Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial.

BACKGROUND: First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data. METHODS: This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population. RESULTS: A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. CONCLUSIONS: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC.

Three-Year Follow-Up and Response-Survival Relationship of Nivolumab in Previously Treated Patients with Advanced Esophageal Squamous Cell Carcinoma (ATTRACTION-3).

PURPOSE: Limited long-term data are available on immune checkpoint inhibitor use in patients with advanced esophageal squamous cell carcinoma (ESCC). We report 3-year follow-up data from our study of nivolumab versus chemotherapy (paclitaxel or docetaxel) in patients with previously treated ESCC. PATIENTS AND METHODS: ATTRACTION-3 was a randomized, multicenter, open-label, phase III trial. Overall survival (OS), time from randomization to death from any cause, was the primary endpoint. An exploratory subanalysis assessed OS according to the best overall response (BOR) with and without landmark at 4 months. RESULTS: Of the enrolled patients, 210 received nivolumab and 209 received chemotherapy. With a minimum follow-up of 36.0 months, OS was longer in the nivolumab versus the chemotherapy group (median, 10.9 vs. 8.5 months; HR, 0.79; P = 0.0264), with 3-year OS rates of 15.3% and 8.7%, respectively. The median OS was longer with nivolumab versus chemotherapy irrespective of the BOR (complete response/partial response: 19.9 vs. 15.4 months; stable disease: 17.4 vs. 8.8 months; and progressive disease: 7.6 vs. 4.2 months). Grade 3 or higher treatment-related adverse events were reported in 40 patients (19.1%) in the nivolumab group and 133 patients (63.9%) in the chemotherapy group. CONCLUSIONS: Nivolumab as second-line therapy demonstrated clinically meaningful long-term improvement in OS compared with chemotherapy in previously treated patients with advanced ESCC. The OS was consistently improved in the nivolumab group compared with the chemotherapy group regardless of BOR. Nivolumab was well tolerated over the 3-year follow-up. See related commentary by Yoon et al., p. 3173.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.

BACKGROUND: First-line chemotherapy for advanced esophageal squamous-cell carcinoma results in poor outcomes. The monoclonal antibody nivolumab has shown an overall survival benefit over chemotherapy in previously treated patients with advanced esophageal squamous-cell carcinoma. METHODS: In this open-label, phase 3 trial, we randomly assigned adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients). RESULTS: A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone. CONCLUSIONS: Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 648 ClinicalTrials.gov number, NCT03143153.).

Definitive chemoradiotherapy plus cetuximab for cancer in the oesophagus or gastro-oesophageal junction.

BACKGROUND: Chemoradiotherapy is standard treatment for localized oesophageal cancer unsuitable for surgery. We aimed to evaluate the efficacy of cetuximab in combination with chemoradiotherapy. METHODS: This non-randomised multicentre phase II trial recruited patients aged 18-75 with WHO performance status 0-2 having squamous cell carcinoma or adenocarcinoma in the oesophagus or gastro-oesophageal junction, T2-4, N0-3, M0 not suitable for surgery. Chemotherapy was three 21-day cycles of fluorouracil 750 mg/m2 D1-5 and oxaliplatin D1 (cycle 1:130mg/m 2, cycle 2-3:85 mg/m 2). Radiotherapy was 50Gy in 2Gy/fraction, 5 days a week, concurrent with cycle 2 and 3 and weekly cetuximab. The primary objective was loco-regional control at one year. RESULTS: 52 patients were included. 51 were eligible for toxicity and survival analysis and 46 for recurrence analysis. Full radiotherapy dose was delivered to 80%, 75% received all three cycles of chemotherapy and 75% received four or more doses of cetuximab. The most common related grade III-IV adverse events were gastro-intestinal(16), hypersensitivity(6) and infection(5). There were two drug-related deaths. Within six months from the end of treatment, six patients died from complications from fistulas. The loco-regional control rate at one year was 47.3%(95%CI 30.9%-62.1%). Overall survival at three years was 29.1%(95% CI 17.4-41.9%). CONCLUSIONS: Oxaliplatin and fluorouracil given concurrent with radiotherapy and cetuximab had an acceptable safety profile and showed a clinical response in patients with locoregionally advanced oesophageal cancer unsuitable for surgery. However, the primary end-point was not met, and the addition of cetuximab to definitive chemoradiotherapy cannot be recommended.

Delineation of whole heart and substructures in thoracic radiation therapy: National guidelines and contouring atlas by the Danish Multidisciplinary Cancer Groups.

BACKGROUND AND PURPOSE: This study presents Danish consensus guidelines for delineation of the heart and cardiac substructures across relevant Danish Multidisciplinary Cancer Groups. MATERIAL AND METHODS: Consensus guidelines for the heart and cardiac substructures were reached among 15 observers representing the radiotherapy (RT) committees of four Danish Multidisciplinary Cancer Groups. The guidelines were validated on CT scans of 12 patients, each with five independent contour sets. The Sørensen-Dice similarity coefficient (DSC), the distance between the centers of the arteries and the mean surface distance were used to evaluate the inter-observer variation. RESULTS: National guidelines for contouring the heart and cardiac substructures were achieved. The median DSC was 0.78-0.96 for the heart and the four cardiac chambers. For the four substructures of the left ventricle, the median DSC was 0.35-0.57. The coronary arteries were contoured in ten segments, with the best agreement for the left anterior descending coronary artery segments, with a median distance between the arteries ranging from 2.4-4.4 mm. The median variation was 3.7-12.8 mm for the right coronary artery segments and 3.7-6.2 mm for the left circumflex coronary artery segments, with the most pronounced inter-observer variation in the distal segment for all three coronary arteries. CONCLUSION: National guidelines for contouring the heart and cardiac substructures were developed across relevant Danish Multidisciplinary Cancer Groups, where RT dose to the heart is of concern. The inter-observer contour overlap was best for the heart and chambers and decreased for smaller structures.

Percutaneous vertebroplasty as treatment of malignant vertebral lesions: a systematic review and GRADE evaluation resulting in a Danish national clinical guideline.

PURPOSE: To summarize the recommendations from the national clinical guideline published by the Danish Health Authority, regarding cemental augmentation as treatment for painful vertebral lesions, in patients with malignant disease. METHODS: A multidisciplinary working group formulated recommendations based on the GRADE approach. RESULTS: Two of the questions were based on randomized studies and one on professional consensus. The guideline recommends cemental augmentation for painful vertebral lesions in patients with malignant diagnosis, either hematological or non-hematological. Fracture of the posterior wall is not a contradiction to cemental augmentation, but care should always be taken while injecting the cement, to decrease the risk of cemental leaks into the spinal canal. CONCLUSION: The recommendations are based on low-to-moderate quality of evidence or professional consensus as well as patient preferences and positive and harmful effects of the intervention. The working group recommends more randomized studies on patients with different malignant diseases and painful vertebral lesions comparing percutaneous vertebroplasty/kyphoplasty and conservative treatment to confirm the conclusion in this guideline. These slides can be retrieved under Electronic Supplementary Material.

Percutaneous vertebroplasty as treatment of malignant vertebral lesions: a systematic review and GRADE evaluation resulting in a Danish national clinical guideline

To summarize the recommendations from the national clinical guideline published by the Danish Health Authority, regarding cemental augmentation as treatment for painful vertebral lesions, in patients with malignant disease. A multidisciplinary working group formulated recommendations based on the GRADE approach. Two of the questions were based on randomized studies and one on professional consensus. The guideline recommends cemental augmentation for painful vertebral lesions in patients with malignant diagnosis, either hematological or non-hematological. Fracture of the posterior wall is not a contradiction to cemental augmentation, but care should always be taken while injecting the cement, to decrease the risk of cemental leaks into the spinal canal. The recommendations are based on low-to-moderate quality of evidence or professional consensus as well as patient preferences and positive and harmful effects of the intervention. The working group recommends more randomized studies on patients with different malignant diseases and painful vertebral lesions comparing percutaneous vertebroplasty/kyphoplasty and conservative treatment to confirm the conclusion in this guideline. These slides can be retrieved under Electronic Supplementary Material.

Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma. METHODS: We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing. FINDINGS: Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5-19·0) in the nivolumab group and 8·0 months (4·6-15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2-13·3 vs 8·4 months, 7·2-9·9; hazard ratio for death 0·77, 95% CI 0·62-0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease). INTERPRETATION: Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients. FUNDING: ONO Pharmaceutical Company and Bristol-Myers Squibb.

Automatic treatment planning facilitates fast generation of high-quality treatment plans for esophageal cancer.

BACKGROUND: The quality of radiotherapy planning has improved substantially in the last decade with the introduction of intensity modulated radiotherapy. The purpose of this study was to analyze the plan quality and efficacy of automatically (AU) generated VMAT plans for inoperable esophageal cancer patients. MATERIAL AND METHODS: Thirty-two consecutive inoperable patients with esophageal cancer originally treated with manually (MA) generated volumetric modulated arc therapy (VMAT) plans were retrospectively replanned using an auto-planning engine. All plans were optimized with one full 6MV VMAT arc giving 60 Gy to the primary target and 50 Gy to the elective target. The planning techniques were blinded before clinical evaluation by three specialized oncologists. To supplement the clinical evaluation, the optimization time for the AU plan was recorded along with DVH parameters for all plans. RESULTS: Upon clinical evaluation, the AU plan was preferred for 31/32 patients, and for one patient, there was no difference in the plans. In terms of DVH parameters, similar target coverage was obtained between the two planning methods. The mean dose for the spinal cord increased by 1.8 Gy using AU (p = .002), whereas the mean lung dose decreased by 1.9 Gy (p < .001). The AU plans were more modulated as seen by the increase of 12% in mean MUs (p = .001). The median optimization time for AU plans was 117 min. CONCLUSIONS: The AU plans were in general preferred and showed a lower mean dose to the lungs. The automation of the planning process generated esophageal cancer treatment plans quickly and with high quality.

Hypoxia-regulated MicroRNAs in Gastroesophageal Cancer.

BACKGROUND/AIM: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC). MATERIALS AND METHODS: microRNA expression changes induced by hypoxia in human GEC cell lines were measured with microarrays and validated by quantitative real-time polymerase chain reaction. Candidate HRMs were measured in pre-therapeutic tumor samples from 195 patients with GEC. RESULTS: Expression of miR-210 was shown to be significantly induced in esophageal squamous cell carcinoma (9.26-fold, p<0.001) and adenocarcinoma cell lines (4.95-fold, p<0.001) and miR-27a-star was significantly up-regulated in adenocarcinoma cell lines (4.79-fold, p=0.04). A weak but significant correlation between miR-210 expression and a 15-gene hypoxia signature was observed (Pearson r correlation: r=0.38, p<0.001). No significant associations of HRMs and clinical outcome in patients with GEC were identified. CONCLUSION: This study supports the involvement of hypoxia on miRNAs in vitro and confirms the role of miR-210 as being a universal HRM.

Trends in upper gastro-intestinal cancer among the elderly in Denmark, 1980-2012.

BACKGROUND: Upper gastro-intestinal cancer (UGIC) includes malignancies in esophagus, stomach and small intestine, and represents some of the most frequent malignancies worldwide. The aim of the present analysis was to describe incidence, mortality and survival in UGIC patients in Denmark from 1980 to 2012 according to differences in age and time periods. MATERIAL AND METHODS: UGIC was defined as ICD-10 codes C15-C17. Data derived from the NORDCAN database with comparable data on cancer incidence mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: The proportion of male patients over the age of 70 years diagnosed with esophageal cancer was constant over time (around 42%) but increased in females to 49% in 2012. Incidence rates increased with time and continued to rise in all ages. Mortality rates were clearly separated by age groups with increasing mortality rates by increasing age group for both sexes. Relative survival increased slowly over time in all age groups. The proportion of older male and female patients with stomach cancer increased to 50% and 54%, respectively, in 2012. Incidence rates decreased steadily with time, especially from 1980 to 1990 but continued to decrease in all age groups. Mortality rates decreased considerably from 1980 to 90 and have been almost constant during the last decade for both women and men. Relative survival increased modest over time in both genders and all age groups. In 2012, only 1471 persons were alive after a diagnosis of stomach cancer. CONCLUSION: There is a need for clinical trials focusing on patients over the age of 70 years with co-existing comorbidity.

Trends in lung cancer in elderly in Denmark, 1980-2012.

BACKGROUND: Lung cancer is an increasing problem in the older patient population due to the improvement in life expectation of the Western population. In this study we examine trends in lung cancer incidence and mortality in Denmark from 1980 to 2012 with special focus on the elderly. MATERIAL AND METHODS: Lung cancer was defined as ICD-10 codes C33-34. Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence, and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: In 2012, about 50% of lung cancers were diagnosed among persons aged 70 years or more. For men and women older than 75 years the incidence rates have been increasing and for those aged 80-84 years, the rates have doubled since 1980. Due to the poor survival, similar trends were seen in mortality rates. Over the period, the one-year relative survival rates almost doubled in patients aged 70 years or more, but still only 25% of the patients aged 80-89 years survived their lung cancer for one year. CONCLUSION: The incidence of lung cancer is closely linked to the pattern of tobacco smoking with the differences between gender and age groups reflecting smoking behavior in birth cohorts. Elderly patients with lung cancer are a heterogeneous group in whom treatment should be offered according to comorbidity and a geriatric assessment.

Evaluation of miR-21 and miR-375 as prognostic biomarkers in esophageal cancer.

BACKGROUND: MicroRNAs (miRNAs) have been associated with prognosis in esophageal cancer, suggesting a role for miRNAs to help guide treatment decisions. Especially, miR-21 and miR-375 have been investigated as prognostic biomarkers. The aim of this study was to evaluate the prognostic potential of miR-21 and miR-375 in primary esophageal squamous cell carcinomas (ESCC) and esophagogastric adenocarcinomas (EAC). MATERIAL AND METHODS: Pre-therapeutic tumor specimens from 195 patients with loco-regional esophageal cancer treated with neoadjuvant or definitive chemoradiotherapy or perioperative chemotherapy were analyzed. Expression levels of miR-21 and miR-375 were quantified using Affymetrix GeneChip miRNA 1.0 Array. The Cox proportional hazards model was used to assess the correlation of miR-21 and miR-375 with disease-specific survival (DSS) and overall survival (OS). Forest plots were performed to evaluate the prognostic impact of miR-21 and miR-375 in the present study and previously published reports. RESULTS: In ESCC, patients with miR-21 expression levels above median showed a trend towards poorer DSS and OS. When dividing miR-21 expression by tertiles, high levels of miR-21 significantly correlated with shortened DSS [HR 1.76 (95% CI 1.05-2.97) but not OS. Similarly for EAC, a significant association between miR-21 expression above median and DSS was observed [HR 3.37 (95% CI 1.41-8.05)], in addition to a trend towards poorer OS for patients with miR-21 expression above median. Multivariate analyses identified miR-21 as an independent prognostic marker for DSS in EAC [HR 3.52 (95% CI 1.06-11.69)]. High miR-375 was not correlated with improved prognosis in either histology. However, Forest plots demonstrated that both miR-21 and miR-375 were of prognostic impact in ESCC. CONCLUSION: In this study, miR-21 was identified as an independent prognostic biomarker for DSS in patients with EAC whereas miR-21 failed to show independent prognostic significance in ESCC. High miR-375 was not associated with enhanced survival in either histology.