Effect of immune-modulating metronomic capecitabine as an adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma.

INTRODUCTION: Metronomic capecitabine used as an adjuvant therapy improves survival in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This therapeutic approach may also contribute to improving immune function, consequently enhancing overall therapeutic efficacy. AIM: We aimed to evaluate the effect of metronomic capecitabine as adjuvant therapy on immune function and survival in cases of LA-NPC. SUBJECTS AND METHODS: 28 patients with LA-NPC were enrolled in the study and equally assigned to two groups of 14 each: experimental and control group. The experimental group received induction chemotherapy + concurrent chemotherapy + adjuvant chemotherapy as well as oral capecitabine at a dose of 650 mg/m² of body surface area twice daily for 1 year, with the option to discontinue in case of intolerance. The control group did not receive additional chemotherapy or targeted drugs after the induction chemotherapy + concurrent chemoradiotherapy; however, they were followed up regularly. Changes in immune function and survival were compared between the two groups. RESULTS: The median follow-up time was 43.5 months. One year after adjuvant chemotherapy, the experimental group showed higher levels of CD8 + cells, CD28 + CD8 + cells, and activated CD8 + cells compared to the control group (P < 0.05). The CD4/CD8 ratio and proportion of monocyte-derived dendritic cells were also higher in the experimental group than in the control group, but the difference was not statistically significant (P ≥ 0.05). Comparisons of 3-year overall survival, local-regional recurrence-free survival, progression-free survival, and distant metastasis-free survival between the two groups showed percentages of 92.9% vs. 78.6%, 92.9% vs. 92.9%, 78.6% vs. 71.4%, and 85.7% vs. 0.78 0.6% respectively, but these differences were not significant (P > 0 0.05 ). CONCLUSION: Metronomic capecitabine chemotherapy was observed to induce an immunomodulatory effect in LA-NPC. TRIAL REGISTRATION: NCT02958111, date of registration 04-11-2016.

A phase I/II study of nintedanib and capecitabine for refractory metastatic colorectal cancer.

BACKGROUND: Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. METHODS: Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of .25. RESULTS: Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. CONCLUSIONS: The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT02393755.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. METHODS: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. INTERPRETATION: Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. FUNDING: Daiichi Sankyo and AstraZeneca.

[Clinical efficacy of induction chemoimmunotherapy for locally advanced hypopharyngeal carcinoma: a prospective phase â ¡ study].

Objective: To evaluate the objective response rate (ORR) of induction chemoimmunotherapy with camrelizumab plus TPF (docetaxel, cisplatin, and capecitabine) for locally advanced hypopharyngeal squamous cell carcinoma (LA HSCC) and potential predictive factors for ORR. Methods: A single-center, prospective, phase 2 and single-arm trial was conducted for evaluating antitumor activity of camrelizumab+TPF(docetaxel+cisplatin+capecitabine) for LA HSCC between May 21, 2021 and April 15, 2023, patients admitted to the Eye & ENT Hospital affiliated with Fudan University. The primary endpoint was ORR, and enrolled patients with LA HSCC at T3-4N0-3M0 received induction chemoimmunotherapy for three cycles: camrelizumab 200 mg day 1, docetaxel 75 mg/m2 day 1, cisplatin 25 mg/m2 days 1-3, and capecitabine 800 mg/m2 days 1-14. Patients were assigned to radioimmunotherapy when they had complete response or partial response (PR)>70% (Group A), or assigned to surgery plus adjuvant radiotherapy/chemoradiotherapy when they had PR≤70% (Group B), and the responses were defined by using tumor volume evaluation system. Tumor diameter was also used to assess the treatment responses by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Use SPSS 23.0 software was used to analyze the data. Results: A total of 51 patients were enrolled who underwent the induced chemoimmunotherapy for three cycles, and all were males, aged 35-69 years old. After three cycles of induction immunochemotherapy, 42 (82.4%) patients existed in Group A (complete response or PR>70%) and 9 patients (17.6%) in Group B (PR≤70%), the ORR was 82.4%. The primary endpoint achieved expected main research objectives. Compared to the patients of Group A, the patients of Group B showed the higher T stage and the larger volume of primary tumor before induced immunochemotherapy, and also had the less regression of tumor volume after induced immunochemotherapy (all P<0.05). The optimal cutoff value of pre-treatment tumor volume for predicting ORR was 39 cm3. The T stage (OR=12.71, 95%CI: 1.4-112.5, P=0.022) and the volume (OR=7.1, 95%CI: 1.4-36.8, P=0.018) of primary tumor were the two main factors affecting ORR rate of induction chemoimmunotherapy. Conclusion: The induction chemoimmunotherapy with camrelizumab plus TPF shows an encouraging antitumor efficacy in LA HSCC.

Efficacy of adjuvant capecitabine in residual triple negative breast cancer: a multicenter observational Turkish Oncology Group (TOG) study.

BACKGROUND: Triple negative breast cancer (TNBC) is characterized by high rates of recurrence, especially in patients with residual disease after neoadjuvant chemotherapy (NAC). Capecitabine is being used as standard adjuvant treatment in residual TNBC. We aimed to investigate the real-life data regarding the efficacy of capecitabine in residual TNBC. DESIGN AND METHODS: In this retrospective multicenter study, TNBC patients with residual disease were evaluated. Patients, who received standard anthracycline and taxane-based NAC and adjuvant capecitabine were eligible. Overall survival (OS), disease free survival (DFS) and toxicity were analyzed. RESULTS: 170 TNBC patients with residual disease were included. Of these, 62.9% were premenopausal. At the time of analysis, the recurrence rate was 30% and death rate was 18%. The 3-year DFS and OS were 66% and 74%, respectively. In patients treated with adjuvant capecitabine, residual node positive disease stood out as an independent predictor of DFS (p = 0.024) and OS (p = 0.032). Undergoing mastectomy and the presence of T2 residual tumor was independent predictors of DFS (p = 0.016) and OS (p = 0.006), respectively. CONCLUSION: The efficacy of capecitabine was found lower compared to previous studies. Selected patients may have further benefit from addition of capecitabine. The toxicity associated with capecitabine was found lower than anticipated.

Adjuvant chemotherapy for adenocarcinoma arising from intraductal papillary mucinous neoplasia: multicentre ADENO-IPMN study.

BACKGROUND: The clinical impact of adjuvant chemotherapy after resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia is unclear. The aim of this study was to identify factors related to receipt of adjuvant chemotherapy and its impact on recurrence and survival. METHODS: This was a multicentre retrospective study of patients undergoing pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia between January 2010 and December 2020 at 18 centres. Recurrence and survival outcomes for patients who did and did not receive adjuvant chemotherapy were compared using propensity score matching. RESULTS: Of 459 patients who underwent pancreatic resection, 275 (59.9%) received adjuvant chemotherapy (gemcitabine 51.3%, gemcitabine-capecitabine 21.8%, FOLFIRINOX 8.0%, other 18.9%). Median follow-up was 78 months. The overall recurrence rate was 45.5% and the median time to recurrence was 33 months. In univariable analysis in the matched cohort, adjuvant chemotherapy was not associated with reduced overall (P = 0.713), locoregional (P = 0.283) or systemic (P = 0.592) recurrence, disease-free survival (P = 0.284) or overall survival (P = 0.455). Adjuvant chemotherapy was not associated with reduced site-specific recurrence. In multivariable analysis, there was no association between adjuvant chemotherapy and overall recurrence (HR 0.89, 95% c.i. 0.57 to 1.40), disease-free survival (HR 0.86, 0.59 to 1.30) or overall survival (HR 0.77, 0.50 to 1.20). Adjuvant chemotherapy was not associated with reduced recurrence in any high-risk subgroup (for example, lymph node-positive, higher AJCC stage, poor differentiation). No particular chemotherapy regimen resulted in superior outcomes. CONCLUSION: Chemotherapy following resection of adenocarcinoma arising from intraductal papillary mucinous neoplasia does not appear to influence recurrence rates, recurrence patterns or survival.

Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer.

Importance: Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC). Objective: To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan. Design, Setting, and Participants: This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022. Exposure: Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose. Main Outcomes and Measures: Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR). Results: A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months. Conclusions and Relevance: In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Capecitabine-induced severe adverse events-therapeutic drug monitoring and DPYD-gene analysis are recommended.

In this report, two cases of patients with severe adverse events after an adjuvant treatment with capecitabine are described in detail. The first patient suffered from a severe ileocolitis, where ultimately intensive care treatment, total colectomy and ileum resection was necessary. The second patient experienced a toxic enteritis, which could be managed conservatively. Post-therapeutic DPYD genotyping was negative in the former and positive in the latter case. Patients can be categorised in normal, moderate and poor DPYD metabolisers to predict the risk of adverse events of capecitabine treatment. Guidelines in various European countries recommend pretherapeutic DPYD genotyping, whereas it is not recommended by the National Comprehensive Cancer Network in the USA. Irrespective of DPYD genotyping, strict therapeutic drug monitoring is highly recommended to reduce the incidence and severity of adverse events.

Impact of Neoadjuvant Radiochemotherapy on Pathological Complete Response for Locally Advanced Rectal Cancer: A Mono Institutional Experience.

BACKGROUND/AIM: Neoadjuvant radiochemotherapy followed by surgery is a standard of care in locally advanced rectal cancer (LARC). Only a subgroup of patients can obtain a pathological complete response (pCR) and achieve good local control. However, the role of pCR on patient survival is debated. The aim of the study was to evaluate the impact of pCR on clinical outcomes and toxicities in LARC patients treated with dose intensification and concomitant capecitabine treatment in a neoadjuvant radiochemotherapy schedule. PATIENTS AND METHODS: This was a single Institution retrospective study including 178 patients. Mandard tumor regression grade (TRG) and pTNM staging system were used to classify pathological response and define pathological complete response (pCR). Patients were divided in: pCR (pT0N0) and Not-pCR (pT>0N>0), according to pTNM and in good responders (TRG1-2) and partial/not responders (TRG3-5), according to Mandard TRG. The Kaplan-Meier method was used to estimate OS, CSS, DFS and LC. RESULTS: A low severe toxicity rate was observed. Acute Grade 3 lower bowel toxicity and Grade 3 cutaneous toxicity were reported in 2 (1.1%) patients, respectively. Late Grade >3 lower bowel toxicity was reported in 6 patients (3%) and late Grade >3 cutaneous toxicity was registered in one patient. No other severe acute and late toxicities were reported. The 5- and 10-year OS, CSS, DFS and LC rates were 85% and 75%, 94% and 92%, 83% and 81%, 88% and 88%, respectively. We observed a pCR rate of 36% and a good responders rate of 62%, in our study population. Both groups showed better rates for each analyzed clinical outcome. CONCLUSION: Neoadjuvant radiochemotherapy with dose intensification in LARC patients resulted in favorable long-term oncological outcomes, pCR rate showed an optimal impact on OS and DFS with an acceptable toxicity.

Hepatic artery infusion chemotherapy with systemic capecitabine and camrelizumab for treating unresectable hilar cholangiocarcinoma: An initial investigation of efficacy and safety.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of sequential treatment of continuous transcatheter hepatic artery infusion chemotherapy (HAIC) with systemic capecitabine monotherapy and camrelizumab for treating unresectable hilar cholangiocarcinoma (HCCA). METHODS: This study retrospectively analyzed patients with unresectable HCCA admitted to Linyi Cancer Hospital in Shandong Province from October 2019 to December 2021. All enrolled patients were treated with HAIC (mFOLFOX7) + camrelizumab for 2-6 cycles and administered systemic therapy with capecitabine and camrelizumab. The objective response rate (ORR), disease control rate (DCR), and adverse reactions of patients were assessed. The Kaplan-Meier method was used to describe overall survival (OS), and univariate and multivariate Cox regression models were utilized to analyze the influencing factors of OS. RESULTS: This study included 34 patients, ORR was 61.76% (21/34), and DCR was 97.06% (33/34) after two HAIC cycles. The median follow-up time was 17.5 months, with an average of 18.32 ± 8.06 months, and the median OS was 20.0 months. HAIC-related adverse reactions included mainly gastrointestinal symptoms and hematological toxicity caused by chemotherapy drugs, all of which were grades 1-2. Further, adverse events for camrelizumab treatment included fatigue, skin rash, and hypothyroidism, all of which were grade <3. Cox regression analysis revealed that the periductal infiltrating type of growth pattern indicated a worse OS, whereas more HAIC cycles (5 ~ 6) were a protective factor for OS. CONCLUSION: HAIC sequentially combined with systemic capecitabine chemotherapy and a programmed death-1 inhibitor displayed favorable effects for unresectable HCCA, with controllable adverse reactions.

Photobiomodulation in the treatment of palmar-plantar erythrodysesthesia: a randomised controlled clinical study protocol.

INTRODUCTION: Hand-foot syndrome, also known as palmar-plantar erythrodysesthesia (PPE), is a complication caused by chemotherapy. Clinically, it manifests as erythema and oedema on the palms of the hands and feet, dry and scaly skin, accompanied by a sensation of tightness and pain. Extreme cases have blisters and ulcerations that may require hospitalisation and/or pause in cancer treatment. It can also be accompanied by paraesthesia. Considering the characteristics, photobiomodulation (PBM) may reduce the PPE effects. The objective of this protocol will be to evaluate the efficacy of PBM in reducing PPE induced by capecitabine and 5-fluorouracil chemotherapy. METHODS AND ANALYSIS: This will be a randomised controlled, double-blind, double-centre clinical trial (Centro Asistencial del Sindicato Médico del Uruguay and Instituto Nacional del Cáncer from Uruguay). The sample population (40 individuals) will be divided into two groups: group 1 will receive moisturising cream plus PBM treatment and group 2 moisturising cream plus PBM sham treatment, at the ratio of 1:1. PBM will be performed at 630 nm two times per week in palmoplantar areas of the hands and feet (4 J/cm2), for 4 weeks. The PPE degree and the data referring to the chemotherapy treatment plan will be measured, prior to the start of treatment in the middle and at the end of it. Quality of life questionnaires will be applied at the beginning of the trial and at the end of treatment. The data will be analysed based on the intention-to-treat analysis and α<0.05 will be considered statistically significant. ETHICS AND DISSEMINATION: The protocol was approved by the Research Ethics Committee of Universidad Católica del Uruguay (220316b), of Centro Asistencial del Sindicato Médico del Uruguay (221989) and of Instituto Nacional del Cáncer (2023-04). The recruitment has already started (March 2023). PROTOCOL VERSION: V.2, 27 October 2023. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05337423).

Efficacy and safety of natural killer cells injection combined with XELOX chemotherapy in postoperative patients with stage III colorectal cancer in China: a prospective randomised controlled clinical trial study protocol.

BACKGROUND: Colorectal cancer (CRC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related death in China. However, resistance to multiple chemotherapeutics after surgery leads to failure of the main therapy to CRC. Natural killer (NK) cells are innate cytotoxic lymphocytes that exhibit strong cytotoxic activity against tumour cells. NK cell-based therapy, either alone or in combination with chemotherapy, has achieved favourable results and holds promise for addressing recurrence and metastasis in CRC patients after surgery. METHODS AND ANALYSIS: This is a prospective, randomised controlled clinical trial to evaluate efficacy and safety of interleukin 2 activated NK cells injection combined with XELOX (capecitabine plus oxaliplatin)-based chemotherapy for postoperative CRC patients. Participants will be randomly divided into treatment group and control group, and every group includes 40 patients. The treatment group will also receive NK cells (5×109) with+XELOX-based chemotherapy, while the control group will receive only XELOX-based chemotherapy. This treatment will be repeated for eight cycles (6 months). The follow-up period lasts about 3 years, during which CEA, CA19-9, CA125, enhancement CT and colonoscopy will be conducted. The primary endpoints of this study are progression-free survival and overall survival, while the secondary endpoint is safety (number and severity of adverse events). Additionally, we aim to identify cancer stem cells in peripheral blood and predictive biomarkers (cytokines secreted by NK cells and activated markers of NK cells) that indicate patients who achieve an effective response. ETHICS AND DISSEMINATION: The study has been approved by the Clinical Research Ethics Committee of our hospital (approval number 2023LLSC006) and the Chinese Clinical Trials. It will be conducted in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all participants. The study findings will be submitted to peer-reviewed journals for publication. TRIAL REGISTRATION NUMBER: Chinese Clinical Trials Registry (ChiCTR2300075861).

Chemotherapy combined with endocrine neoadjuvant therapy for hormone receptor-positive local advanced breast cancer: a case report and literature review.

Background: Early studies have revealed antagonistic effects associated with stacking chemotherapy (CT) and endocrine therapy (ET), thereby conventional wisdom does not advocate the simultaneous combination of these two treatment modalities. Limited clinical studies exist on the combined use of neoadjuvant CT (NACT) and neoadjuvant ET (NET), and there are no reported instances of concurrent neoadjuvant treatment for locally advanced breast cancer (LABC) using capecitabine and fulvestrant (FUL). Case presentation: We reported a 54-year-old woman who was diagnosed with hormone receptor-positive (HR+) LABC at our hospital. After neoadjuvant treatment involving two distinct CT regimens did not lead to tumor regression. Consequently, the patient was transitioned to concurrent capecitabine and FUL therapy. This change resulted in favorable pathological remission without any significant adverse events during treatment. Conclusions: A novel approach involving concurrent neoadjuvant therapy with CT and endocrine therapy may offer a potentially effective treatment avenue for some cases with HR+ LABC.

Comparison of neoadjuvant treatment and surgery first for resectable or borderline resectable pancreatic carcinoma: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Current treatment recommendations for resectable or borderline pancreatic carcinoma support upfront surgery and adjuvant therapy. However, neoadjuvant therapy (NT) seems to increase prognosis of pancreatic carcinoma and come to everyone's attention gradually. Randomized controlled trials offering comparison with the NT are lacking and optimal neoadjuvant treatment regimen still remains uncertain. This study aims to compare both treatment strategies for resectable or borderline resectable pancreatic cancer. METHODS: The PRISMA checklist was used as a guide to systematically review relevant peer-reviewed literature reporting primary data analysis. We searched PubMed, Medline, EMBASE, Cochrane Datebase and related reviews for randomized controlled trials comparing neoadjuvant therapy with surgery first for resectable or borderline resectable pancreatic carcinoma. We estimated relative hazard ratios (HRs) for median overall survival and ratios risks (RRs) for microscopically complete (R0) resection among different neoadjuvant regimens and major complications. We assessed the effects of neoadjuvant therapy on R0 resection rate and median overall survival with Bayesian analysis. RESULTS: Thirteen eligible articles were included. Eight studies performed comparison neoadjuvant therapy with surgery first, and R0 resection rate was recorded in seven studies. Compared with surgery first, neoadjuvant therapy did increase the R0 resection rate (RR = 1.53, I2 = 0%, P< 0.00001), there was a certain possibility that gemcitabine + cisplatin (Gem+Cis) + Radiotherapy was the most favorable in terms of the fact that there was no significant difference concerning the results from the individual studies. In direct comparison, four studies were included and estimated that Neoadjuvant therapy improved mOS compared with upfront surgery (HR 0.68, 95% CI 0.58-0.92; P = 0.012; I2 = 15%), after Bayesian analysis it seemed that regimen with Cisplatin/ Epirubicin then Gemcitabine/ Capecitabine (PEXG) was most likely the best with a relatively small sample size. The rate of major surgical complications was available for six studies and ranged from 11% to 56% with neoadjuvant therapy and 11% to 45% with surgery first. There was no significant difference between neoadjuvant therapy and surgery first, also with a high heterogeneity (RR = 0.96, 95%CI = 0.65-1.43; P = 0.85; I2 = 46%). CONCLUSION: In conclusion neoadjuvant therapy might offer benefit over up-front surgery. Neoadjuvant therapy increased the R0 resection rate with gemcitabine + cisplatin + Radiotherapy that was the most favorable and improved mOS with Cisplatin/ Epirubicin then Gemcitabine/ Capecitabine (PEXG) that was most likely the best.

Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma

Purpose To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). Method and materials All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8 years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. Results ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5 days, P = 0.042) than in the MF group. Conclusion The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC (AU)

Deciphering drug resistance in gastric cancer: Potential mechanisms and future perspectives.

Gastric cancer (GC) is a malignant tumor that originates from the epithelium of the gastric mucosa. The latest global cancer statistics show that GC ranks fifth in incidence and fourth in mortality among all cancers, posing a serious threat to public health. While early-stage GC is primarily treated through surgery, chemotherapy is the frontline option for advanced cases. Currently, commonly used chemotherapy regimens include FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine). However, with the widespread use of chemotherapy, an increasing number of cases of drug resistance have emerged. This article primarily explores the potential mechanisms of chemotherapy resistance in GC patients from five perspectives: cell death, tumor microenvironment, non-coding RNA, epigenetics, and epithelial-mesenchymal transition. Additionally, it proposes feasibility strategies to overcome drug resistance from four angles: cancer stem cells, tumor microenvironment, natural products, and combined therapy. The hope is that this article will provide guidance for researchers in the field and bring hope to more GC patients.

Identification of potential inhibitor against Leishmania donovani mitochondrial DNA primase through in-silico and in vitro drug repurposing approaches.

Leishmania donovani is the causal organism of leishmaniasis with critical health implications affecting about 12 million people around the globe. Due to less efficacy, adverse side effects, and resistance, the available therapeutic molecules fail to control leishmaniasis. The mitochondrial primase of Leishmania donovani (LdmtPRI1) is a vital cog in the DNA replication mechanism, as the enzyme initiates the replication of the mitochondrial genome of Leishmania donovani. Hence, we target this protein as a probable drug target against leishmaniasis. The de-novo approach enabled computational prediction of the three-dimensional structure of LdmtPRI1, and its active sites were identified. Ligands from commercially available drug compounds were selected and docked against LdmtPRI1. The compounds were chosen for pharmacokinetic study and molecular dynamics simulation based on their binding energies and protein interactions. The LdmtPRI1 gene was cloned, overexpressed, and purified, and a primase activity assay was performed. The selected compounds were verified experimentally by the parasite and primase inhibition assay. Capecitabine was observed to be effective against the promastigote form of Leishmania donovani, as well as inhibiting primase activity. This study's findings suggest capecitabine might be a potential anti-leishmanial drug candidate after adequate further studies.

ADJUBIL: phase II study of adjuvant immunotherapy with STRIDE regimen with/without capecitabine in biliary tract cancers.

Biliary tract cancer is a highly heterogeneous group of gastrointestinal cancers, and the only curative treatment is surgery, which is only applicable at early stages of the malignancy. ADJUBIL, a phase II trial (NCT05239169), aims to evaluate immunotherapy with durvalumab and tremelimumab with or without capecitabine in adjuvant situations for biliary tract cancers. A total of 40 prospective patients will be randomly assigned following surgery, consisting of a two-arm feasibility pilot part with a pick-the-winner design with durvalumab and tremelimumab in combination with or without capecitabine.

This article describes the design of a phase II clinical trial called ADJUBIL, which evaluates the use of immunotherapy (durvalumab and tremelimumab) with or without classic chemotherapy (capecitabine) in biliary tract cancer patients who have undergone curative surgery. This type of treatment is also called adjuvant therapy, meaning it is used after the primary treatment. Biliary tract cancer is a rare type of liver cancer, often diagnosed late. Following surgery, patients may experience an early return of the disease, called tumor relapse. To avoid or delay tumor relapse, patients need extra treatment. Pure chemotherapy (capecitabine) is the standard after curative surgery. For patients with no option for cure, chemotherapy together with new powerful immunotherapy has become standard. This study will recruit 40 adult patients with tumor removal, who will be randomly divided into two groups. Half of them will be treated with immunotherapy only (durvalumab and tremelimumab). The other half will be treated with capecitabine together with immunotherapy. This study will continue for 12 months, but the treatment can be stopped if, for example, the tumor reoccurs or any possible side effect of the therapy is detected. The most effective treatment type will be selected. This type of selection is called pick-the winner.