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Background Tumor-infiltrating immune cells are present in various malignant tumors, but their clinical significance in gastric cancer (GC) remains unclear. This study aimed to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). Methods Using a prospective database containing 401 cases of GC, we evaluated TIL (cluster of differentiation 8 (CD8) expression) and TAM (cluster of differentiation 68 (CD68) expression) statuses via immunohistochemical staining. Results Compared with CD8+ TIL-negative cases ( n  = 196, 48.6%), CD8+ TIL-positive cases ( n  = 205, 51.1%) showed significantly better recurrence-free survival (RFS) [log-rank p <0.001; multivariate HR: 0.372; 95% confidence interval (CI): 0.239–0.579, p <0.001]. In contrast, compared with CD68+ TAM-negative cases ( n  = 217, 54.1%), CD68+ TAM-positive cases ( n  = 184, 45.9%) had significantly poor RFS [log-rank p <0.001; multivariate HR: 2.182; 95% CI: 1.435–3.318, p <0.001]. Thus, patients with a positive CD8+ TIL and negative CD68+ TAM status exhibited significantly increased RFS. Multivariate analysis demonstrated that CD8+ TILs and CD68+ TAMs may serve as independent prognostic markers for RFS. Incorporating CD8+ TIL and CD68+ TAM statuses into the AJCC TNM system generated a predictive model with better predictive accuracy for RFS. More importantly, patients with a positive TIL and negative TAM status showed a tendency of improved RFS after postoperative adjuvant chemotherapy (PAC). Similar results were obtained by overall survival (OS) analysis. Conclusions CD8+ TIL and CD68+ TAM statuses were identified as independent prognostic factors that may be integrated into the current TNM staging system to refine risk stratification and to better predict the survival benefit from PAC in patients with GC. Trial registration The current controlled trial was registered at ClinicalTrials.gov (ID: NCT02327481 ) on December 30, 2014.

Background The utility of the immune prognostic index (IPI) for esophageal squamous cell carcinoma (ESCC) has yet to be established after minimally invasive esophagectomy (MIE). The purpose of this study was to investigate the value of IPI in predicting the prognosis and postoperative adjuvant chemotherapy (AC) benefits of ESCC patients. Methods Between January 2011 and December 2018, 613 ESCC patients underwent MIE at our center and were divided into two groups: low IPI and high IPI . Log-rank tests were used to compare the overall survival (OS) and disease-free survival (DFS) of patients in different groups based on Kaplan–Meier survival analysis. Differences in clinical characteristics between groups were eliminated by propensity score matching (PSM) analysis. To identify independent risk factors influencing OS and DFS, the Cox proportional risk model was used. Results In comparison to the high IPI group, the low IPI group had a better 5-year OS and DFS in both the entire and matched cohorts ( P  < 0.05). IPI was found to be an independent prognostic factor for OS and DFS in a multivariate analysis of the entire cohort and the matched cohort ( P  < 0.05). In subgroup analyses of most clinicopathological factors, high IPI was associated with a higher risk of death or recurrence in the matched cohorts. When combined with 8th TNM staging, the 5-year OS and DFS of stage II or III patients with low IPI in the AC group were not different from those in the non-AC group ( P  > 0.05), and AC of stage III patients with high IPI significantly prolonged 5-year OS and DFS (OS: 37.4% vs 26.2%, P  = 0.018; DFS: 33.6% vs 19.8%, P  = 0.042). Conclusion Preoperative IPI is a promising predictor of ESCC after MIE. For stage III ESCC patients with high IPI, AC can significantly reduce the risk of death or recurrence.

Background Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. Methods/design MEDOCC-CrEATE follows the ‘trial within cohorts’ (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. Discussion The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. Trial registration Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281

Background At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. Methods In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3–4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. Discussion The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. Trial registration clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

Gene expression profiling (GEP) testing using 12-gene recurrence score (RS) assay (EndoPredict®), 58-gene RS assay (Prosigna®), and 21-gene RS assay (Oncotype DX®) is available to aid in chemotherapy decision-making when traditional clinicopathological predictors are insufficient to accurately determine recurrence risk in women with axillary lymph node-negative, hormone receptor-positive, and human epidermal growth factor-receptor 2-negative early-stage breast cancer. We examined the cost-effectiveness of incorporating these assays into standard practice. A decision model was built to project lifetime clinical and economic consequences of different adjuvant treatment-guiding strategies. The model was parameterized using follow-up data from a secondary analysis of the Anastrozole or Tamoxifen Alone or Combined randomized trial, cost data (2017 Canadian dollars) from the London Regional Cancer Program (Canada) and secondary Canadian sources. The 12-gene, 58-gene, and 21-gene RS assays were associated with cost-effectiveness ratios of $36,274, $48,525, and $74,911/quality-adjusted life year (QALY) gained and resulted in total gains of 379, 284.3, and 189.5 QALYs/year and total budgets of $12.9, $14.2, and $16.6 million/year, respectively. The total expected-value of perfect information about GEP assays’ utility was $10.4 million/year. GEP testing using any of these assays is likely clinically and economically attractive. The 12-gene and 58-gene RS assays may improve the cost-effectiveness of GEP testing and offer higher value for money, although prospective evidence is still needed. Comparative field evaluations of GEP assays in real-world practice are associated with a large societal benefit and warranted to determine the optimal and most cost-effective assay for routine use.

The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.

Purpose Achieving a pathologic complete response (pCR) with neoadjuvant therapy for HER2-positive breast cancer is associated with less recurrence and improved clinical outcomes compared to having residual cancer at surgery. However, recent data have demonstrated favorable outcomes for patients with residual HER2-positive cancer who received adjuvant trastuzumab emtansine (TDM-1). Therefore, we sought to determine the optimal chemotherapy/anti-HER2 treatment strategy. Methods We created a decision-analytic model for patients with stage II–III HER2-positive cancer that incorporated utilities based on toxicity and recurrence. We separately modeled hormone receptor-negative (HR−) and positive (HR+) disease and calculated quality-adjusted life years (QALYs) and costs through 5 years. Simulated patients received one of the following neoadjuvant treatments: three ‘intensive’ regimens (TCHP: docetaxel, carboplatin, trastuzumab, pertuzumab; THP + AC: taxol, trastuzumab, pertuzumab then doxorubicin and cyclophosphamide; THP: taxol, trastuzumab, pertuzumab) and two ‘de-escalated’ regimens (TH: taxol, trastuzumab; TDM-1) followed by adjuvant treatment based on pathologic response. Results Among ‘intensive’ neoadjuvant strategies, treatment with THP was more effective and less costly than TCHP or THP + AC. When ‘de-escalated’ strategies were included, TH became the most cost-effective. For HR-negative cancer, TH had 0.003 fewer quality-adjusted life years (QALYs) than THP but was less costly by $55,831, resulting in an incremental cost-effectiveness ratio of over $18M/QALY for THP, well above any threshold. For HR-positive cancer, neoadjuvant TH dominated the THP strategy. Conclusion An adaptive-treatment strategy beginning with neoadjuvant THP or TH followed by tailoring post-operative therapy reduces treatment costs, and spares toxicity compared to more intensive chemotherapy regimens for women with HER2-positive breast cancer.

The number of breast cancer (BC) cases is growing worldwide, being most frequently diagnosed in the early-setting. Mammaprint™ is a 70-gene-expression signature, originally designed for selecting early BC patients with low risk of developing metastasis, so that they could be spared adjuvant chemotherapy. Its use as a prognostic biomarker has been extensively validated, both retrospectively and prospectively. However, its value as a predictive tool and as a clinically useful tool remains controversial. This review will describe how the test works, its application in the clinic and its limitations. Cost-effectiveness studies will be summarized. Finally, we will provide a perspective on the use of Mammaprint in the near future, as a valuable tool for personalizing the treatment of early BC patients.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer presents considerable treatment challenges owing to its aggressive nature. Global guidelines have endorsed a full year of HER2-targeted therapy for early-stage breast cancer. However, previous cost-effectiveness analyses of dual HER2-targeted therapies have been limited. This study aimed to examine the cost effectiveness of dual HER2-targeted therapy for early-stage breast cancer within the Japanese healthcare system context. In the Markov model-based study, the cost effectiveness of dual anti-HER2 therapy, combining pertuzumab and trastuzumab, was assessed in comparison to trastuzumab monotherapy. Patients in whom treatment was initiated at a median age of 51 years were included. The study utilized quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) as comparison units. Subgroup analyses were conducted to explore variations in cost effectiveness, focusing on node-positive and node-negative patients. Both one-way deterministic and broader probabilistic sensitivity analyses using Monte Carlo simulations with 10,000 samples were performed from the Japanese healthcare payers perspective. Dual HER2-targeted therapy led to 0.17 QALYs increment at an additional cost of $US15,289, resulting in an ICER of $US92,232 per QALY. In the subgroup of node-positive patients, the benefit of the dual HER2-targeted therapy was more pronounced, with an increase of 0.64 QALYs and an ICER of $US24,561 per QALY. Sensitivity analyses revealed the model's susceptibility to changes in the transition probabilities from invasive disease-free survival to death, from invasive disease-free survival to first-line metastatic breast cancer, and to costs associated with pertuzumab. Probabilistic sensitivity analysis suggests that for node-positive patients, dual HER2-targeted therapy may be a cost-effective option. The economic viability of dual HER2-targeted therapy was most pronounced in patients with node-positive high-risk early breast cancer. This study highlights the potential of dual HER2-targeted therapy as a cost-effective addition for these cases.

Objectives The ALINE trial demonstrated the superiority of alectinib over platinum‐based chemotherapy in resected Anaplastic Lymphoma Kinase (ALK)‐positive non‐small‐cell lung cancer (NSCLC). Considering the high cost of alectinib, this study aimed to evaluate the economic value of alectinib compared to platinum‐based chemotherapy for treating early‐stage ALK‐positive NSCLC from the perspective of the Chinese health care system. Materials and Methods We developed a five‐state Markov model with monthly cycles to estimate the lifetime costs, life‐years (LYs), quality‐adjusted life‐years (QALYs), and incremental cost‐effectiveness ratios (ICERs) in terms of cost per LY gained and per QALY gained. Costs were obtained from database, expert opinions and published literature, and utilities were primarily derived from a multicenter cross‐sectional study based on the Chinese population. Costs and outcomes were discounted at 5% per year. Sensitivity analyses and scenario analyses were conducted to assess uncertainty in model results. Results Compared to platinum‐based chemotherapy, alectinib increased total costs by$16,245 and provided gains of 2.02 LYs and 1.84 QALYs over a lifetime horizon. ICERs were $ 8,052/LY and$8,806/QALY. The ICER in terms of cost per QALY gained was most sensitive to the outcome discount rate. Probabilistic sensitivity analysis indicated a 93% probability of alectinib being cost‐effective at a willing‐to pay (WTP) threshold of $ 12,367/QALY (1 GDP per capita), rising to 100% at $37,100/QALY (3 GDP per capita). Conclusion Alectinib appears to be the preferred cost‐effective option in the adjuvant treatment for Chinese patients with resected early‐stage ALK‐positive NSCLC.