Neoadjuvant Treatment Strategies Research Articles

Multimodal Approaches to Patient Selection for Pancreas Cancer Surgery.

With an overall 5-year survival rate of 12%, pancreas ductal adenocarcinoma (PDAC) is an aggressive cancer that claims more than 50,000 patient lives each year in the United States alone. Even those few patients who undergo curative-intent resection with favorable pathology reports are likely to experience recurrence within the first two years after surgery and ultimately die from their cancer. We hypothesize that risk factors for these early recurrences can be identified with thorough preoperative staging, thus enabling proper patient selection for surgical resection and avoiding unnecessary harm. Herein, we review evidence supporting multidisciplinary and multimodality staging, comprehensive neoadjuvant treatment strategies, and optimal patient selection for curative-intent surgical resections. We further review data generated from our standardized approach at the Mayo Clinic and extrapolate to inform potential future investigations.

Treatment strategies for borderline resectable pancreatic neuroendocrine tumors: a narrative review.

Well-differentiated pancreatic neuroendocrine tumors (pNETs) are a group of rare, heterogeneous tumors that originate in the endocrine tissue of the pancreas and account for 1-2% of all pancreatic neoplasms. The majority of pNETs are non-functional and typically follow a more indolent course. Especially at early stages, the primary management of pNETs is surgical resection which is associated with relatively low rates of recurrence and excellent long-term prognosis. On the other hand, some patients will present with locally advanced primary tumors or low volume metastatic disease in which complete surgical resection may be more difficult to achieve and recurrence rates are significant. Unlike treatment of borderline resectable (BR) pancreatic adenocarcinoma, in which neoadjuvant treatment strategies are becoming standardized, borderline resectability is not a currently established terminology for pNETs and the optimal multidisciplinary treatment approach is poorly understood. We performed a literature search on PubMed, Google Scholar, and ClinicalTrials.gov using keywords, including 'pancreatic neuroendocrine tumor' and 'borderline resectable'. All studies and review articles in English with full text were considered. Each publication was independently reviewed. We introduce the concept of BR-pNETs, focusing on important criteria that should be included in their definition by balancing the feasibility of resection and the clinical utility of surgery. We suggest that extended resection, involving vascular reconstruction, adjacent organ resection, and/or liver metastasis, should be considered at experienced, high volume centers. Furthermore, we outline multidisciplinary treatment strategies, including systemic and locoregional treatment options, for optimizing outcomes for this growing patient population. Formalizing the definition of resectability in pNETs through multidisciplinary collaborative research will be important for standardizing the indications for multimodality treatment and aggressive surgical approaches for patients.

Influence of neoadjuvant treatment strategy on perioperative outcomes in locally advanced rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer facilitates tumour downstaging and complete pathological response (pCR). The goal of neoadjuvant systemic chemotherapy (total neoadjuvant chemotherapy, TNT) is to further improve local and systemic control. While some patients forgo surgery, total mesorectal excision (TME) remains the standard of care. While TNT appears to be noninferior to nCRT with respect to short-term oncological outcomes few data exist on perioperative outcomes. Perioperative morbidity including anastomotic leaks is associated with a negative effect on oncological outcomes, probably due to a delay in proceeding to adjuvant therapy. Thus, we aimed to compare conversion rates, rates of sphincter-preserving surgery and anastomosis formation rates in patients undergoing rectal resection after either TNT or standard nCRT. An institutional colorectal oncology database was searched from January 2018 to July 2023. Inclusion criteria comprised patients with histologically confirmed rectal cancer who had undergone neoadjuvant therapy and TME. Exclusion criteria comprised patients with a noncolorectal primary, those operated on emergently or who had local excision only. Outcomes evaluated included rates of conversion to open, sphincter-preserving surgery, anastomosis formation and anastomotic leak. A total of 119 patients were eligible for inclusion (60 with standard nCRT, 59 with TNT). There were no differences in rates of sphincter preservation or primary anastomosis formation between the groups. However, a significant increase in conversion to open (p = 0.03) and anastomotic leak (p = 0.03) was observed in the TNT cohort. In this series TNT appears to be associated with higher rates of conversion to open surgery and higher anastomotic leak rates. While larger studies will be required to confirm these findings, these factors should be considered alongside oncological benefits when selecting treatment strategies.

Economic Evaluation of Neoadjuvant Treatment Strategies for HER2 Positive Breast Cancer: A Systematic Review

Context: There are several neoadjuvant treatment strategies for HER2-positive breast cancer (BC). Studies have investigated different aspects of these strategies and presented different findings. Objectives: This study aimed at collecting and interpreting economic evaluation studies related to neoadjuvant treatment strategies for HER2-positive BC. Methods: In this systematic review, PubMed, Web of Science (WOS), ScienceDirect, and Scopus databases were searched without a time limit between May and October 2023. Google Scholar search engine was also used to complete the search process. Two authors independently determined the eligibility of the study. To assess the quality of the studies, the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines were used. Disagreements were resolved by discussion or consultation with a third researcher. As this review is descriptive, numerical data were not extracted for statistical analysis. Results: Out of 234 studies found in the first stage, 21 studies from 14 countries were included. The strategies that have been approved by studies include THP (taxol, trastuzumab, pertuzumab), PTD (Pertuzumab in combination with trastuzumab and docetaxel), TH (docetaxel and trastuzumab), T-DM1 (trastuzumab emtansine), and HP (trastuzumab plus pertuzumab). Conclusions: The findings of this systematic review show that the reported strategies in the treatment of HER2-positive BC patients are cost-effective in different settings. While the findings of this review provide largely positive results, the characteristics of each strategy should be considered.

Comparison of perioperative and histopathologic outcomes among neoadjuvant treatment strategies for locoregional gastric cancer.

The National Cancer Database queried patients who received NAC or NCRT followed by resection for T2-T4 and/or node-positive gastric cancer (2006-2018). Logistic and Poisson regression assessed perioperative (30-day readmission, 30- and 90-day mortality, length of stay [LOS]) and histopathologic outcomes (pathologic complete response [PCR], margin status, and negative pathologic lymph nodes [ypN0]). Kaplan-Meier methods and Cox regression assessed overall survival (OS). Of 9831 patients, 4221 (42.9%) received NAC and 5610 (57.1%) NCRT. There were no differences in perioperative outcomes, apart from patients treated with NCRT exhibiting increased LOS (incidence rate ratio 1.09, 95% confidence interval [CI] 1.03-1.16). Patients who received NCRT were more likely to achieve PCR, margin-negative resection, and ypN0 (all p < 0.05). Median OS was 36.8 months for NAC and 33.6 months for NCRT (p < 0.001). NCRT independently predicted worse OS (vs.NAC, hazard ratio 1.10, 95%CI 1.03-1.18). NCRT was associated with better histologic tumor response although NAC was associated with improved OS. Better understanding prognostication through histologic assessment following neoadjuvant therapy is needed.

Minimally Invasive Breast Biopsy After Neoadjuvant Systemic Treatment to Identify Breast Cancer Patients with Residual Disease for Extended Neoadjuvant Treatment: A New Concept

BackgroundBreast cancer patients with residual disease after neoadjuvant systemic treatment (NAST) have a worse prognosis compared with those achieving a pathologic complete response (pCR). Earlier identification of these patients might allow timely, extended neoadjuvant treatment strategies. We explored the feasibility of a vacuum-assisted biopsy (VAB) after NAST to identify patients with residual disease (ypT+ or ypN+) prior to surgery.MethodsWe used data from a multicenter trial, collected at 21 study sites (NCT02948764). The trial included women with cT1-3, cN0/+ breast cancer undergoing routine post-neoadjuvant imaging (ultrasound, MRI, mammography) and VAB prior to surgery. We compared the findings of VAB and routine imaging with the histopathologic evaluation of the surgical specimen.ResultsOf 398 patients, 34 patients with missing ypN status and 127 patients with luminal tumors were excluded. Among the remaining 237 patients, tumor cells in the VAB indicated a surgical non-pCR in all patients (73/73, positive predictive value [PPV] 100%), whereas PPV of routine imaging after NAST was 56.0% (75/134). Sensitivity of the VAB was 72.3% (73/101), and 74.3% for sensitivity of imaging (75/101).ConclusionResidual cancer found in a VAB specimen after NAST always corresponds to non-pCR. Residual cancer assumed on routine imaging after NAST corresponds to actual residual cancer in about half of patients. Response assessment by VAB is not safe for the exclusion of residual cancer. Response assessment by biopsies after NAST may allow studying the new concept of extended neoadjuvant treatment for patients with residual disease in future trials.

The impact of oncogenic driver mutations on neoadjuvant immunotherapy outcomes in patients with resectable non-small cell lung cancer.

Neoadjuvant immunotherapy has been demonstrated to be effective and safe in resectable non-small cell lung cancer (NSCLC) patients. However, the presence of different oncogenic driver mutations may affect the tumor microenvironment and consequently influence the clinical benefit from immunotherapy. This retrospective study included consecutive NSCLC patients (stage IIA to IIIB) who underwent radical surgery after receiving neoadjuvant immunotherapy at a single high-volume center between December 2019 and August 2022. Pathological response and long-term outcomes were compared based on the driver oncogene status, and RNA sequencing analysis was conducted to investigate the transcriptomic characteristics before and after treatment. Of the 167 patients included in this study, 47 had oncogenic driver mutations. KRAS driver mutations were identified in 28 patients, representing 59.6% of oncogenic driver mutations. Of these, 17 patients had a major pathological response, which was significantly higher than in the non-KRAS driver mutation group (60.7% vs. 31.6%, P = 0.049). Multivariate Cox regression analysis further revealed that the KRAS driver mutation group was an independent prognostic factor for prolonged disease-free survival (hazard ratio: 0.10, P = 0.032). The median proportion of CD8+ T cells was significantly higher in the KRAS driver mutation NSCLCs than in the non-driver mutation group (18% vs. 13%, P = 0.030). Furthermore, immune-related pathways were enriched in the KRAS driver mutation NSCLCs and activated after immunotherapy. Our study suggests that NSCLC patients with KRAS driver mutations have a superior response to neoadjuvant immunotherapy, possibly due to their higher immunogenicity. The findings highlight the importance of considering oncogenic driver mutations in selecting neoadjuvant treatment strategies for NSCLC patients.

Type of neoadjuvant treatment strategy is associated with differential pathologic responses in pancreatic ductal adenocarcinoma

BackgroundTumor fibrosis after neoadjuvant treatment (NAT) for pancreatic ductal adenocarcinoma (PDAC) correlates with treatment response. Herein we assessed how different NAT strategies influence pathologic responses and survival. MethodsPatients with surgically resected PDAC who received NAT (1991–2020) were included. Descriptive statistics compared outcomes amongst fibrosis groups (none, minor <50 ​%, partial 51%–94 ​%, major ≥95 ​%) and NAT (chemotherapy alone, chemoradiation, or chemotherapy ​+ ​chemoradiation (total neoadjuvant therapy, TNT)). ResultsPatients with major fibrosis most often received TNT (65.8 ​%, p ​< ​0.001). Major fibrosis was associated with the greatest rate of downstaging (77.8 ​%, p ​< ​0.001), highest R0 margin rate (100 ​%, p ​< ​0.01), and lowest mean positive lymph node ratio (0.80, p ​< ​0.01). Amongst complete responders, 11/14 (78.6 ​%) received TNT. Median overall (66.3 months, p ​= ​0.003) and disease-free (54.7months, p ​= ​0.05) survival were highest with major fibrosis. ConclusionsMajor fibrosis and complete pathologic responses after NAT are most frequent with a TNT strategy and are associated with improved outcomes.

Incidence and risk factors of lymph node metastasis in breast cancer patients without preoperative chemoradiotherapy and neoadjuvant therapy: analysis of SEER data.

Breast cancer (BC) is the leading cause of death in the female reproductive system, often linked to lymph node involvement, indicating poor prognosis. This study investigated lymph node metastasis incidence and risk factors in M0 stage BC patients who hadn't received preoperative chemoradiotherapy or neoadjuvant therapy. We explored the influence of various factors on lymph node metastasis. We conducted a retrospective analysis using Surveillance, Epidemiology, and End Results data from BC patients diagnosed between 2010 and 2015. Binary logistic regression and propensity score matching (PSM) assessed significant factors in BC patients without preoperative treatment. We developed predictive nomograms and evaluated model performance using the concordance index, calibration curve, area under the curve, and decision curve analysis. Among 256,504 eligible BC patients, 25.57% had lymph node metastasis. Multivariate logistic regression revealed associations between lymph node metastasis and younger age, African-American ethnicity, central/nipple location, lobular carcinoma, human epidermal growth factor receptor 2 (HER2)-positive status, grade III classification, and T3 stage. PSM confirmed these findings. Interactions were identified between age, race, primary site, histology, breast subtype, grade, and T stage, all influencing lymph node metastasis. This retrospective study identified lymph node metastasis in female BC patients with distinct clinicopathological characteristics who received no preoperative treatment. We constructed valuable nomograms, revealing that: (I) young age (<35 years), African-American race, central/nipple location, infiltrating duct carcinoma, HER2 positivity, high histological grade (grade III), and larger tumor size are risk factors for regional lymph node metastasis; (II) lymph node metastasis may not solely represent the invasive nature of triple-negative BC; (III) patients with different BC subtypes in T1c-T2 stages may benefit from individualized neoadjuvant treatment strategies.

Great Debate: Chemoradiation Should be Added to Chemotherapy as a Neoadjuvant Treatment Strategy for Resectable Gastric Adenocarcinoma.

Most patients with resectable gastric cancer present with locally advanced disease and warrant neoadjuvant chemotherapy based on level 1 evidence. However, the incremental benefit of adding radiation to chemotherapy as a neoadjuvant treatment strategy for these patients is less clear. While awaiting the results of two ongoing randomized clinical trials attempting to specifically address this question (TOPGEAR and CRITICS-II), this article presents the debate between two gastric cancer surgery experts supporting each side of the argument on the use or omission of neoadjuvant radiation in this setting. On the one hand, neoadjuvant radiation may be better tolerated compared with modern triplet chemotherapy and may be associated with higher rates of major pathologic response. Additionally, there is evidence to suggest that radiation may offer a survival benefit when the tumor is located at the gastroesophageal junction or there is concern for a margin-positive resection. However, in the setting of adequate surgery, no survival benefit has been demonstrated by adding radiation to modern chemotherapy, likely reflecting the fact that death from gastric cancer is a result of distant recurrence, which is not addressed by local treatment such as radiotherapy. While awaiting the results of the TOPGEAR and CRITICS-II trials, this discussion of current evidence can facilitate the refinement of an optimal neoadjuvant therapy strategy in patients with resectable gastric cancer.

Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer-A Literature Review.

The overexpression of the human epidermal growth factor receptor 2 (HER2+) accounts for 15-20% of all breast cancer phenotypes. Even after the completion of the standard combination of chemotherapy and trastuzumab, relapse events occur in approximately 15% of cases. The neoadjuvant approach has multiple benefits that include the potential to downgrade staging and convert previously unresectable tumors to operable tumors. In addition, achieving a pathologic complete response (pCR) following preoperative systemic treatment is prognostic of enhanced survival outcomes. Thus, optimal evaluation among the suitable strategies is crucial in deciding which patients should be selected for the neoadjuvant approach. A literature search was conducted in the Embase, Medline, and Cochrane electronic libraries. The evaluation of tumor and LN staging and, hence, stratifying BC recurrence risk are decisive factors in guiding clinicians to optimize treatment decisions between the neoadjuvant versus adjuvant approaches. For each individual case, it is important to consider the most likely postsurgical outcome, since, if the patient does not obtain pCR following neoadjuvant treatment, they are eligible for adjuvant T-DM1 in the case of residual disease. This review of HER2-positive female BC outlines suitable neoadjuvant and adjuvant systemic treatment strategies for guiding clinical decision making around the selection of an appropriate therapy.

FTP3.7 Influence of neoadjuvant treatment strategy on operability in locally advanced rectal cancer

Abstract Background Neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer facilitates tumour downstaging and complete pathological response (pCR). Neoadjuvant systemic chemotherapy (total neoadjuvant chemotherapy, TNT) further improves pCR rates. While some patients forgo surgery, total mesorectal excision (TME) remains the standard of care. While TNT appears to be non-inferior to nCRT with respect to short-term oncological outcomes, little data exists on perioperative outcomes. Factors such as conversion, sphincter preservation and anastomosis rates do not impact oncological outcomes but affect quality of life (QOL). Methods An institutional colorectal oncology database was interrogated from inception (2009) to November 2022. Inclusion criteria comprised patients with histologically confirmed rectal cancer who had undergone neoadjuvant therapy and TME. Exclusion criteria comprised patients with a non-colorectal primary, those operated on emergently or who had local excision only. Primary outcomes were rates of conversion to open, sphincter preserving surgery and anastomosis formation. Results In total 156 patients were eligible for inclusion (standard nCRT, n= 111, TNT, n=45). Sphincter preservation and anastomosis formation were more frequent in the nCRT cohort, while conversion rates were higher in the TNT cohort. Although these differences were not statistically different, the conversion value approached significance (sphincter preservation, 70% vs 62%, p=0.3484; anastomosis, 72% vs 64%, p=0.4632, conversion, 34% vs 17%, p=0.0501). Conclusions In this series TNT appears to be associated with higher conversion rates and lower rates of anastomosis formation. While larger studies will be required to confirm these findings, QOL factors should be considered alongside oncological benefits when selecting treatment strategies.

Treatment characteristics and outcomes of pure Acinar cell carcinoma of the pancreas – A multicentric European study on radically resected patients

BackgroundAcinar cell carcinomas (ACC) belong to the exocrine pancreatic malignancies. Due to their rarity, there is no consensus regarding treatment strategies for resectable ACC. MethodsThis is a retrospective multicentric study of radically resected pure pancreatic ACC. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Further endpoints were oncologic outcomes related to tumor stage and therapeutic protocols. Results59 patients (44 men) with a median age of 64 years were included. The median tumor size was 45.0 mm. 61.0% were pT3 (n = 36), nodal positivity rate was 37.3% (n = 22), and synchronous distant metastases were present in 10.1% of the patients (n = 6). 5-Years OS was 60.9% and median DFS 30 months. 24 out of 31 recurred systemically (n = 18 only systemic, n = 6 local and systemic). Regarding TNM-staging, only the N2-stage negatively influenced OS and DFS (p = 0.004, p = 0.001). Adjuvant treatment protocols (performed in 62.7%) did neither improve OS (p = 0.542) nor DFS (p = 0.159). In 9 cases, radical resection was achieved following neoadjuvant therapy. DiscussionRadical surgery is currently the mainstay for resectable ACC, even for limited metastatic disease. Novel (neo)adjuvant treatment strategies are needed, since current systemic therapies do not result in a clear survival benefit in the perioperative setting.

ShorTrip Trial: A Prospective, Multicentric Phase II Single-Arm Trial of Short-Course Radiotherapy Followed by Intensified Consolidation Chemotherapy With the Triplet FOLFOXIRI as Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer

BackgroundIn patients with locally advanced rectal cancer (LARC) treated with preoperative (chemo) radiotherapy and surgery, adjuvant chemotherapy is poorly feasible and its benefit is questionable. In the last years, several total neoadjuvant treatment (TNT) strategies, moving the adjuvant chemotherapy to the neoadjuvant setting, have been investigated with the aim of improving compliance to systemic chemotherapy, treating micrometastases earlier and then reducing distant recurrence. Patients and MethodsShorTrip (NTC05253846) is a prospective, multicentre, single-arm phase II trial where 63 patients with LARC will be treated with short-course radiotherapy followed by intensified consolidation chemotherapy with FOLFOXIRI regimen and surgery. Primary endpoint is pCR. Among the first 11 patients who started consolidation chemotherapy, a preliminary safety analysis showed a high rate of grade 3 to 4 neutropenia (N = 7, 64%) during the first cycle of FOLFOXIRI. Therefore, the protocol has been emended with the recommendation to omit irinotecan during the first cycle of consolidation chemotherapy. After amendment, in a subsequent safety analysis focused on the first 9 patients treated with FOLFOX as first cycle and then with FOLFOXIRI, grade 3 to 4 neutropenia was reported in only one case during the second cycle. Aim of the studyThe aim of this study is to assess the safety and activity of a TNT strategy including SCRT, intensified consolidation treatment with FOLFOXIRI and delayed surgery. After protocol amendment, the treatment seems feasible without safety concern. Results are expected at the end of 2024.

[Data from the 2022 ASCO Annual Meeting on surgical therapy].

Last year, studies on immuno-oncologic treatment approaches for recurrent or metastatic head and neck cancer were the main focus at the two major international cancer congresses of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO). The success of these therapeutic strategies has led to many new studies, including their use in the neoadjuvant setting. This review article summarizes presented studies from ASCO 2022 in which surgical therapy is the focus of the study protocol and also includes study results on neoadjuvant treatment strategies. No surgical trials were presented at ESMO 2022. At ASCO 2022 as well as in previous years, it became increasingly clear that treatment de-escalation in the context of human papillomavirus (HPV)-associated oropharyngeal carcinoma treatment involving surgical measures appears to be oncologically safe and functionally beneficial. In addition, anumber of studies indicate that in the setting of neoadjuvant administration of immuno-oncologic agents, aproportion of patients have pathologic complete remission. In this fraction of patients, which is usually significantly smaller than 50%, survival data are better than in those who have already failed to respond to neoadjuvant therapy. Unfortunately, however, significant toxicities or tumor progression with the risk of inoperability were also seen under these current therapeutic regimens, leading to discontinuation of therapy in 5-20% of cases. It remains to be seen whether neoadjuvancy with immune checkpoint inhibitors can establish itself, in contrast to the failed attempts of the past with the use of cytostatics.

Influence of high COL19A1 expression on the effectiveness of neoadjuvant immunotherapy plus chemotherapy and long-term survival in patients with esophageal squamous cell carcinoma.

e16013 Background: Neoadjuvant immunotherapy plus chemotherapy may enhance the resectability rate in locally advanced Esophageal Squamous Cell Carcinoma (ESCC). Nevertheless, due to the complex nature of the tumor immune microenvironment, an unmet need remains for biomarkers to identify NPC patients used to identify patients who benefit most from this neoadjuvant treatment strategy. Methods: Two independent cohorts of ESCC patients were enrolled in the study., including retrospective cohort (N=66) and prospective cohort (N=37). A total of 103 NPC FFPE samples were subjected to RNA sequencing. Single sample GSEA (ssGSEA) were performed to explore the Tumor microenvironment (TME). Differential genes associated with survival were analyzed using logistic regression and Kaplan-Meier methods. To reveal the expression of biomarker and TME, immunohistochemistry and multiplex immunofluorescence were used. Results: We demonstrated that COL19A1 high expression facilitates anti-PD-1 therapy [ COL19A1 high, OR (95% CI): 0.31 (0.1−0.97), p = 0.044]. COL19A1high patients could benefit more from neoadjuvant immunotherapy (p &lt; 0.01), high mortality (63.3%, p &lt; 0.01), and have a trend towards a better RFS (p = 0.13) and OS (p = 0.056). Further analyses confirmed increased B cells infiltration and COL19A1 high expression could be seen in the immune-activated subgroup, which resulted in favorable survival and response to neoadjuvant immunotherapy plus chemotherapy. Conclusions: This study revealed an ESCC subpopulation presenting high COL19A1 expression, which responded well to neoadjuvant immunotherapy plus chemotherapy and was associated with good prognosis. It provided a convincing basis for designing biomarker-guided individual treatment.

Real-world impact of time-to-treatment initiation and initial treatment modality on survival in pancreatic and colorectal cancers.

e15646 Background: Overall survival for patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancers (CRC) has increased significantly over the past decade; however, the optimal time-to-treatment initiation (TTI) and initial treatment modality (ITM) have not been defined. These variables have likely been affected by increased adoption and changes in types of neoadjuvant treatment strategies for these cancer types. Thus, we performed a retrospective observational study of TTI and ITM in patients with CRC and PDAC within the MHealth/Fairview medical system. Methods: We identified 424 patients with stage I-III RC and 316 patients with stage I-III PDAC within the MHealth/Fairview system (Minneapolis, MN) from 2011-2021 with North American Association of Central Cancer Registries data enriched by the electronic health record. Patients were stratified by TTI from diagnoses as: 0-7 days, 8-14 days, 15-28 days, 29-42 days, and over 43 days. ITM, defined as initial chemotherapy/chemoradiation, surgery, or radiation, was analyzed independently for patients with rectal cancer (N = 267) and PDAC. Effect of TTI and ITM on overall survival was calculated using a Cox proportional Hazard (CPH) model controlling for clinical stage. Results: TTI was significantly associated with survival in CRC, with patients treated in 8-14 days and 15-28 days showing increased survival over patients treated in over 43 days (HR 0.397, p = 0.007 and HR 0.276 p &lt; 0.001, respectively). There was no significant hazard for TTI and survival in PDAC. We also found that neoadjuvant chemotherapy/chemoradiation had a lower hazard for death in rectal cancer relative to upfront surgery (HR 0.323, p = 0.002), when controlling for stage. Surgery was significantly more likely to be correlated with stage I or II disease than chemotherapy/chemoradiation (68.5% vs 24.7%, p &lt; 0.0001 by Spearman method). There was no significant association between ITM and survival in patients with PDAC. Conclusions: Early treatment for CRC is associated with improved survival in this population, implying that treatment delays decrease the efficacy of curative-intent therapy. Evaluation of treatment modality in the rectal sub-group showed improved outcomes with neoadjuvant chemotherapy and chemoradiation, despite upfront surgery being associated with lower stage. The lack of association between TTI and survival in PDAC is likely related to the relatively poor outcomes observed with this disease and highlights the need for better screening and treatment for resectable disease. These results are notable because they suggest that a thorough workup and appropriate therapy may be more important than rapid treatment.

Phase 2 study of preoperative chemotherapy with nab-paclitaxel and gemcitabine followed by chemoradiation for borderline resectable or node-positive pancreatic ductal adenocarcinoma.

Neoadjuvant treatment with nab-paclitaxel and gemcitabine for potentially operable pancreatic adenocarcinoma has not been well studied in a prospective interventional trial and could down-stage tumors to achieve negative surgical margins. A single-arm, open-label phase 2 trial (NCT02427841) enrolled patients with pancreatic adenocarcinoma deemed to be borderline resectable or clinically node-positive from March 17, 2016 to October 5, 2019. Patients received preoperative gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on Days 1, 8, 15, every 28 days for two cycles followed by chemoradiation with 50.4 Gy intensity-modulated radiation over 28 fractions with concurrent fluoropyrimidine chemotherapy. After definitive resection, patients received four additional cycles of gemcitabine and nab-paclitaxel. The primary endpoint was R0 resection rate. Other endpoints included treatment completion rate, resection rate, radiographic response rate, survival, and adverse events. Nineteen patients were enrolled, with the majority having head of pancreas primary tumors, both arterial and venous vasculature involvement, and clinically positive nodes on imaging. Among them, 11 (58%) underwent definitive resection and eight of 19 (42%) achieved R0 resection. Disease progression and functional decline were primary reasons for deferring surgical resection after neoadjuvant treatment. Pathologic near-complete response was observed in two of 11 (18%) resection specimens. Among the 19 patients, the 12-month progression-free survival was 58%, and 12-month overall survival was 79%. Common adverse events were alopecia, nausea, vomiting, fatigue, myalgia, peripheral neuropathy, rash, and neutropenia. Gemcitabine and nab-paclitaxel followed by long-course chemoradiation represents a feasible neoadjuvant treatment strategy for borderline resectable or node-positive pancreatic cancer.

Surgical outcomes of gallbladder cancer: the OMEGA retrospective, multicentre, international cohort study

Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p=0.711 and HR 1.18 [0.95-1.46], p=0.13 respectively) or OS (HR 0.96 [0.79-1.17], p=0.67 and HR 1.48 [1.16-1.88], p=0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p=0.037) and OS (HR 1.26 [1.03-1.53], p=0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p<0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p<0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p<0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p=0.031) but not OS (HR 1.05 [0.91-1.22], p=0.48). Adjuvant and neoadjuvant treatments were infrequently used. In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Cambridge Hepatopancreatobiliary Department Research Fund.

Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating Tcells following neoadjuvant immunotherapy in head and neck cancer.

Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8+ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-β and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-β-driven CD103 expression on CD8+ Tcells is reversed following TGF-β neutralization invitro, implicating TGF-β in Tcell tissue retention and impaired systemic immunity. Transcriptional changes implicate Tcell receptor signaling and glutamine metabolism as important determinants of enhanced or reduced Tex treatment response, respectively. Our analysis illustrates physiological and metabolic changes underlying Tcell responses to NIT, highlighting the interplay between immunosuppression, tissue retention, and systemic anti-tumor immunity and suggest antagonism of Tcell tissue retention as a promising neoadjuvant treatment strategy.