Curative immune checkpoint inhibitors therapy in patients with mismatch repair-deficient locally advanced rectal cancer: a real-world observational study.

BACKGROUND: Sustained clinical complete remissions were reported in all of 23 mismatch repair deficient/microsatellite instable (dMMR/MSI) locally advanced rectal cancer (LARC) patients treated with dostarlimab alone in a recent phase II study. These results led to off-label use of dostarlimab or other immune checkpoint inhibitors (ICIs) in dMMR/MSI-LARC even before regulatory approval. The present study [STAR(t)-IT-REDUCE] describes the outcome of dMMR/MSI-LARC patients treated with ICI in Italy. MATERIALS AND METHODS: Investigator-initiated, observational, retrospective-cohort, multicentric study of ICI treatment in dMMR/MSI-LARC. Patients were eligible if treated with ≥1 ICI dose from July 2022 to December 2023 (date of approval of dostarlimab for this indication in Italy). RESULTS: Seventeen dMMR/MSI-LARC patients (13 of 17 treatment-naïve) were eligible. Fourteen patients completed 6 months of treatment, two discontinued after four doses and one after five doses because of immune-related pneumonia, social constraints, or non-oncological bowel obstruction, respectively. Overall, 16 of 17 assessable patients [94.1%; 95% confidence interval (CI) 69.24% to 99.69%, 'ITT analysis'] achieved complete clinical response (cCR). Ten of 11 treatment-naïve patients completing 6 months of treatment had cCR (90.9%; 95% CI 57.12% to 99.52%, 'per-protocol analysis'). One patient with near-CR underwent rectal surgery and minimal residual intramucosal tumor was found. With a median follow-up of 9.5 months, no local relapse occurred. One patient developed unconfirmed lung metastases. Two grade 3 and no grade 4 adverse events were reported. CONCLUSION: The present STAR(t)-IT-REDUCE study documents the immunoablative and curative activity of ICI monotherapy in dMMR/MSI-LARC. Toxicity and compliance issues inherent to real-world practice are limited and do not affect achievement of initial complete tumor response but may limit response duration.

Survival Analysis of Conversion Surgery in Borderline Resectable and Locally Advanced Unresectable Pancreatic Ductal Adenocarcinoma Addressing Selection and Immortal Time Bias: A Retrospective Single-Center Study.

BACKGROUND: The purpose of this study was to provide a detailed evaluation of the oncological advantages of surgery following neoadjuvant chemotherapy (NAC) for patients with borderline resectable (BR) or unresectable (UR) pancreatic ductal adenocarcinoma (PDAC), with a focus on minimizing biases. Recently, NAC has become the standard care for BR or UR locally advanced (UR-LA) PDAC, however, many studies have assessed survival benefits and favorable variables without consideration for biases, particularly immortal time bias. PATIENTS AND METHODS: This study included patients diagnosed with BR or UR-LA PDAC at Juntendo University Hospital from 2019 to 2022. To mitigate bias, we applied methods such as propensity score matching (PSM), time-dependent covariate Cox proportional hazard regression analysis (TDC), landmark analysis, and multivariable Cox proportional hazards regression model. RESULTS: The study analyzed 124 patients, dividing them into a surgery group (n = 57) and a chemotherapy-only group (n = 67). After PSM, there were 21 matched pairs. Survival analysis using TDC analysis showed that the surgery group had significantly better overall survival compared with the chemotherapy-only group in both the entire cohort and the matched pairs. Cox regression analysis of the entire cohort also revealed a similar superiority of surgery, while the landmark analysis showed varying results depending on the landmark setting. CONCLUSIONS: After careful adjustment for selection and immortal time biases, surgery following NAC appears to significantly extend survival in patients with BR or UR PDAC.

Para-aortic and pelvic lymphadenectomy in locally advanced cervical cancer with pelvic lymph node metastasis.

OBJECTIVE: This study sought to explore the efficiency of para-aortic and pelvic lymphadenectomy in the treatment of locally advanced cervical cancer (LACC) with pelvic lymph node (PLN) metastasis. METHODS: A total of 171 LACC patients with imaging-confirmed pelvic lymph node metastasis were included in this study. These patients were divided into two groups: the surgical staging group, comprising 58 patients who had received para-aortic and pelvic lymphadenectomy (surgical staging) along with concurrent chemoradiation therapy (CCRT), and the imaging staging group, comprising 113 patients who had received only CCRT. The two groups' progression-free survival (PFS), overall survival (OS) and treatment-related complications were compared. RESULTS: The surgical staging group started radiotherapy 10.2 days (range 9-12 days) later than the imaging staging group. The overall incidence of lymphatic cysts was 9.30%. In the surgical staging group, para-aortic lymph node metastasis was identified in 34.48% (20/58) of patients, while pathology-negative PLN was observed in 12.07% (7/58). Over a median follow-up period of 52 months, no significant differences in PFS and OS rates were found between the two groups (p > 0.05). Subgroup analysis of patients with lymph node diameters of ≥ 1.5 cm revealed a five-year PFS rate of 75.0% and an OS rate of 80.0% in the surgical staging group, compared to 41.5% and 50.1% in the imaging staging group, respectively, showing statistically significant differences (p = 0.022, HR:0.34 [0.13, 0.90] and p = 0.038, HR: 0.34 [0.12,0.94], respectively for PFS and OS). Additionally, in patients with two or more metastatic lymph nodes, the five-year PFS and OS rates were 69.2% and 73.1% in the surgical staging group, versus 41.0% and 48.4% in the imaging staging group, with these differences also being statistically significant (p = 0.025, HR: 0.41[0.19,0.93] and p = 0.046, HR: 0.42[0.18,0.98], respectively). CONCLUSION: Performing surgical staging before CCRT is safe and delivers accurate lymph node details crucial for tailoring radiotherapy. This approach merits further investigation, particularly in women with pelvic lymph nodes measuring 1.5 cm or more in diameter or patients with two or more imaging-positive PLNs.

A Phase II Clinical Study on Apatinib Plus Vinorelbine in Refractory HER2-Negative Breast Cancer and its Metabolic Implications of Drug Resistance.

BACKGROUND: Apatinib, a tyrosine-kinase inhibitor that targets the vascular endothelial growth factor receptor 2, contributes to the inhibition of angiogenesis. Vinorelbine, a semisyn-thetic vinca alkaloid, primarily inhibits metaphase mitosis of cancer cells through its interactions with tubulin. This study aimed to evaluate whether apatinib combined with vinorelbine was ef-fective and safe for refractory human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who failed taxanes and/or anthracycline and analyze the possible mechanism of drug resistance through metabolomic analysis. METHODS: Eligible patients were HER2-negative, inoperable, locally advanced, or metastatic breast cancer patients who progressed after at least one chemotherapy regimen in this present prospective phase II study. Patients took oral apatinib (250-500 mg/day) plus intravenous infusion of vinorelbine (25 mg/m2 on day 1, day 8 at 3-week intervals). Objective response rate (ORR) was our primary endpoint, while disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity were our secondary endpoints. The exploratory purpose was to identify biomarkers or drug resistance mechanisms through metabolomics changes before and after the combination therapy. RESULTS: Between September, 2019 and June, 2022, a total of 34 patients were included. ORR and DCR were 32.4% (11/34) and 85.3% (29/34), respectively. The median PFS was 5.0 months (95% CI, 3.766-6.234), while the median OS was 13.0 months (95% CI, 8.714-17.286). Side effects included hematologic toxicity, gastrointestinal reaction, and sinus tachycardia, which were mild to moderate. The mainly disturbed metabolic pathways were the cAMP signaling pathway, the alanine/aspartate/glutamate metabolism, the central carbon metabolism in cancer, the beta-alanine metabolism, the butanoate metabolism, and the glyoxylate and dicarboxylate metabolism, which may lead to the resistance of patients to this combination therapy. CONCLUSION: Apatinib combined with vinorelbine is effective and safe in patients with locally advanced or metastatic refractory HER2-negative breast cancer. The findings of this study con-tribute to a better understanding of the metabolic effect of apatinib and vinorelbine therapy.

A case of neoadjuvant targeted therapy with pralsetinib for locally advanced lung adenocarcinoma with RET fusion mutation.

This case report details the successful treatment of a 68-year-old male patient with locally advanced RET-rearranged lung adenocarcinoma using neoadjuvant pralsetinib. The patient initially presented with a suspicious right upper lobe nodule, which was later diagnosed as lung adenocarcinoma following genetic testing that revealed a RET exon 12 fusion. After 2 months of neoadjuvant treatment with pralsetinib, a significant radiological response was observed, with a reduction in tumor size and metabolic activity. Subsequently, the patient underwent video-assisted thoracoscopic right upper lobectomy and mediastinal lymph node dissection. Postoperative pathological analysis revealed a major pathological response, with only 5% residual tumor cells in the primary lesion and no viable tumor cells in the lymph nodes. Postoperative pathological staging of TNM was ypT1aN0M0, stage IA1(AJCC, 8th edition). The patient recovered well after surgery, demonstrating the potential efficacy of neoadjuvant pralsetinib in locally advanced RET-rearranged lung adenocarcinoma. However, further clinical validation is required to establish the role of neoadjuvant targeted therapy and postoperative adjuvant therapy in this patient population.

Maximum standardised uptake value of positron emission tomography as a predictor of oesophageal cancer outcomes.

OBJECTIVES: This study aimed to analyse the value of pre-operative 18F-fluorodeoxyglucose positron emission tomography (PET)-computed tomography that can predict tumour pathological complete response, tumour histology grade, overall survival, and recurrence-free survival in patients with locally advanced oesophageal squamous cell carcinoma who underwent neoadjuvant chemoradiotherapy (NCRT) followed by surgery. METHODS: We retrospectively reviewed the cases of patients with locally advanced oesophageal squamous cell carcinoma undergoing NCRT followed by surgery. Patients who did not undergo PET within 3 months of surgery were excluded. We set a pre-operative PET maximum standardised uptake value (SUVmax) of > 5 as the threshold and classified the patients into two groups. We analysed the tumour response and histology grade, and compared the overall survival and recurrence-free survival between the two groups. RESULTS: This cohort included 92 patients with oesophageal squamous cell carcinoma who underwent NCRT followed by surgery; 49 patients had a pre-operative PET SUVmax < 5, and 43 patients had a pre-operative PET SUVmax > 5. The patients' pre-operative PET SUVmax correlated with tumour histology, ypT stage, and tumour response. Patients with a pre-operative SUVmax < 5 had better 2-year-overall survival (78% vs. 62%, P < 0.05) and 2-year recurrence-free survival (62% vs. 34%, P < 0.05) than those with a pre-operative SUV > 5. CONCLUSIONS: Pre-operative SUVmax may be useful to predict tumour response, survival, and recurrence in patients with locally advanced oesophageal squamous cell carcinoma who undergo NCRT followed by surgery.

Outcomes and failure patterns after chemoradiotherapy for locally advanced rectal cancer with positive lateral pelvic lymph nodes: a propensity score-matched analysis.

PURPOSE: This study aimed to use propensity score matching (PSM) to explore the long-term outcomes and failure patterns in locally advanced rectal cancer (LARC) patients with positive versus negative lateral pelvic lymph node (LPLN). MATERIALS AND METHODS: Patients with LARC were retrospectively divided into LPLN-positive and LPLN-negative groups. Clinical characteristics were compared between the groups using the chi-square test. PSM was applied to balance these differences. Progression-free survival (PFS) and overall survival (OS), and local-regional recurrence (LRR) and distant metastasis (DM) rates were compared between the groups using the Kaplan-Meier method and log-rank tests. RESULTS: A total of 651 LARC patients were included, 160 (24.6%) of whom had positive LPLN and 491 (75.4%) had negative LPLN. Before PSM, the LPLN-positive group had higher rates of lower location (53.1% vs. 43.0%, P = 0.025), T4 stage (37.5% vs. 23.2%, P = 0.002), mesorectal fascia (MRF)-positive (53.9% vs. 35.4%, P < 0.001) and extramural venous invasion (EMVI)-positive (51.2% vs. 27.2%, P < 0.001) disease than the LPLN-negative group. After PSM, there were 114 patients for each group along with the balanced clinical factors, and both groups had comparable surgery, pathologic complete response (pCR), and ypN stage rates. The median follow-up was 45.9 months, 3-year OS (88.3% vs. 92.1%, P = 0.276) and LRR (5.7% vs. 2.8%, P = 0.172) rates were comparable between LPLN-positive and LPLN-negative groups. Meanwhile, despite no statistical difference, 3-year PFS (78.8% vs. 85.9%, P = 0.065) and DM (20.4% vs. 13.3%, P = 0.061) rates slightly differed between the groups. 45 patients were diagnosed with DM, 11 (39.3%) LPLN-positive and 3 (17.6%) LPLN-negative patients were diagnosed with oligometastases (P = 0.109). CONCLUSIONS: Our study indicates that for LPLN-positive patients, there is a tendency of worse PFS and DM than LPLN-negative patients, and for this group patients, large samples are needed to further confirm our conclusion.

Survival benefits of radiotherapy in locally advanced unresectable and metastatic pancreatic cancer: a single-institution cohort and SEER database analysis.

Background: Chemotherapy (CT) remains the primary treatment for locally advanced unresectable pancreatic cancer (LAUPC) and metastatic pancreatic cancer (MPC). The role of radiotherapy (RT) in these conditions remains unclear. This study compares the outcomes of CT alone versus CT combined with RT (combined-modality therapy [CMT]) in LAUPC and MPC patients. Materials and methods: We conducted a retrospective analysis of LAUPC and MPC patients treated with either CT or CMT from a single institution and Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier curves and Cox hazards models evaluated the association between treatment modalities and overall survival (OS). Propensity score matching (PSM) ensured balanced comparisons. Landmark analysis addressed immortal time bias. Subgroup analyses were based on clinical characteristics. eXtreme Gradient Boosting (XGBoost) and Shapley Additive Explanations (SHAP) assessed outcome prediction and influence of significant predictors. Results: The study included 102 patients receiving CMT and 155 receiving CT at single institution, along with 1733 CMT and 9310 CT patients from the SEER dataset. In the single-institution cohort, CMT showed superior survival compared to CT both before (median OS: 20.5 vs. 11.5 months, hazard ratio [HR]: 0.47, 95% CI: 0.34-0.65, P=0.001) and after PSM (median OS: 22.2 vs. 11.8 months, HR: 0.49, 95% CI: 0.30-0.79, P=0.003). Multivariate analyses confirmed that CMT was independently associated with improved OS both before (HR: 0.54, 95% CI: 0.38-0.77, P=0.001) and after PSM (HR: 0.45, 95% CI: 0.27-0.73, P=0.001). Landmark analysis indicated better OS for patients receiving CMT compared to CT alone. Subgroup analysis revealed an OS benefit for CMT across most subgroups. SHAP value analysis indicated that CMT was the most significant contributor to survival outcomes. SEER database validation confirmed these findings. Conclusions: This study demonstrates that CMT significantly improves OS in LAUPC and MPC patients compared to CT alone. Integrating RT with CT could be beneficial for treating LAUPC and MPC.

Comparison of pathologic response and survival outcomes between neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant immunochemotherapy (nICT) in patients with locally advanced esophageal squamous cell carcinoma: a propensity score-matched analysis.

BACKGROUND: In locally advanced, operable esophageal squamous cell carcinoma (ESCC), neoadjuvant immunochemotherapy (nICT) has shown results that are somewhat comparable to those of standard neoadjuvant chemoradiotherapy (nCRT). The impact of these neoadjuvant treatments on survival outcomes, however, has yet to be elucidated. METHODS: This study included 489 patients with locally advanced ESCC who underwent surgery at Sichuan Cancer Hospital after receiving neoadjuvant treatment between June 2017 and September 2023. Patients were categorized into nCRT and nICT groups based on whether they received neoadjuvant treatment. To mitigate potential biases and balance covariates between the two cohorts, 1:2 propensity score matching (PSM) was conducted using a caliper width of 0.05. RESULTS: After PSM, the baseline characteristics of the 360 patients remained balanced between the two groups. The findings indicated a superior pathological response in the nCRT group, as evidenced by significantly greater rates of complete response (32.87% vs 14.58%, P < 0.001) and favorable tumor regression grade (TRG), as well as reduced ypT stages and less perineural and angioinvasion, despite comparable ypN stages. Despite the improvement in complete pathological response (pCR) in the nCRT group, the 3-year disease-free survival (DFS) and overall survival (OS) rates did not significantly differ between the groups (DFS: 58.32% vs 56.16%, P = 0.67; OS: 69.96% vs 71.99%, P = 0.99). Crucially, The nICT group showed a lower incidence of grade 3 and 4 adverse events in Leukopenia (2.8% vs 29%; P < 0.001) and Neutropenia (2.8% vs 24%; P < 0.001) during neoadjuvant treatment, comparing with nCRT group. CONCLUSIONS: Our preliminary findings suggest that nICT followed by surgery offers comparable survival rates to nCRT, despite being less effective in pathologic outcomes. Nonetheless, nICT is a safe and feasible strategy for locally advanced ESCC, warranting further exploration to understand its impact on long-term survival.

Achieving a Pathologic Complete Response for Locally Advanced Esophageal Adenocarcinoma Using Cone-Beam Computed Tomography-Based Online Adaptive Radiotherapy.

Neo-adjuvant chemoradiotherapy (CRT) and perioperative chemotherapy are different strategies for treating non-metastatic esophageal cancer (EC). The advantages of neo-adjuvant therapies are primarily seen in patients who achieve a pathologic complete response (pCR) and therefore show higher survival rates and better prognosis. In general, less than one-third of patients with EC experience pCR after neo-adjuvant therapies; however, patients with esophageal adenocarcinoma (AC) demonstrate lower rates of pCR compared to those with esophageal squamous cell carcinoma (SCC), respectively. Herein, we describe two cases of locally advanced esophageal AC treated with cone-beam computed tomography (CBCT)-based online adaptive radiotherapy (ART) on the ETHOS platform. Both patients received CRT with 50.4 Gy in 28 fractions, combined with weekly carboplatin and paclitaxel. For each fraction, we evaluated scheduled and adapted plans using dose-volume histogram (DVH) data, and patients were treated with the superior plan. We prioritized ensuring optimal coverage of the planning target volume (PTV) over limiting the dose to organs at risk (OARs) when selecting the superior treatment plan. In this instance, we present the translation of superior dosimetric data into clinical benefits, as evidenced by an excellent pathologic response.

Toripalimab combined with definitive chemoradiotherapy for locally advanced cervical squamous cell carcinoma patients (TRACE): A single-arm, phase I/II trial.

PURPOSE: This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma. METHODS AND MATERIALS: Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m2, once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS). RESULTS: All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%. CONCLUSIONS: Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer.

Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for initially unresectable locally advanced colon cancer: short-term outcomes of an open-label, single-centre, randomised, controlled, phase 3 trial.

Background: Neoadjuvant chemotherapy (NACT) is commonly used to downstage the tumor in locally advanced colon cancer (LACC) and improve the R0 resection rate. Neoadjuvant chemoradiotherapy (NACRT) is the standard treatment for locally advanced rectal and esophageal cancers, but its benefits in LACC remain poorly understood. This study aimed to compare the effects and safety of NACRT and NACT on R0 resection and survival rates in initially unresectable LACC. Methods: This was an open-label, single-center, randomized, controlled trial conducted between May 11, 2019 and May 30, 2022. Forty-five patients with initially unresectable LACC were randomly allocated to the NACT (control, n = 20) or NACRT (research, n = 25) group. The NACT group received XELOX (oxaliplatin 100-130 mg/m2, qd, d1, every 3 weeks; and capecitabine 1000 mg/m2, bid, d1-d14, every 3 weeks) for 4 cycles. The NACRT group, in addition to chemotherapy, received daily irradiation (GTV 45-50 Gy/25 F; CTV 42.5-45 Gy/25 F). Surgery was scheduled 6-12 weeks after neoadjuvant treatment and adjuvant chemotherapy was administered if the patient developed resectable LACC. The primary endpoint was the 5-year overall survival (OS) rate. The secondary outcomes included the 3-year progression-free survival (PFS) and R0 resection rates. This study was registered with ClinicalTrials.gov (NCT03970694). Findings: In short-term outcome analysis, NACRT significantly improved the R0 resection rate (80% for NACRT vs. 20% for NACT, P < 0.001). The NACRT and NACT groups had a 3-year OS of 87.6% and 75% (P = 0.037) and a 3-year PFS of 76% and 45% (P = 0.049), respectively. The 5-year OS was not reached. In the NACRT group, no local or regional recurrence was observed in patients who underwent surgery during the follow-up period, compared to two patients in the NACT group. Both NACT and NACRT were well tolerated, with no significant differences in severe adverse events. The most commonly observed grade 3-4 AE was myelosuppression (39% for NACRT and 47% for NACT, P = 0.609). No grade 5 AEs were observed between the two groups. Interpretation: Adding radiation to NACT increased the R0 resection rate, prolonged the PFS, and potentially improved OS in selected patients with initially unresectable LACC. The trial findings indicate that this approach is safe, feasible, and may confer a survival benefit. Funding: This study was supported by grants from the National Natural Science Foundation of China (82373213 to Dr Gao, 82202952 to Dr Wang); and the Natural Science Foundation of Guangdong Province (2023A1515010290 to Dr Chang). Funding sources were not involved in the study design, data collection, analysis and interpretation, writing of the report, or decision to submit the article for publication.

Node-sparing modified short-course Radiotherapy Combined with CAPOX and Tislelizumab for locally Advanced MSS of Middle and low rectal Cancer (mRCAT): an open-label, single-arm, prospective, multicentre clinical trial.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision is a standard treatment for locally advanced rectal cancer. Mismatch repair-deficient locally advanced rectal cancer (LARC) was highly sensitive to PD-1 blockade. However, most rectal cancers are microsatellite stable (MSS) or mismatch repair-proficient (pMMR) subtypes for which PD-1 blockade is ineffective. Radiation can trigger the activation of CD8 + T cells, further enhancing the responses of MSS/pMMR rectal cancer to PD-1 blockade. Radioimmunotherapy offers a promising therapeutic modality for rectal cancer. Progenitor T exhausted cells are abundant in tumour-draining lymph nodes and play an important role in immunotherapy. Conventional irradiation fields include the mesorectum and regional lymph nodes, which might cause considerable damage to T lymphocytes and radiation-induced fibrosis, ultimately leading to a poor response to immunotherapy and rectal fibrosis. This study investigated whether node-sparing modified short-course irradiation combined with chemotherapy and PD-1 blockade could be effective in patients with MSS/ pMMR LARC. METHODS: This was a open-label, single-arm, multicentre, prospective phase II trial. 32 LARC patients with MSS/pMMR will receive node-sparing modified short-course radiotherapy (the irradiated planned target volume only included the primary tumour bed but not the tumour-draining lymph nodes, 25 Gy/5f, 5 Gy/f) followed by CAPOX and tislelizumab. CAPOX and tislelizumab will be started two days after the completion of radiotherapy: oxaliplatin 130 mg/m2 intravenous infusion, day 1; capecitabine 1000 mg/m2 oral administration, days 1-14; and tislelizumab 200 mg, intravenous infusion, day 1. There will be four 21-day cycles. TME will be performed at weeks 14-15. We will collect blood, tumour, and lymphoid specimens; perform flow cytometry and in situ multiplexed immunofluorescence detection; and analyse the changes in various lymphocyte subsets. The primary endpoint is the rate of pathological complete response. The organ preservation rate, tumour regression grade, local recurrence rate, disease-free survival, overall survival, adverse effects, and quality of life will also be analysed. DISCUSSION: In our research, node-sparing modified radiotherapy combined with immunotherapy probably increased the responsiveness of immunotherapy for MSS/pMMR rectal cancer patients, reduced the occurrence of postoperative rectal fibrosis, and improved survival and quality of life. This is the first clinical trial to utilize a node-sparing radiation strategy combined with chemotherapy and PD-1 blockade in the neoadjuvant treatment of rectal cancer, which may result in a breakthrough in the treatment of MSS/pMMR rectal cancer. TRIAL REGISTRATION: This study was registered at www. CLINICALTRIALS: gov . TRIAL REGISTRATION NUMBER: NCT05972655. Date of registration: 31 July 2023.

CapeOX as neoadjuvant chemotherapy for locally advanced rectal cancer: might less be more?

BACKGROUND: Locally advanced rectal cancer (LARC) poses unique challenges in treatment, with current neoadjuvant chemoradiotherapy (NA-CRT) showing limitations. The CapeOX regimen emerges as a potential less aggressive neoadjuvant chemotherapy (NAC) for LARC. METHODS: We conducted a retrospective study involving treatment-naïve patients with LARC from March 2014 to March 2021 who received 2-4 cycles of CapeOX NAC followed by radical surgery. Treatment response was evaluated using tumor regression grade (TRG), MRI-based TRG (MRI-TRG), and Neoadjuvant Rectal (NAR) score. RESULTS: 94.7% of patients experienced symptom improvement and 96.4% achieved sphincter-preserving surgery. Post-NAC showed significant tumor regression and MRI confirmed a tumor length reduction (P < 0.001). Clinical and pathological staging discrepancies post-NAC suggest broader therapeutic advantages. 5-year overall and disease-free survival rates were 78.4% and 73.4%. NAR scores provided better prognostic accuracy than MRI-TRG. CONCLUSION: CapeOX NAC presents notable benefits for LARC patients and its clinical significance may be underestimated. The NAR score demonstrates superior prognostic value over MRI-TRG.

Combination of intravoxel incoherent motion histogram parameters and clinical characteristics for predicting response to neoadjuvant chemoradiation in patients with locally advanced rectal cancer.

OBJECTIVE: To explore the value of histogram parameters derived from intravoxel incoherent motion (IVIM) for predicting response to neoadjuvant chemoradiation (nCRT) in patients with locally advanced rectal cancer (LARC). METHODS: A total of 112 patients diagnosed with LARC who underwent IVIM-DWI prior to nCRT were enrolled in this study. The true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and microvascular volume fraction (f) calculated from IVIM were recorded along with the histogram parameters. The patients were classified into the pathological complete response (pCR) group and the non-pCR group according to the tumor regression grade (TRG) system. Additionally, the patients were divided into low T stage (yp T0-2) and high T stage (ypT3-4) according to the pathologic T stage (ypT stage). Univariate logistic regression analysis was implemented to identify independent risk factors, including both clinical characteristics and IVIM histogram parameters. Subsequently, models for Clinical, Histogram, and Combined Clinical and Histogram were constructed using multivariable binary logistic regression analysis for the purpose of predicting pCR. The area under the receiver operating characteristic (ROC) curve (AUCs) was employed to evaluate the diagnostic performance of the three models. RESULTS: The values of D_ kurtosis, f_mean, and f_ median were significantly higher in the pCR group compared with the non-pCR group (all P < 0.05). The value of D*_ entropy was significantly lower in the pCR group compared with the non-pCR group (P < 0.05). The values of D_ kurtosis, f_mean, and f_ median were significantly higher in the low T stage group compared with the high T stage group (all P < 0.05). The value of D*_ entropy was significantly lower in the low T stage group compared with the high T stage group (P < 0.05). The ROC curves indicated that the Combined Clinical and Histogram model exhibited the best diagnostic performance in predicting the pCR patients with AUCs, sensitivity, specificity, and accuracy of 0.916, 83.33%, 85.23%, and 84.82%. CONCLUSIONS: The histogram parameters derived from IVIM have the potential to identify patients who have achieved pCR. Moreover, the combination of IVIM histogram parameters and clinical characteristics enhanced the diagnostic performance of IVIM histogram parameters.

Prediction and validation of pathologic complete response for locally advanced rectal cancer under neoadjuvant chemoradiotherapy based on a novel predictor using interpretable machine learning.

BACKGROUND: Precise evaluation of pathological complete response (pCR) is essential for determining the prognosis of patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (NCRT) and can offer clues for the selection of subsequent treatment strategies. Most current predictive models for pCR focus primarily on pre-treatment factors, neglecting the dynamic systemic changes that occur during neoadjuvant chemoradiotherapy, and are constrained by low accuracy and lack of integrity. PURPOSE: This study devised a novel predictor of pCR using dynamic alterations in systemic inflammation-nutritional marker indexes (SINI) during neoadjuvant therapy and developed a machine-learning model to predict pCR. METHODS: Two cohorts of patients with LARC from center one from 2012 to 2017 and from center two from 2020 to 2023 were integrated for analysis. This study compared dynamic changes in blood indexes before and after neoadjuvant therapy and surgical operation. A least absolute shrinkage and selection operator (LASSO) regression analysis was conducted to mitigate collinearity and identify key indexes, constructing the SINI. Univariate and multiple logistic regression analyses were used to identify the independent risk factors associated with pCR. Additionally, 10 machine learning algorithms were employed to develop predictive models to assess risk. The hyperparameters of the machine learning models were optimized using a random search and 10-fold cross-validation. The models were assessed by examining various metrics, including the area under the receiver operating characteristic curves (AUC), the area under the precision-recall curve (AUPRC), decision curve analysis, calibration curves, and the precision and accuracy of the internal and external validation cohorts. Additionally, Shapley's additive explanations (SHAP) were employed to interpret the machine learning models. RESULTS: The study cohort comprised 677 patients from the center one and 224 patients from the center two. Six key indexes were identified, and a predictive index, SINI, was constructed. Univariate and multiple logistic regression analyses revealed that SINI, clinical T-stage, clinical N-stage, tumor size, and the distance from the anal verge were independent risk factors for pCR in patients with LARC following NCRT. The mean AUC value of the extreme gradient boosting (XGB) model in the 10-fold cross-validation of the training set was 0.877. The XGB model demonstrated superior performance in the internal and external validation sets. Specifically, in the internal test set, the XGB model achieved an AUC of 0.86, AUPRC of 0.707, accuracy of 0.82, and precision of 0.80. In the external validation set, the XGB model exhibited an AUC of 0.83, AUPRC of 0.702, accuracy of 0.81, and precision of 0.81. Additionally, the predictions generated by the XGB model were analyzed using SHAP. CONCLUSION: This study involved developing and validating an XGB model using SINI to predict pCR in patients with LARC. Besides, a SINI-based machine learning model shows promise in accurately predicting pCR following NCRT in patients with resectable LARC, offering valuable insights for personalized treatment approaches.

A phase II study of daily carboplatin plus irradiation followed by durvalumab therapy for older adults (≥75 years) with unresectable III non-small-cell lung cancer and performance status of 2: NEJ039A.

BACKGROUND: Standard care for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) involves chemoradiotherapy followed by durvalumab. The clinical significance of durvalumab after chemoradiotherapy in patients with LA-NSCLC having a performance status of 2 or aged ≥75 years, however, remains unclear. Therefore, we investigated the clinical benefit of durvalumab after daily carboplatin plus thoracic concurrent radiotherapy. PATIENTS AND METHODS: In this prospective phase II study, daily low-dose carboplatin (30 mg/m2) was administered before radiotherapy for the first 20 fractions and concurrent radiotherapy (60 Gy) followed by durvalumab. The primary endpoint was 12 months progression-free survival (PFS) rate from durvalumab initiation. The secondary endpoints included rate of therapeutic completion, PFS, overall survival, objective response rate, and safety. RESULTS: Of 86 patients who underwent chemoradiotherapy with daily carboplatin from September 2019 to October 2021, 61 (70.9%) received durvalumab consolidation. The performance status was 0, 1, and 2 in 28 (45.9%), 26 (42.6%), and 7 (11.5%) patients, respectively. The rate of therapeutic completion for durvalumab was 26.2% (16/61). The PFS rate of 12 months after durvalumab initiation was 51.0%, indicating that the primary endpoint was achieved because the expected value of 35% calculated from previous studies was exceeded. The objective response rate after chemoradiotherapy and durvalumab was 47.0% and 57.4%, respectively. The median PFS and overall survival were 12.3 and 28.1 months, respectively. The most common adverse event in grades 3 or 4 was pneumonitis (8.2%). One patient died because of interstitial pneumonitis. CONCLUSIONS: Durvalumab consolidation after daily carboplatin with radiotherapy was effective and tolerable for LA-NSCLC vulnerable patients.

Radiomics-based machine learning models for differentiating pathological subtypes in cervical cancer: a multicenter study.

Purpose: This study was designed to determine the diagnostic performance of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) radiomics-based machine learning (ML) in the classification of cervical adenocarcinoma (AC) and squamous cell carcinoma (SCC). Methods: Pretreatment 18F-FDG PET/CT data were retrospectively collected from patients who were diagnosed with locally advanced cervical cancer at two centers. Radiomics features were extracted and selected by the Pearson correlation coefficient and least absolute shrinkage and selection operator regression analysis. Six ML algorithms were then applied to establish models, and the best-performing classifier was selected based on accuracy, sensitivity, specificity, and area under the curve (AUC). The performance of different model was assessed and compared using the DeLong test. Results: A total of 227 patients with locally advanced cervical cancer were enrolled in this study (N=136 for the training cohort, N=59 for the internal validation cohort, and N=32 for the external validation cohort). The PET radiomics model constructed based on the lightGBM algorithm had an accuracy of 0.915 and an AUC of 0.851 (95% confidence interval [CI], 0.715-0.986) in the internal validation cohort, which were higher than those of the CT radiomics model (accuracy: 0.661; AUC: 0.513 [95% CI, 0.339-0.688]). The DeLong test revealed no significant difference in AUC between the combined radiomics model and the PET radiomics model in either the training cohort (z=0.940, P=0.347) or the internal validation cohort (z=0.285, P=0.776). In the external validation cohort, the lightGBM-based PET radiomics model achieved good discrimination between SCC and AC (AUC = 0.730). Conclusions: The lightGBM-based PET radiomics model had great potential to predict the fine histological subtypes of locally advanced cervical cancer and might serve as a promising noninvasive approach for the diagnosis and management of locally advanced cervical cancer.

Assessment of Outcomes by Intention-to-Treat Comparison for Locally Advanced Pancreatic Cancer: A Population-Derived Cohort Study.

BACKGROUND: The overall treatment response among patients with locally advanced pancreatic cancer (LAPC) is poorly understood as most studies report solely on resected patients. We aimed to investigate the outcomes in patients with LAPC as an intention-to-treat-analysis from the time of diagnosis from a complete source population. PATIENTS AND METHODS: An observational cohort study in a population-defined region within a universal healthcare system. All consecutive patients discussed at multi-disciplinary tumour board (MDT), aged ≥ 18 years and diagnosed with LAPC were included. Exposure was set as recommended treatment by MDT (i.e. upfront surgery, neoadjuvant therapy, palliative treatment or best supportive care). Outcome measures were overall survival analysed by Kaplan-Meier survival estimates and multivariable analyses using logistic regression for odds ratios (OR) and Cox proportional hazard analysis for hazard ratios (HR). RESULTS: In total, 8803 MDT events (6055 unique patients) with pancreatic disease were held during the study period. Some 1436 (24%) had pancreatic cancer, of which 162 (11%) had LAPC and 134 met the population-defined criteria. In overall survival analyses, the patients who were recommended neoadjuvant therapy (± surgery) demonstrated no significant difference to palliative chemotherapy (median 11.0 months vs. 11.8 months; p = 0.226). In multivariable analysis, adjusted OR for overall survival comparing the treatment groups was 0.27 (95% CI 0.02-3.29, p = 0.306) and Cox proportional HR 0.96 (95% CI 0.58-1.59, p = 0.865). CONCLUSIONS: In patients with LAPC, survival was not statistically different between those recommended for attempt at neoadjuvant (± surgery) compared with those recommended palliative chemotherapy. The findings suggest that conversion/downstaging chemotherapy is successful in only a select few.

Neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer.

OBJECTIVE: This study aimed to explore the efficacy of neoadjuvant chemotherapy plus programmed death-1 (PD-1) inhibitor camrelizumab for the treatment of locally advanced esophageal cancer. METHODS: This was a retrospective analysis. 87 patients with locally advanced esophageal cancer were included who received neoadjuvant chemotherapy plus immunotherapy between June 2018 and April 2021 in our oncology department. The postoperative clinical outcomes and varying expressions of PD-1 were evaluated in all enrolled patients. RESULTS: The post-treatment disease control rate (DCR) was 83.91%, and the objective response rate (ORR) was 59.77%. Cancer tissues were categorized based on PD-1 expression into PD-1 negative (39 cases) and PD-1 positive (33 cases), with a PD-1 positive rate of 45.83%. Patients with PD-1-positive tumors exhibited a significantly higher ORR compared to those with PD-1-negative tumors, although DCRs did not differ significantly between the groups. The 12-month progression-free survival rate was significantly higher in PD-1-positive patients. In contrast, no significant difference was found in the 12-month overall survival rate between the two groups. The incidence of grade III adverse events was 10.34%, and no grade IV or higher adverse events were observed. CONCLUSION: In patients with locally advanced esophageal cancer, neoadjuvant chemotherapy plus immunotherapy demonstrates good efficacy and safety, especially for PD-1-positive patients, and significantly improves prognosis.