, has been associated with more frequent complications after esophagectomy. This study compared hand-grip strength, muscle mass, and intramuscular adipose tissue as predictors of postoperative outcomes and mortality after esophagectomy. METHODS: Minimally invasive esophagectomy was performed on 175 patients with esophageal cancer. Skeletal muscle index and skeletal muscle density were derived from preoperative CTs. Hand-grip strength was measured using dynamometer. Univariate and multivariable analyses were performed. RESULTS: Preoperative hand-grip strength was normal in 91 (52%), intermediate in 43 (25%), and weak in 41 (23%) patients. Hand-grip strength was significantly correlated with both skeletal muscle index and skeletal muscle density. Postoperative pneumonia occurred in 8/41 (20%) patients with weak strength compared to 4/91 (4%) with normal strength (p = 0.006; Cochran-Armitage Test). Prolonged postoperative ventilation occurred in 11/41 (27%) patients with weak strength compared to 11/91 (12%) with normal strength (p = 0.036). Median length of stay was 9 days in patients with weak strength compared to 7 days for those with normal strength (p = 0.005; Kruskal-Wallis Test). Discharge to non-home location occurred in 15/41 (37%) with weak strength compared to 8/91 (9%) with normal strength (p < 0.001). Postoperative mortality at 90 days was 4/41 (10%) with weak strength compared with no mortalities (0/91) in the normal strength group (p = 0.004). Mortality at 1 year was 18/39 (46%) in patients with weak strength compared to 6/81 (7%) with normal strength, among 158 patients with 1-year follow-up (p < 0.001). CONCLUSIONS: Preoperative hand-grip strength was found to be a powerful predictor of postoperative pneumonia, length of stay, discharge to non-home location, and mortality after esophagectomy.

Jejunostomy at the time of esophagectomy is associated with improved short-term perioperative outcomes: analysis of the NSQIP database.

Adequate preoperative and perioperative nutrition has been shown to improve outcomes for patients undergoing esophagectomy. The most effective way to provide enteral nutrition for patients after esophagectomy is via jejunostomy tube. There is an open debate whether a feeding jejunostomy tube is necessary at the time of esophagectomy. This study evaluated short term surgical outcomes for patients undergoing esophagectomy with and without concurrent jejunostomy tube placement. Esophageal cancer patients were identified from the NSQIP database who underwent esophagectomy between 2005 through 2016. Patients were classified into 2 cohorts: patients with concurrent jejunostomy tube placement and those without jejunostomy placement at the time of esophagectomy. Clinical and demographic data was collected. Differences in short term outcomes were assessed by univariate and multivariable analysis, including prolonged hospital stay (>30 days), in-hospital mortality, and 30-day mortality for both cohorts. We identified 8,632 patients that underwent esophagectomy for esophageal cancer with 80% males and mean age of 63.2±10.6 years. Twenty percent (n=1,723) had preoperative weight loss in the 6-month period preceding surgery. Forty-five percent (n=3,900) patients had jejunostomy placement at the time of esophagectomy. Overall, the rate of prolonged hospital stay (P=0.006), in-hospital mortality (P<0.001) and 30-day mortality (P<0.001) were significantly higher in patients without concurrent jejunostomy in both univariable and multivariable models. This study demonstrates that patients with jejunostomy placement at the time of esophagectomy have improved short term perioperative outcomes.

Effect of Surgical Approach on Node Harvest in Robotic Gastrectomy.

There has been increasing utilization of minimally invasive surgical approaches. This study evaluates the effect of surgical approach on total lymph node harvest in gastrectomy. Patients undergoing gastrectomy for gastric adenocarcinoma between 2007 and 2018 were reviewed retrospectively. Data collected included age, gender, race, BMI, neoadjuvant therapy, tumor stage, surgical approach, and total number of lymph nodes harvested. The total number of harvested lymph nodes for open, laparoscopic, and robotic gastrectomy was compared using the Kruskal-Wallis test for univariate analysis and a Poisson regression model for multivariable analysis. One hundred four patients were identified. Median node harvest for open, laparoscopic, and robotic approaches were 16, 17, and 36, respectively. Multivariable analysis controlling for gender, BMI, pathological T stage, and year of operation demonstrates that surgical approach is statistically significantly associated with lymph node harvest (F = 83.4, P < 0.0001). In multivariable analysis, robotic approach was associated with greater lymph node harvest than both open (P < 0.0001) and laparoscopic (P < 0.0001) approaches, whereas laparoscopic approach was associated with greater lymph node harvest than open (P < 0.0001) approach. These data demonstrate that for patients undergoing gastrectomy for gastric adenocarcinoma at our institution, robotic approach is associated with greater lymph node harvest than both laparoscopic and open approaches.

Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials.

PURPOSE: Malignant pleural mesothelioma (MPM) carries a poor prognosis due to chemoresistance. The European Organisation for Research and Treatment of Cancer (EORTC) prognostic model was reported to predict survival in MPM. Our retrospective analysis set out to test the validity of the model as a prognostic tool in patients treated in three phase II trials at St Bartholomew's Hospital (London, United Kingdom) between 1999 and 2003. PATIENTS AND METHODS: A total of 145 patients were treated in three phase II trials; vinorelbine (VIN; 70 patients), vinorelbine/oxaliplatin (VO; 26 patients), and irinotecan/cisplatin/mitomycin C (IPM; 49 patients). Two subgroups, high-risk and low-risk, were defined by EORTC prognostic score (EPS). EPS was determined by a five-parameter model incorporating age, sex, histology, probability of diagnosis, and leukocyte count. An EPS cutoff of less than 1.27 (low risk) or more than 1.27 (high risk) was used to stratify Kaplan-Meier survival curves. Each of the EPS variables exhibited either trends or significant stratification of overall survival (OS). RESULTS: Multivariate analysis confirmed leukocyte count, Eastern Cooperative Oncology Group performance status, and sarcomatous histology as independent prognostic variables. EPS stratified OS in both individual and pooled trial datasets. No association between objective tumor response and EPS classification was identified by multinomial logistic regression. EPS stratified progression-free survival for the VO and IPM cohorts, but not for VIN. CONCLUSION: This study validates the EPS system as a robust tool for stratifying small trials into low- and high-risk subgroups. EPS should facilitate patient selection and analysis in randomized clinical trials.

A randomised comparison of radical radiotherapy with or without chemotherapy for patients with non-small lung cancer: results from the Big Lung Trial.

BACKGROUND: A meta-analysis of trials comparing primary treatment with or without chemotherapy for patients with non-small cell lung cancer published in 1995 suggested a survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings studied, but it included many small trials, and trials with differing eligibility criteria and chemotherapy regimens. METHODS: The Big Lung Trial was a large pragmatic trial designed to confirm the survival benefits seen in the meta-analysis, and this paper reports the findings in the radical radiotherapy setting. The trial closed before the required sample size was achieved due to slow accrual, with a total of 288 patients randomised to receive radical radiotherapy alone (146 patients) or sequential radical radiotherapy and cisplatin-based chemotherapy (142 patients). RESULTS: There was no evidence that patients allocated sequential chemotherapy and radical radiotherapy had a better survival than those allocated radical radiotherapy alone, HR 1.07 (95% CI 0.84-1.38, P=0.57), median survival 13.0 months for the sequential group and 13.2 for the radical radiotherapy alone group. In addition, exploratory analyses could not identify any subgroup that might benefit more or less from chemotherapy. CONCLUSIONS: Despite not suggesting a survival benefit for the sequential addition of chemotherapy to radical radiotherapy, possibly because of the relatively small sample size and consequently wide confidence intervals, the results can still be regarded as consistent with the meta-analysis, and other similarly designed recently published large trials. Combining all these results suggests there may be a small median survival benefit with chemotherapy of between 2 and 8 weeks.

Randomized double-blind placebo-controlled trial of thalidomide in combination with gemcitabine and Carboplatin in advanced non-small-cell lung cancer.

PURPOSE: Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL). RESULTS: The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001). CONCLUSION: In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.

Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis.

PURPOSE: To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. RESULTS: TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). CONCLUSION: This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.