BACKGROUND:In the era of individualized gastric cancer (GC) treatment, accurate determination of histological subtype becomes increasingly relevant. As yet, it is unclear whether preoperative chemotherapy may affect the histological subtype. The aim of this study was to assess concordance in histological subtype between pretreatment biopsies and surgical resection specimens before and after the introduction of perioperative treatment.METHODS:Histological subtype was centrally determined in paired GC biopsies and surgical resection specimens of patients treated with either surgery alone (SA) in the Dutch D1/D2 study or with preoperative chemotherapy (CT) in the CRITICS trial. The histological subtype as determined in the resection specimen was considered the gold standard. Concordance rates and sensitivity and specificity of intestinal, diffuse, mixed, and "other" subtypes of GC were analyzed.RESULTS:In total, 105 and 515 pairs of GC biopsies and resection specimens of patients treated in the SA and CT cohorts, respectively, were included. Overall concordance in the histological subtype was 72% in the SA and 74% in the CT cohort and substantially higher in the diffuse subtype (83% and 86%) compared to the intestinal (70% and 74%), mixed (21% and 33%) and "other" subtypes (54% and 54%). In the SA cohort, sensitivities and specificities were 0.88 and 0.71 in the intestinal, 0.67 and 0.93 in the diffuse, 0.20 and 0.98 in the mixed, and 0.50 and 0.93 in the "other" subtypes, respectively.CONCLUSION:Our results suggest that accurate determination of histological subtype on gastric cancer biopsies is suboptimal but that the impact of preoperative chemotherapy on histological subtype is negligible.

Introduction/Background Hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly used for patients with stage III ovarian cancer undergoing interval cytoreductive surgery (CRS). It is uncertain whether routine postoperative admittance to an intensive care setting following CRS-HIPEC for ovarian cancer is necessary. We estimated the incidence of patients requiring critical care support and tried to identify patients in whom admission to an intensive care setting can be safely omitted. Methodology We analyzed 154 patients with primary ovarian cancer, who underwent CRS-HIPEC between 2007–2021 in two Dutch HIPEC-centers. Patients were routinely transferred to an Intensive Care Unit (ICU) or Post Anesthesia Care Unit (PACU). Patients requiring critical care support were identified by predefined criteria based on respiratory, circulatory, and metabolic parameters. Logistic regression analyses with backward selection were used to predict the need for critical care support in individual patients and the are-under-the-ROC-curve (AUC) of the model was estimated. Results Median ICU/PACU length of stay was 21 hours (IQR 19–29) and 38% of patients received postoperative critical care support, mainly consisting of hemodynamic interventions (37%). Independent predictors for critical care support are age, blood loss, norepinephrine dose during surgery, and peritonectomy extent (table 1). AUC of the model is 0.81 (95% CI 0.73–0.88). Using a 20% cut-off to define low-risk of critical care support, 37% of patients would be eligible to forego ICU/PACU admission. Conclusion Postoperative admission to an intensive care setting is not routinely required for ovarian cancer patients undergoing CRS-HIPEC. Following prospective validation, a decision tool based on pre- and intra-operative parameters can help to identify low-risk patients.

Purpose/Objective(s) In the phase II ARTFORCE PET-Boost trial, two individualized dose escalation strategies, utilizing hypofractionation and functional imaging, were tested aiming to improve local control in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Before randomization, plans for both arms were optimized and normalized to the mean lung dose, approximating isotoxicity. The purpose of this study is to assess the isotoxicity of the two treatment plans for each patient, by comparing planned dose to organs at risk (OAR). Materials/Methods The PET-Boost trial included patients with stage II-III NSCLC, with a large primary tumor >4cm. Patients received an escalated dose either to the primary tumor as a whole (arm A), or the FDG-avid areas within the primary tumor (>50% SUVmax) (arm B). Before randomization, two treatment plans were created for each patient, one for each arm, with equal mean lung dose (max 20 Gy). In both arms, the escalated dose was delivered in 24 fractions of 3.0-5.4 Gy, defined by OAR constraints. As the PET-subvolume is smaller than the whole tumor, the dose per fraction could be escalated further. Involved lymph nodes received 66 Gy (24 × 2.75 Gy) in both arms. In this analysis, dose metrics were compared for OARs in the whole tumor vs PET-subvolume arm for each patient. Difference was calculated as metricarmB – metricarmA. Wilcoxon sign rank tests were applied to assess intrapatient differences. Results Between 2010 and 2017, 107 patients were randomized in seven European centers. For 87 patients, data from both treatment plans was available for current analysis. The median (+IQR) differences in dose to OARs between arm A and B were as follows: lung Dmean EQD2α/β=3 -0.3 Gy (-0.5 – 0; p<0.005), lung V5physical +1.1% (0.2 - 2.7; p < 0.005), lung V20physical +0.5% (0.1 – 1.3; p<0.005), esophagus Dmean EQD2α/β=10 +0.1 Gy (-0.9 – 0.6; p = 0.76), esophagus V36physical +0.1% (-0.7 – 1.2; p = 0.45), esophagus Dmax EQD2α/β=10 -0.2 Gy (-2.85 – 0.8; p = 0.05), heart Dmax -0.5 Gy EQD2α/β=3 (-2.1 – 0.6; p = 0.04), heart Dmean -0.1 Gy EQD2α/β=3 (-1.5 – 0.1; p < 0.005), brachial plexus Dmaxphysical -0.3 Gy (-2.1 – 0.1; p=0.01), and spinal cord Dmaxphysical -0.4 Gy (-2.1 – 0.8; p=0.03). We found that outliers with larger differences tended to have either very large primary tumors, or relatively small (≤ 70 cm3) tumor volumes. Conclusion An international trial was performed which randomized LA-NSCLC patients between two dose-escalation strategies that aimed to be isotoxic. Though most statistically significance, we found generally small differences in dose to OAR between the two plans. Our results confirm by aiming at an equal mean lung dose, doses to heart, esophagus, brachial plexus and spinal cord were also to a large extent kept isotoxic. Analyses of dose volume histograms in relation to adverse events reported in the trial is ongoing. This study has the ClinicalTrials.gov identifier NCT01024829.

Introduction/Background The optimal management of FIGO 2018 stage IB2 cervical cancer patients who desire to preserve fertility is unknown. Therefore, the CONTESSA/NEOCON-F trial (NCT04016389) aims to evaluate a promising, new fertility-sparing treatment: neoadjuvant chemotherapy (NACT) followed by fertility-sparing surgery (FSS). Methodology This trial is an ongoing, phase II clinical trial, which will accrue 90 pre-menopausal, lymph-node negative, FIGO 2018 stage IB2 cervical cancer patients, aged between 18 and 40 years and who desire to preserve their fertility. All patients will receive three cycles of paclitaxel and platinum containing chemotherapy. Following NACT the response will be evaluated by clinical examination and MRI. Patients must achieve a complete or partial response (residual lesion <2 cm) to be eligible for FSS: a conisation or simple trachelectomy. Patients with suboptimal response (residual lesion ≥2 cm) will go off-study and receive definitive treatment, radical hysterectomy or chemoradiation as per local protocol. Patients will be followed for three years following FSS. The safety of this trial will be continuously monitored using Bayesian posterior probability and the stopping rule will be activated if there is at least 70% probability that two-year recurrence rate is above 10%. Results The primary outcome is the rate of functional uterus defined as successful FSS and no need for adjuvant therapy post procedure. Secondary outcomes include the safety of the treatment, the response rate to NACT, and the recurrence-free and overall survival after two and three years. Finally, this trial will also explore the effect of NACT on ovarian function. Translational research will explore disease monitoring in blood plasma (HPV ctDNA) and cervical scrapes (DNA hypermethylation), and patients' quality of life will be assessed by questionnaires. Conclusion The CONTESSA/NEOCON-F trial is opened for accrual in the Netherlands, Canada, and the United States. Currently, 10% of the target accrual has been reached.

Neoadjuvant immunotherapy has shown promising responses in several cancer types. For colon cancer (CC), NICHE was the first neoadjuvant immunotherapy study to show pathologic responses in 100% of dMMR tumors. Importantly, disease-free survival (DFS) in patients (pts) with stage III dMMR CC is similar to that of pMMR pts, with 3-year recurrence risks of over 40% in high-risk (T4 and/or N2) stage III tumors despite adjuvant chemotherapy. Improving outcome for this patient population is urgently needed.

Background Survival is a key metric of the effectiveness of a health system in managing cancer. We set out to provide a comprehensive examination of worldwide variation and trends in survival from brain tumors in adults, by histology. Methods We analyzed individual data for adults (15-99 years) diagnosed with a brain tumor (ICD-O-3 topography code C71) during 2000-2014, regardless of tumor behavior. Data underwent a 3-phase quality control as part of CONCORD-3. We estimated net survival for 11 histology groups, using the unbiased nonparametric Pohar Perme estimator. Results The study included 556,237 adults. In 2010-2014, the global range in age-standardized 5-year net survival for the most common sub-types was broad: in the range 20%-38% for diffuse and anaplastic astrocytoma, from 4% to 17% for glioblastoma, and between 32% and 69% for oligodendroglioma. For patients with glioblastoma, the largest gains in survival occurred between 2000-2004 and 2005-2009. These improvements were more noticeable among adults diagnosed aged 40-70 years than among younger adults. Conclusions To the best of our knowledge, this study provides the largest account to date of global trends in population-based survival for brain tumors by histology in adults. We have highlighted remarkable gains in 5-year survival from glioblastoma since 2005, providing large-scale empirical evidence on the uptake of chemoradiation at population level. Worldwide, survival improvements have been extensive, but some countries still lag behind. Our findings may help clinicians involved in national and international tumor pathway boards to promote initiatives aimed at more extensive implementation of clinical guidelines.

Objectives The primary objective of the CONTESSA/NEOCON-F trial (NCT04016389) is to assess the feasibility of preserving fertility in women with FIGO 2018 stage IB2 cervical cancer by administering neo-adjuvant chemotherapy (NACT) followed by fertility sparing surgery (FSS). Methods This ongoing multi-center, phase II clinical trial will accrue 90 premenopausal women, aged between 18 and 40 years, who are diagnosed with lymph-node negative, FIGO 2018 stage IB2 cervical cancer and who have a desire to preserve fertility. Patients will receive three cycles paclitaxel and platinum-based chemotherapy. Following NACT the response will be evaluated by clinical examination and MRI. Patients with complete or partial response (residual lesion <2 cm) will be eligible for FSS: a conization or simple trachelectomy. Patients with suboptimal response (residual lesion ≥2 cm) will go off-study and receive definitive treatment as per local protocol. The follow-up is three years. The primary outcome is the rate of functional uterus defined as successful FSS and no adjuvant therapy. Secondary outcomes include the safety of NACT and FSS, the response rate to NACT, and the recurrence-free and overall survival after two and three years. Furthermore, this trial will evaluate patients' quality of life and ovarian function, and will explore the possibilities for disease monitoring in blood plasma (HPV ctDNA) and cervical scrapes (DNA hypermethylation). Results 'Trial in progress: there are no available results at the time of submission.' Conclusions The CONTESSA/NEOCON-F trial is opened for accrual in the Netherlands, Canada, and the United States. Currently, 10% of the target accrual has been reached.

Background: Epstein-Barr virus positivity (EBV+) and microsatellite instability (MSI-high) have been shown to be positive prognostic factors for long term survival in resectable gastric cancer (GC) in several studies. However, the benefit of perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcome of patients with EBV+ and MSI-high GCs treated with surgery only in the Dutch D1/D2 trial, and treated with chemotherapy or chemoradiotherapy after preoperative chemotherapy and surgery in the CRITICS trial. Patients and methods: EBV was determined in tumor tissue using EBV-encoded RNA in situ hybridization (EBER-ISH). PCR and/or immunohistochemistry were performed to determine MSI status. Results were correlated to histopathological response, morphological tumor characteristics and survival. Results: In the Dutch D1/D2 trial 10.5% (47/447) of tumors were EBV+ and 10.5% (47/447) were MSI-high. In the CRITICS trial 5.5% (25/451) of tumors were EBV+ and 5.5% (25/451) were MSI-high tumors. In the Dutch D1/D2 trial, five-year overall survival probability was 51.1% for EBV+, 46.8% for MSI-high, and 42.5% for EBV-/MSS (P=0.19). In the CRITICS trial, five-year overall survival was 56.0% for EBV+, 47.3% for MSI-high, and 36.5% for EBV-/MSS (P=0.22). In the CRITICS trial, 3 (12.5%) MSI-high tumors showed moderate to complete histopathological response. Interestingly, all three showed a mucinous phenotype. Eight (36.4%) EBV+ and 114 (29.9%) EBV-/MSS tumors showed moderate to complete histopathological response. None of the EBV+ GCs showed mucinous differentiation. Conclusions: The favorable outcome of GC patients with resectable EBV+ or MSI-high tumors compared to EBV-/MSS tumors remains after perioperative chemotherapy. In MSI-high tumors significant histopathological response to neoadjuvant chemotherapy was found only in those with a mucinous phenotype. Citation Format: H.D. Biesma, A.T.T.D. Soeratram, K. Sikorska, I.A. Caspers, H.F. van Essen, J.M.P. Egthuijsen, A. Mookhoek, D.M. Hoek, W. Vos, H.W.M. van Laarhoven, M. Nordsmark, D.L. van der Peet, F.A.R.M. Warmerdam, M.M. Geenen, O.J.L. Loosveld, J.E.A. Portielje, M. Los, E. Meershoek - Klein Kranenbarg, H.H. Hartgrink, J. van Sandick, C.J.H. van de Velde, M. Verheij, A. Cats, B. Ylstra, N.C.T. van Grieken, On behalf of the CRITICS investigators. Mucinous phenotype is associated with response to neoadjuvant chemotherapy in microsatellite instable resectable gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 354.

Background: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial. Patients and methods: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib-Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival. Results: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios. Conclusion: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma. Long-term outcomes and biomarker analyses of two neoadjuvant immunotherapy clinical trials in melanoma patients support the clinical benefit of this treatment approach and uncover prognostic correlates of response.

While high local control rates were achieved in this phase II trial of hypofractionated dose escalation in patients with stage II-III NSCLC, distant metastases were frequently seen in this patient cohort with large primary tumors.

Targeting the human epidermal growth factor receptor-2 (HER2) is the cornerstone of the treatment of HER2+ breast cancer patients. The mechanism of action of trastuzumab is partly based on lysis of tumor cells via antibody dependent cellular cytotoxicity (ADCC), which among others involves NK cells. However, NK cell and CD8+ T-cell activity is inhibited by binding of the inhibitory receptor NKG2A to HLA-E. HLA-E expression is upregulated upon tumor cells and preserved throughout disease progression. Monalizumab is an antibody targeting the NKG2A receptor, thereby blocking NKG2A-HLA-E interaction. Monalizumab has shown clinical activity in head and neck cancer when combined with cetuximab (anti-EGFR). We hypothesize that monalizumab improves trastuzumab-mediated ADCC and thereby helps to overcome trastuzumab-resistance and can promote anti-tumor immunity by unleashing NK cells and CD8+ T cells in HER2+ breast cancer. The MIMOSA-trial (NCT04307329) is an explorative phase II trial in which patients will be treated biweekly with trastuzumab and monalizumab. Clinical efficacy will be assessed separately in patients with high stromal tumor-infiltrating lymphocytes (sTILs) (≥ 5%) and in patients with low sTILs (< 5%) using a Simon's-two stage design. In stage I, eleven patients will be accrued per cohort. If two or more responders are observed, another eight patients will be accrued. Inclusion criteria comprise histologically confirmed HER2+ breast cancer on a metastatic lesion, progression during previous trastuzumab or TDM-1 therapy, administration of at least one and maximum of three lines of palliative chemotherapy, a metastatic lesion accessible for biopsy and LDH <500 U/l. Primary endpoint is the objective response rate according to RECIST1.1. Secondary endpoints include to evaluate clinical benefit and progression-free survival according to RECIST1.1, overall survival and safety. Before and on-treatment blood and biopsies will be used for translational research to explore treatment-induced intra-tumoral and systemic changes with a focus on NK-cells and CD8+ T-cells. The MIMOSA-trial is currently open for enrollment at the Netherlands Cancer Institute. NCT04307329. Netherlands Cancer Institute. AstraZeneca.