Host immunity may affect the outcome in patients with esophageal cancer. We sought to identify factors that influenced absolute lymphocyte count (ALC) nadir during chemoradiation therapy (CRT) for ...esophageal cancer (EC) and looked for clinically relevant associations with survival.
504 patients with stage I-III EC (2007-2013) treated with neoadjuvant or definitive CRT with weekly ALC determinations made during treatment were analyzed. Grade of lymphopenia from ALC nadir during CRT was based on Common Terminology Criteria for Adverse Events version 4.0. Associations of ALC nadir with survival were examined using multivariate Cox proportional hazards analysis (MVA) and competing risks regression analysis.
The median follow-up time was 36 months. The incidences of grade 1, 2, 3, and 4 ALC nadir during CRT were 2%, 12%, 59%, and 27%, respectively. The impact was lymphocyte-specific because this was not seen for monocyte or neutrophil count. On MVA, grade 4 ALC nadir (G4 nadir) was significantly associated with worse overall and disease-specific survival outcomes. Predictors of G4 nadir included distal tumor location, definitive CRT, taxane/5-fluorouracil chemotherapy, and photon-based radiation type (vs proton-based). Radiation type strongly influenced the mean body dose exposure, which was a strong predictor for G4 nadir (odds ratio 1.22 per Gray, P<.001).
G4 nadir during CRT for EC was associated with poor outcomes, suggesting a role of host immunity in disease control. This observation provides a rationale to prospectively test chemotherapeutic and radiation treatment strategies that may have a lower impact on host immunity.
The aim of this study was to provide an overview of the burden of esophageal cancer in 185 countries in 2020 and projections for the year 2040.
Estimates of esophageal cancer cases and deaths were ...extracted from the GLOBOCAN database for 2020. Age-standardized incidence and mortality rates were calculated overall, by sex, histologic subtype (adenocarcinoma AC and squamous cell carcinoma SCC), country, and level of human development for 185 countries. The predicted burden of incidence and mortality in 2040 was calculated based on global demographic projections.
Globally, there were an estimated 604,100 new cases of, and 544,100 deaths from, esophageal cancer in 2020, corresponding to age-standardized incidence and mortality rates of 6.3 and 5.6 per 100,000, respectively. Most cases were SCCs (85% 512,500 cases) and 14% (85,700 cases) were ACs. Incidence and mortality rates were 2- to 3-fold higher in male (9.3 and 8.2, respectively) compared with female (3.6 and 3.2, respectively) individuals. Global variations in incidence and mortality were observed across countries and world regions; the highest rates occurred in Eastern Asia and Southern and Eastern Africa and the lowest occurred in Western Africa and Central America regions. If rates remain stable, 957,000 new cases (141,300 AC cases and 806,000 SCC cases) and 880,000 deaths from esophageal cancer are expected in 2040.
These updated estimates of the global burden of esophageal cancer represent an important baseline for setting priorities in policy making and developing and accelerating cancer control initiatives to reduce the current and projected burden. Although primary prevention remains key, screening and early detection represent important components of esophageal cancer control in high-risk populations.
The global variation of new cases and deaths from esophageal cancer in 2020 was studied. The study highlights major increases expected in the future, emphasizing the importance of preventing this cancer.
In the human papillomavirus (HPV) era, the best way to assess oropharyngeal squamous carcinomas (SCC) for risk stratification is not clear. Many recommend use of both p16 immunohistochemistry and HPV ...in situ hybridization (ISH). A significant minority of tumors are p16 positive and HPV ISH negative, the significance of which is unclear.
Two hundred thirty-nine oropharyngeal SCC were tested by immunohistochemistry for p16 and by ISH for high-risk HPV. For p16 positive, HPV ISH negative cases, PCR was conducted for HPV. The findings were correlated with pathologic and clinical findings.
Of the 239 cases, 187 (78%) were positive for p16. Of these, 139 (74%) were positive for HPV by ISH. Of the remaining 48 cases, 45 had material for PCR. Nineteen were positive for HPV, leaving a group of 26 p16 positive and HPV undetectable SCCs. In the p16 positive cohort, there was no difference in survival between HPV ISH positive and negative cases. Comparing the HPV ISH positive and HPV ISH and PCR negative SCC, there was again no difference in survival. p16 positive, HPV negative SCC still had significantly better survival than p16 negative SCC in univariate and multivariate analysis.
Outcomes for p16 positive, HPV negative oropharyngeal SCC are not significantly different from p16 positive, HPV positive tumors and are significantly better than for p16 negative tumors. These results suggest that p16 immunohistochemistry alone is the best test to use for risk stratification in oropharyngeal SCC.
Summary Background With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has ...been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. Methods In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390. Findings Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16·0 months (95% CI 13·9–18·1) with erlotinib plus bevacizumab and 9·7 months (5·7–11·1) with erlotinib alone (hazard ratio 0·54, 95% CI 0·36–0·79; log-rank test p=0·0015). The most common grade 3 or worse adverse events were rash (19 25% patients in the erlotinib plus bevacizumab group vs 15 19% patients in the erlotinib alone group), hypertension (45 60% vs eight 10%), and proteinuria (six 8% vs none). Serious adverse events occurred at a similar frequency in both groups (18 24% patients in the erlotinib plus bevacizumab group and 19 25% patients in the erlotinib alone group). Interpretation Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted. Funding Chugai Pharmaceutical Co Ltd.
To examine the prognostic impact of the programmed death ligand 1 (PD-L1) expression, tumor-infiltrating lymphocyte (TIL) status, and their combination in esophageal cancer.
PD-L1 has garnered much ...attention for its roles in tumor immunology and as an immune-based therapeutic target. To ensure a response to PD-L1 checkpoint inhibitor, a new framework based on PD-L1 expression and the presence or absence of TILs is required.
Using a nonbiased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (cluster of differentiation 8 (CD8) expression) by immunohistochemical analysis. The Cox proportional hazard model was used to compute the hazard ratio (HR) for mortality.
Compared with PD-L1 negative cases (n=252), PD-L1 positive cases (n = 53) showed significantly worse overall survival log-rank P = 0.016; HR: 1.71; 95% confidence interval: 1.08-2.61; P = 0.024; multivariate HR: 1.69; 95% confidence interval: 1.05-2.67; P = 0.033. TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001) and high CD8 expression (P < 0.0001). A stratification based on PD-L1 expression and TIL status was also significantly associated with overall survival (log rank P < 0.0001).
PD-L1 expression was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. In addition, the combination with TIL status enabled further classification patients according to clinical outcome. PD-L1 expression and TIL status may serve as predictive tissue biomarkers and can be used for patient selection in clinical trials of drugs targeting the PD-1/PD-L1 pathways.
Summary Background Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain ...survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. Methods We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov , numbers NCT02048020 and NCT01716195. Findings Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54–67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26–37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77–97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 39%) and neutropenia (five 11%), and during chemoradiotherapy were dysphagia (four 9%) and mucositis (four 9%). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. Interpretation Chemoradiotherapy with radiation doses reduced by 15–20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. Funding University of California.
Human papillomavirus (HPV)-positive (HPV
) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent ...(8th) edition of the UICC/AJCC staging system separates HPV
OPSCC from its HPV-negative (HPV
) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV
OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV
OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes.
The aim of the study was to determine the optimal extent of lymph node dissection for the 2 histological types of esophagogastric junction (EGJ) tumors based on the incidence of metastasis in a ...prospective nationwide multicenter study.
Because most previous studies were retrospective, the optimal surgical procedure for EGJ tumors has not been standardized.
Patients with cT2-T4 adenocarcinoma or squamous cell carcinoma located within 2.0 cm of the EGJ were enrolled before surgery. Surgeons dissected all lymph nodes prespecified in the protocol, using either the abdominal transhiatal or right transthoracic approach. The primary endpoint was the metastasis rate of each lymph node. Lymph nodes were classified according to metastasis rate, as follows: category-1 (strongly recommended for dissection), rate more than 10%; category-2 (weakly recommended for dissection), rate from 5% to 10%; and category-3 (not recommended for dissection), rate less than 5%.
Between 2014 and 2017, 1065 patients with EGJ tumor were screened, and 371 were enrolled. Among 358 patients who underwent surgical resection, category-1 nodes included abdominal stations 1, 2, 3, 7, 9, and 11p, whereas category-2 nodes included abdominal stations 8a, 19, and lower mediastinal station 110. If esophageal involvement exceeded 2.0 cm, station 110 was assigned to category-1. Among 98 patients who had either adenocarcinoma with esophageal involvement over 3.0 cm or squamous cell carcinoma, there were no category-1 nodes in the upper/middle mediastinal field, whereas category-2 nodes included upper mediastinal station 106recR and middle mediastinal station 108. When esophageal involvement exceeded 4.0 cm, station 106recR was assigned to category-1.
The study accurately identified the distribution of lymph node metastases from EGJ tumors and the optimal extent of subsequent lymph node dissection.
Substantial heterogeneity exists within cervical cancer that is generally infected by human papillomavirus (HPV). However, the most common histological subtype of cervical cancer, cervical squamous ...cell carcinoma (CSCC), is poorly characterized regarding the association between its heterogeneity and HPV oncoprotein expression. We filtered out 138 CSCC samples with infection of HPV16 only as the first step; then we compressed HPV16 E6/E7 expression as HPVpca and correlated HPVpca with the immunological profiling of CSCC based on supervised clustering to discover subtypes and to characterize the differences between subgroups in terms of the HPVpca level, pathway activity, epigenetic dysregulation, somatic mutation frequencies, and likelihood of responding to chemo/immunotherapies. Supervised clustering of immune signatures revealed two HPV16 subtypes (namely, HPV16-IMM and HPV16-KRT) that correlated with HPVpca and clinical outcomes. HPV16-KRT is characterized by elevated expression of genes in keratinization, biological oxidation, and Wnt signaling, whereas HPV16-IMM has a strong immune response and mesenchymal features. HPV16-IMM exhibited much more epigenetic silencing and significant mutation at FBXW7, while MUC4 and PIK3CA were mutated frequently for HPV16-KRT. We also imputed that HPV16-IMM is much more sensitive to chemo/immunotherapy than is HPV16-KRT. Our characterization tightly links the expression of HPV16 E6/E7 with biological and clinical outcomes of CSCC, providing valuable molecular-level information that points to decoding heterogeneity. Together, these results shed light on stratifications of CSCC infected by HPV16 and shall help to guide personalized management and treatment of patients.
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