PURPOSE: Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS: From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS: The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent ( P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION: The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.

The incidence of venous thromboembolism (VTE) in cancer patients may have changed in the past decade, possibly due to novel cancer therapies, improved survival, and high-resolution imaging. Danish medical registries were used to identify 499 092 patients with a first-time cancer diagnosis between 1997 and 2017, who were matched to 1 497 276 comparison individuals without cancer from the general population. We computed cumulative incidences of VTE 6 and 12 months after the diagnosis/index date. Hazard ratios (HRs) were calculated using Cox regression. Risk factors were examined by computing subdistribution hazard ratios (SHRs) in a competing-risk analysis. Cumulative incidence of VTE 12 months after the cancer diagnosis/index date was 2.3% (95% confidence interval [CI], 2.2% to 2.3%) in the cancer cohort and 0.35% (95% CI, 0.34% to 0.36%) in the comparison cohort (HR, 8.5; 95% CI, 8.2-8.8). Important risk factors for cancer patients were prior VTE (SHR, 7.6; 95% CI, 7.2-8.0), distant metastasis (SHR, 3.2; 95% CI, 2.9-3.4), and use of chemotherapy (SHR, 3.4; 95% CI, 3.1-3.7), protein kinase inhibitors (SHR, 4.1; 95% CI, 3.4-4.9), antiangiogenic therapy (SHR, 4.4; 95% CI, 3.8-5.2), and immunotherapy (SHR, 3.6; 2.8-4.6). Twelve-month incidence in the cancer cohort increased from 1.0% (95% CI, 0.9% to 1.2%) in 1997 to 3.4% (95% CI, 2.9% to 4.0%) in 2017, which was paralleled by improved 12-month survival and increased use of computed tomography scans, chemotherapy, and targeted therapies. In conclusion, the risk of VTE in cancer patients is increasing steadily and is ninefold higher than in the general population.

Purpose: The CROSS trial established neoadjuvant chemoradiotherapy (nCRT) for patients with resectable esophageal adenocarcinoma (rEAC). In the PERFECT trial, we investigated the feasibility and efficacy of nCRT combined with programmed-death ligand-1 (PD-L1) inhibition for rEAC. Patients and Methods: Patients with rEAC received nCRT according to the CROSS regimen combined with five cycles of atezolizumab (1,200 mg). The primary endpoint was the feasibility of administering five cycles of atezolizumab in ≥75% patients. A propensity score–matched nCRT cohort was used to compare pathologic response, overall survival, and progression-free survival. Exploratory biomarker analysis was performed on repeated tumor biopsies. Results: We enrolled 40 patients of whom 85% received all cycles of atezolizumab. Immune-related adverse events of any grade were observed in 6 patients. In total, 83% proceeded to surgery. Reasons for not undergoing surgery were progression (n = 4), patient choice (n = 2), and death (n = 1). The pathologic complete response rate was 25% (10/40). No statistically significant difference in response or survival was found between the PERFECT and the nCRT cohort. Baseline expression of an established IFNγ signature was higher in responders compared with nonresponders (P = 0.043). On-treatment nonresponders showed either a high number of cytotoxic lymphocytes (CTL) with a transcriptional signature consistent with expression of immune checkpoints, or a low number of CTLs. Conclusions: Combining nCRT with atezolizumab is feasible in patients with rEAC. On the basis of our exploratory biomarker study, future studies are necessary to elucidate the potential of neoadjuvant immunotherapy in patient subgroups. See related commentary by Catenacci, p. 3269

PURPOSE: To analyze the effect of radiation dose escalation to the primary tumor on local tumor control in definitive chemoradiation (dCRT) for patients with esophageal cancer. PATIENTS AND METHODS: Patients with medically inoperable and/or irresectable esophageal carcinoma, referred for dCRT, were randomly assigned between a standard dose (SD) of 50.4 Gy/1.8 Gy for 5.5 weeks to the tumor and regional lymph nodes and a high dose (HD) up to a total dose of 61.6 Gy to the primary tumor. Chemotherapy consisted of courses of concurrent carboplatin (area under the curve 2) and paclitaxel (50 mg/m²) in both arms once a week for 6 weeks. The primary end point was local progression-free survival. RESULTS: Between September 2012 and June 2018, 260 patients were included. Squamous cell carcinoma (SCC) was present in 61% of patients, and 39% had adenocarcinoma (AC). Radiation treatment was completed by 94%, and 85% had at least five courses of chemotherapy. The median follow-up time for all patients was 50 months. The 3-year local progression-free survival (LPFS) was 70% in the SD arm versus 73% in the HD arm (not significant). The LPFS for SCC and AC was 75% versus 79% and 61% versus 61% for SD and HD, respectively (not significant). The 3-year locoregional progression-free survival was 52% and 59% for the SD and HD arms, respectively ( P = .08). Overall, grade 4 and 5 common toxicity criteria were 12% and 5% in the SD arm versus 14% and 10% in the HD arm, respectively ( P = .15). CONCLUSION: In dCRT for esophageal cancer, radiation dose escalation up to 61.6 Gy to the primary tumor did not result in a significant increase in local control over 50.4 Gy. The absence of a dose effect was observed in both AC and SCC.

Epidemiologic data indicate a significant increase in the incidence of colorectal cancer in younger populations in the past three decades. Moreover, recent evidence also demonstrates a similar trend in gastric, pancreatic, and biliary tract cancers. A majority of these early-onset cases are sporadic and lack hereditary or familial background, implying a potential key role for behavioral, lifestyle, nutritional, microbial, and environmental factors. This review explores the current data on early-onset gastrointestinal cancer, exploring the etiology, unique treatment considerations for this population, future challenges, as well as implications for research and practice. Significance: The worrisome trend of an increasing incidence of early-onset gastrointestinal cancers appears to be correlated with nonhereditary etiologies in which behavioral, lifestyle, nutritional, microbial, and environmental factors, as well as host mechanisms, may play a key role. Further epidemiologic and pathogenetic research is urgently needed to better understand the underlying mechanisms and to develop preventive strategies and tailored early detection. Young patients with gastrointestinal cancer face unique challenges and unmet needs. These must be addressed in the future management of the disease to minimize treatment-related somatic morbidity and prevent psychosocial sequelae.

Weight gain during chemotherapy in women with breast cancer is commonly reported. However, there are important differences between studies that examined weight change during chemotherapy; e.g. type of chemotherapy, menopausal status, time between body weight measurements and sample size. The purpose of this meta-analysis was to quantify changes in body weight during chemotherapy for women with breast cancer, taking these differences into account. We identified relevant studies using PubMed, Scopus and Embase databases. The search was limited to human studies published in English up to and including December 2015. Only studies among women with early stage breast cancer treated with chemotherapy, with reported body weight before and after chemotherapy and type of chemotherapy were included. Random-effect models were used, and heterogeneity between studies was explored through stratified analyses and meta-regression. Sensitivity analyses were done to explore whether a specific study markedly affected the results. In total 25 papers were found, including data from 2620 women. Overall, body weight increased during chemotherapy: 2.7 kg (95% CI 2.0, 7.5) with a high degree of heterogeneity (I2 = 94.2%). Stratified analyses showed weight gain in all strata, but did not substantially reduce heterogeneity. Univariate meta-regression showed less weight gain in prospective studies compared to chart review studies (−2.0, 95% CI: -3.1, −0.8). Studies including cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimes showed a greater weight gain compared to those that did not (2.2, 95% CI: 1.1, 3.3); and papers published until the year 2000 showed a greater weight gain compared to those published after 2000 (1.9, 95% CI:-0.8, 3.1). In the multivariate models only studies including CMF regimes and studies published until 2000 were associated with significant weight gain of respectively 1.3 and 1.4 kg. Despite the high heterogeneity, this meta-analysis shows significant weight gain during chemotherapy for women with breast cancer. Weight gain was more pronounced in papers published until 2000 and women receiving CMF as chemotherapy regime. Although weight gain after chemotherapy has decreased over the course of time, weight gain is still substantial and deserves clinical attention.