Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with lenvatinib and PD-1 inhibitors for advanced hepatocellular carcinoma with macrovascular invasion.

BACKGROUND AND AIMS: The prognosis of hepatocellular carcinoma (HCC) with macrovascular invasion(MaVI)is poor, and the treatment is limited. This study aims to explore the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC), combined with lenvatinib and programmed cell death-1(PD-1) inhibitor in the first-line treatment of HCC with MaVI. METHODS: From July 2020 to February 2022, we retrospectively analyzed consecutive patients with HCC with MaVI who received hepatic arterial infusion FOLFOX(oxaliplatin, 5-fluorouracil, and leucovorin)combined with lenvatinib and PD-1 inhibitor. The efficacy was evaluated by RECIST 1.1. Kaplan-Meier was used to explore the overall survival and progression-free survival (PFS), and the COX regression model was used to analyze the risk factors of PFS. Adverse events (AEs) were evaluated according to CTCAE5.0. RESULTS: Thirty-two patients with HCC complicated with MaVI were recruited from the Second Affiliated Hospital of Nanchang University. Among the patients treated with HAIC combined with lenvatinib and PD-1 inhibitor, ten patients (31.25%) got partial response, eighteen patients (56.25%) maintained stable disease and four patients (12.50%) suffered progressive disease during follow-up; and objective response rate was 31.25%, and disease control rate was 87.5%. The median PFS was 179 days. Univariate and multivariate Cox analysis showed that the extrahepatic metastases and Child-Pugh score were independent prognostic factors of PFS. Twenty-two (68.75%) patients suffered adverse reactions. The main AEs were elevated transaminase (46.87%), thrombocytopenia (40.63%), hypoalbuminemia (28.13%), nausea and vomiting (21.88%), leukopenia (18.76%), abdominal pain (15.63%), hypertension (15.63%) and fever (15.63%). There were seven cases (21.88%) that had grade 3 or above AEs; Among them, two cases with elevated transaminase (6.25%), leukopenia, thrombocytopenia, nausea and vomiting, abdominal pain, and diarrhea occurred in one case respectively. Moreover, no treatment-related death was observed. CONCLUSIONS: Hepatic arterial infusion of FOLFOX combined with lenvatinib and PD-1 inhibitor as the first-line treatment for HCC complicated with MaVI is effective, and adverse reactions are tolerable.

A preliminary study of optimal treatment response rates in patients undergoing hepatic arterial infusion chemotherapy combined with molecular targeting and immunotherapy.

Objectives: This study aimed to examine the effectiveness of the best response rate (BRR) as a surrogate for overall survival (OS), using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), in patients with unresectable hepatocellular carcinoma (HCC) undergoing hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) combined with molecular targeting and immunotherapy. Methods: This study enrolled 111 consecutive patients who had complete imaging data. The median age of patients was 58 years (IQR 50.5-65.0). Among the patients, those with Barcelona Clinic Liver Cancer (BCLC) stage A, BCLC stage B, and BCLC stage C comprised 6.4%, 19.1%, and 73.6%, respectively. The optimal threshold of BRR can be determined using restricted cubic splines (RCS) and the rank sum statistics of maximum selection. Survival curves of patients in the high rating and low rating groups were plotted. We then used the change-in-estimate (CIE) method to filter out confounders and the inverse probability of treatment weighting (IPTW) to balance confounders between the two groups to assess the robustness of the results. Results: The median frequency of the combination treatment regimens administered in the overall population was 3 times (IQR 2.0-3.0). The optimal BRR truncation value calculated was -0.2. Based on this value, 77 patients were categorized as the low rating group and 34 as the high rating group. The differences in the OS between the high and low rating groups were statistically significant (7 months [95%CI 6.0-14.0] vs. 30 months [95%CI 30.0-]; p< 0.001). Using the absolute 10% cut-off value, the CIE method was used to screen out the following confounding factors affecting prognosis: successful conversion surgery, baseline tumor size, BCLC stage, serum total bilirubin level, number of interventional treatments, alpha-fetoprotein level, presence of inferior vena cava tumor thrombus, and partial thrombin activation time. The survival curve was then plotted again using IPTW for confounding factors, and it was found that the low rating group continued to have better OS than the high rating group. Finally, the relationship between BRR and baseline factors was analyzed, and inferior vena cava tumor thrombus and baseline tumor size correlated significantly with BRR. Conclusions: BRR can be used as a surrogate endpoint for OS in unresectable HCC patients undergoing FOLFOX-HAIC in combination with molecular targeting and immunotherapy. Thus, by calculating the BRR, the prognosis of HCC patients after combination therapy can be predicted. Inferior vena cava tumor thrombus and baseline tumor size were closely associated with the BRR.

[An update on total neoadjuvant treatment of adenocarcinoma of the rectum]. / Actualisation des données sur le traitement néoadjuvant total de l'adénocarcinome du rectum.

A major advance has been made in the management of rectal cancer, with the emergence in 2021 of total neoadjuvant treatment. The main publications from the RAPIDO and PRODIGE-23 trials reported a significant improvement in progression-free survival and the pathological complete response rate. The aim of this review is to synthesize recent data on neoadjuvant treatment of rectal cancer, to explain the long-term results of the RAPIDO and PRODIGE-23 trials, and to put them into perspective, considering current advances in de-escalation strategies. The update of the 5-year survival data from the RAPIDO trial highlights an increased risk of loco-regional relapse, with 11.7% of relapses in the experimental group and 8.1% in the control group, while the update of the PRODIGE-23 trial confirms the benefits of this treatment regimen, with a significant improvement in overall survival. In addition, the results of the OPRA and PROPSPECT trials confirm the benefit of total neoadjuvant treatment with induction chemotherapy, as well as the possibility of surgical de-escalation in the OPRA trial and radiotherapy in the PROSPECT trial. The challenge for the future is to identify patients who require total neoadjuvant treatment with the aim of curative surgery to obtain a cure without local or distant relapse, and those for whom therapeutic de-escalation can be envisaged.

Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer.

PURPOSE: A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects. METHODS: We trained a new machine learning model, referred to as the colon oxaliplatin signature (COLOXIS) model, for predicting response to oxaliplatin-containing regimens. We examined whether COLOXIS was predictive of oxaliplatin benefits in the CC adjuvant setting among 1,065 patients treated with 5-fluorouracil plus leucovorin (FULV; n = 421) or FULV + oxaliplatin (FOLFOX; n = 644) from NSABP C-07 and C-08 phase III trials. The COLOXIS model dichotomizes patients into COLOXIS+ (oxaliplatin responder) and COLOXIS- (nonresponder) groups. Eight-year recurrence-free survival was used to evaluate oxaliplatin benefits within each of the groups, and the predictive value of the COLOXIS model was assessed using the P value associated with the interaction term (int P) between the model prediction and the treatment effect. RESULTS: Among 1,065 patients, 526 were predicted as COLOXIS+ and 539 as COLOXIS-. The COLOXIS+ prediction was associated with prognosis for FULV-treated patients (hazard ratio [HR], 1.52 [95% CI, 1.07 to 2.15]; P = .017). The model was predictive of oxaliplatin benefits: COLOXIS+ patients benefited from oxaliplatin (HR, 0.65 [95% CI, 0.48 to 0.89]; P = .0065; int P = .03), but COLOXIS- patients did not (COLOXIS- HR, 1.08 [95% CI, 0.77 to 1.52]; P = .65). CONCLUSION: The COLOXIS model is predictive of oxaliplatin benefits in the CC adjuvant setting. The results provide evidence supporting a change in CC adjuvant therapy: reserve oxaliplatin only for COLOXIS+ patients, but further investigation is warranted.

Non-metastatic colon cancer: French Intergroup Clinical Practice Guidelines for diagnosis, treatments, and follow-up (TNCD, SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, SFP, AFEF, and SFR).

INTRODUCTION: This article is a summary of the French intergroup guidelines regarding the management of non-metastatic colon cancer (CC), revised in November 2022. METHODS: These guidelines represent collaborative work of all French medical and surgical societies involved in the management of CC. Recommendations were graded in three categories (A, B, and C) according to the level of evidence found in the literature published up to November 2022. RESULTS: Initial evaluation of CC is based on clinical examination, colonoscopy, chest-abdomen-pelvis computed tomography (CT) scan, and carcinoembryonic antigen (CEA) assay. CC is usually managed by surgery and adjuvant treatment depending on the pathological findings. The use of adjuvant therapy remains a challenging question in stage II disease. For high-risk stage II CC, adjuvant chemotherapy must be discussed and fluoropyrimidine monotherapy or oxaliplatin-based chemotherapy proposed according to the type and number of poor prognostic features. Oxaliplatin-based chemotherapy (FOLFOX or CAPOX) is the current standard for adjuvant therapy of patients with stage III CC. However, these regimens are associated with significant oxaliplatin-induced neurotoxicity. The results of the recent IDEA study provide evidence that 3 months of treatment with CAPOX is as effective as 6 months of oxaliplatin-based therapy in patients with low-risk stage III CC (T1-3 and N1). A 6-month oxaliplatin-based therapy remains the standard of care for high-risk stage III CC (T4 and/or N2). For patients unfit for oxaliplatin, fluoropyrimidine monotherapy is recommended. CONCLUSION: French guidelines for non-metastatic CC management help to offer the best personalized therapeutic strategy in daily clinical practice. Each individual case must be discussed within a multidisciplinary tumor board and then the treatment option decided with the patient.

Complete Pathologic Response to Neoadjuvant Chemoimmunotherapy and Oxaliplatin-Induced Fever Associated With IL-6 Release in a Patient With Locally Advanced Colon Cancer

Neoadjuvant systemic therapy is a preferred treatment approach for a number of tumor types due to many potential advantages over upfront surgery, including tumor downstaging, early treatment of micrometastatic disease, and providing an in vivo test of tumor biology. For colon cancer, current standard of care is upfront surgery followed by adjuvant systemic therapy in high-risk patients. Concerns about inaccurate radiological staging and tumor progression during preoperative treatment, as well the lack of randomized data demonstrating benefit, are among the reasons for the limited use of neoadjuvant therapy in this disease. Locally advanced colon cancer, defined as primary colon cancer with direct invasion into the adjacent structures or extensive regional lymph node involvement, is not always amenable to pathological complete resection, and when attempted it comes with high incidence of postoperative morbidity and mortality because of the required multivisceral resection. Clinical trials of neoadjuvant chemotherapy for colon cancer to date have been promising with downstaging of disease and higher rates of R0 resection. Here, we report a case of a patient with locally advanced, unresectable, mismatch repair deficient sigmoid colon cancer who was treated with neoadjuvant chemoimmunotherapy followed by surgical resection leading to a complete pathologic response after preoperative systemic chemoimmunotherapy.

First American Cancer Patient to Receive Dicycloplatin (DCP) Chemotherapy Achieves Remission After Seven Weeks of DCP Capsules - A Case Report.

BACKGROUND: The majority of bladder cancer patients experience recurrence. Cisplatin is the standard chemotherapy for muscle-invasive bladder cancer though adverse effects are often severe. CASE REPORT: Intravenous (IV) dicycloplatin (DCP) sustained remission in an American bladder cancer patient for five years. A recurrent mass was observed in July 2021. The patient received DCP capsules for seven weeks with no significant side-effects. Complete blood count with differential and a basic metabolic panel showed no adverse effects of DCP capsules on the bone marrow, liver or renal parameters. Cystoscopy after oral DCP found no evident bladder tumors; cytology was negative for high-grade urothelial carcinoma. CONCLUSION: In this patient, DCP-capsules appeared to be as effective as DCP-IV for achieving bladder cancer remission. Both forms of DCP chemotherapy are convenient, active against several cancer types, with decreased adverse effects compared to cisplatin. Both have been available for treating cancer patients in China. A USA clinical trial of DCP in bladder and other cancers appears warranted.

Phase III randomized trial comparing systemic versus intra-arterial oxaliplatin, combined with LV5FU2 +/- irinotecan and a targeted therapy, in the first-line treatment of metastatic colorectal cancer restricted to the liver (OSCAR): PRODIGE 49.

INTRODUCTION: In patients with unresectable liver metastases from colorectal cancer (CRCLM), systemic doublet or triplet chemotherapy and targeted therapy is considered a standard first-line treatment. Hepatic arterial infusion of oxaliplatin (HAI-ox) generates a high response rate, but this still needs to be confirmed in a randomized trial. We incorporated HAI-ox in doublet or triplet + targeted therapy to validate its efficacy. AIM: The OSCAR study is an ongoing randomized phase III trial comparing FOLFOX + targeted therapy according to RAS status, or FOLFOXIRI + bevacizumab in patients eligible for triplet therapy, with the same regimen but with HAI-ox instead of IV-ox as the first-line treatment for CRCLM. MATERIALS AND METHODS: Main eligibility criteria are colorectal cancer, unresectable liver metastasis, no extra-hepatic metastases except pulmonary nodules if ≤3 and <10 mm, ECOG performance status 0 or 1. ENDPOINT: The primary endpoint is progression-free survival (PFS). A difference of 4 months for the median PFS in favor of HAI-ox is expected (HR = 0.73). Secondary endpoints include overall survival, overall response rate, secondary liver resection, safety, and quality of life. CONCLUSION: This study is planned to include 348 patients to demonstrate the superiority of HAI-ox over systemic oxaliplatin in first-line CRCLM treatment (NCT02885753).

Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.

BACKGROUND: The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). METHODS: We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. RESULTS: In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. CONCLUSIONS: TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.

Oxaliplatin facilitates tumor-infiltration of T cells and natural-killer cells for enhanced tumor immunotherapy in lung cancer model.

Platinum is reported to have adjuvant immune properties, whether oxaliplatin (OXA) could be utilized to synergize with anti-programmed cell death-1 (PD-1) antibody or anti-NKG2D (natural-killer group 2, member D) antibody is investigated. Subcutaneous A549 lung cancer and murine Lewis lung carcinoma (LLC) models were constructed, which were further intravenously injected with platinum-based drugs or concomitant administrated with anti-PD-1 antibody and or anti-NKG2D antibody. The tumor volume and the proportion of myeloid cells (CD45+CD11b+), CD3+T cells and NK (NK1.1+) cells were detected. The relative expression of chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10 and CXCL11 and C-X-C motif chemokine receptor 3 (CXCR3) was detected with the ELISA, western blot and flow cytometry. The three platinum drugs (cisplatin, DDP; carboplatin, CBP; OXA) showed similar effects to inhibit A549 tumor growth in immune-deficient mice. While OXA exhibited better antitumor efficacy in wild-type mice bearing LLC with downregulated myeloid cells proportion, upregulated concentration of CXCL9, CXCL10 and CXCL11, and upregulated proportion and CXCR3 expression on T cells and NK cells. OXA combined with anti-PD1 or anti-NKG2D synergistically improved tumor growth inhibition and survival. The combination of OXA to anti-PD1 and anti-NKG2D antibodies will provide the most appropriate treatment benefit. Oxaliplatin promotes T cells and NK cells infiltration through the CXCL9/10/11-CXCR3 axis to enhance anti-PD1 or anti-NKG2D immunotherapy in lung cancer.

Perioperative FOLFOX in Patients With Locally Advanced Oesogastric Adenocarcinoma.

BACKGROUND: We hypothesized that perioperative FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) might be used as an alternative to standard FLOT (docetaxel, 5-fluorouracil, leucovorin, and oxaliplatin) in patients with locally advanced oesogastric adenocarcinomas (OGA), particularly those with frailties. PATIENTS AND METHODS: We reviewed the charts of 61 consecutives patients treated with FOLFOX for resectable OGA to estimate overall survival, recurrence-free survival, and safety. RESULTS: The median follow-up was 69.7 (range=3.6-97.9) months. Few patients experienced grade 3 adverse events during the preoperative (n=6; 10%) and postoperative (n=6; 16%) phases. One patient experienced a fatal grade 5 adverse events (cardiogenic shock). Median overall survival was 51.7 months [95% confidence interval (CI)=31.6-93.2 months] and the 5-year survival rate was 44.4% (95% CI=30.3%-57.5%). CONCLUSION: Regarding its comparable efficacy and its favourable toxicity profile, perioperative FOLFOX is a reasonable alternative to FLOT for frail patients with resectable OGA.

Triplet chemotherapy in combination with anti-EGFR agents for the treatment of metastatic colorectal cancer: Current evidence, advances, and future perspectives.

Doublet or triplet chemotherapy regimens in combination with anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (mAb), such as cetuximab or panitumumab, or the anti-vascular endothelial growth factor mAb bevacizumab, are the current recommended standard of care therapies for unresectable metastatic colorectal cancer (mCRC). While the recommended dosing schedule for the triplet chemotherapy regimen with 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) in combination with bevacizumab is well established, the optimal dosing of FOLFOXIRI in combination with anti-EGFR agents is unknown. Several randomized, phase 3 clinical trials of patients with mCRC have demonstrated improved survival and response rates with FOLFOXIRI, alone or when combined with bevacizumab, compared with doublet chemotherapy regimens. Trials of anti-EGFR agents in combination with FOLFOXIRI have also shown promising results. In this review, we summarize the emerging evidence regarding the safety and efficacy of anti-EGFR agents in combination with triplet chemotherapy regimens and discuss the potential for this combination as a future treatment option for patients with RAS-wild-type mCRC.

19 F NMR Allows the Investigation of the Fate of Platinum(IV) Prodrugs in Physiological Conditions.

PtIV prodrugs can overcome resistance and side effects of conventional PtII anticancer therapies. By 19 F-labeling of a PtIV prodrug (Pt-FBA, FBA=p-fluorobenzoate), the activation under physiological conditions could be investigated. Unlike single-electron reductants, multi-electron agents can efficiently promote the two electrons reduction of PtIV to PtII . The activation of Pt-FBA in cell lysate is highly dependent upon the type of cancer cells. When administered to E. coli, Pt-FBA is reduced intracellularly and free FBA can shuttle out of the cell. The reduction rate greatly increases by inducing metallothionein overexpression and is lowered by addition of ZnII ions. When injected into mice, Pt-FBA undergoes fast reduction in the bloodstream accompanied by metabolic degradation of FBA; nevertheless, unreduced Pt-FBA can accumulate to detectable levels in liver and kidneys. The 19 F NMR approach has the advantage of avoiding the interference of all background signals.

Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: The aim of the present study was to evaluate the efficacy of TJ-107 for oxaliplatin-induced peripheral neurotoxicity in prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trials using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire (FACT-GOG-NTX-12). PATIENTS AND METHODS: The patients who were registered to the Goshajinkigan oxaliplatin neurotoxicity evaluation study (UMIN000002211) were analyzed. A NTX-12 from the validated FACT/GOG-NTX-12 was assessed before treatment and at the end of every 2 cycles. RESULTS: The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks were as follows: numbness or tingling in the hands (P = 0.5820), numbness or tingling in the feet (P = 0.3236), feeling of discomfort in the hands (P = 0.8219), feeling of discomfort in the feet (P = 0.5361), joint pain or muscle cramps (P = 0.1974), feeling weak all over (P = 0.2771), trouble hearing (P = 0.2832), ringing or buzzing in ears (P = 0.1031), trouble buttoning buttons (P = 0.1653), trouble feeling the shape of small objects when held in hand (P = 0.2919), trouble walking (P = 0.5406), and pain in the hands or feet when exposed to cold temperatures (P = 0.1872). CONCLUSION: There might be no clinically significant difference between the use of TJ-107 and the severity and quality of life for patients treated with oxaliplatin.

Efficacy and safety of traditional Chinese medicine injections combined with FOLFOX4 regimen for gastric cancer: A protocol for systematic review and network meta-analysis.

BACKGROUND: Traditional Chinese medicine injections (TCMJs) combined with FOLFOX4 regimen could achieve favorable effects in the treatment of gastric cancer. However, the efficacy and safety of different TCMJs combined with FOLFOX4 in the treatment of gastric cancer have not been fully clarified. Due to the fact that there are as many as 10 kinds of TCMJs, how to choose an appropriate TCMJ has become an urgent clinical problem. The objective of this network meta-analysis is to explore the optimal options among different TCMJs for gastric cancer. METHODS: PubMed, Web of Science, Scopus, Cochrane Library, Embase, China Scientific Journal Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang Data were searched to identify randomized controlled trials which focused on TCMJs combined with FOLFOX4 against gastric cancer from its inception to September 2021. Subsequently, 2 researchers will be independently responsible for literature screening, data extraction, and assessment of their quality. Standard pair-wise and Bayesian network meta-analysis will be performed to compare the efficacy and safety of different TCMJs combined with FOLFOX4 regimen via Stata 14.0 and WinBUGS1.4 software. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSIONS: The conclusion of this systematic review will provide evidence for selecting an optimal TCMJ combined with FOLFOX4 for patients with gastric cancer.

Genetic variants predictive of chemotherapy-induced peripheral neuropathy symptoms in gynecologic cancer survivors.

OBJECTIVE: To identify genetic variants associated with chemotherapy-induced peripheral neuropathy (CIPN) symptoms among gynecologic cancer survivors and determine the variants' predictive power in addition to age and clinical factors at time of diagnosis. METHODS: Participants of a prospective cohort study on gynecologic cancers provided a DNA saliva sample and reported CIPN symptoms (FACT/GOG-Ntx). Genotyping of 23 single nucleotide polymorphisms (SNPs) previously identified as related to platinum- or taxane-induced neuropathy was performed using iPLEX Gold method. Risk allele carrier frequencies of 19 SNPs that passed quality checks were compared between those with/without high CIPN symptoms using logistic regression, adjusting for age. Receiver operating characteristic (ROC) curves using clinical risk factors (age, diabetes, BMI, Charlson Comorbidity Index, previous cancer diagnosis) with and without the identified SNPs were compared. RESULTS: 107 individuals received platinum or taxane-based chemotherapy and provided sufficient DNA for analysis. Median age was 65.1 years; 39.6% had obesity and 8.4% diabetes; most had ovarian (58.9%) or uterine cancer (29.0%). Two SNPs were significantly associated with high CIPN symptomatology: rs3753753 in GPX7, OR = 2.55 (1.13, 5.72) and rs139887 in SOX10, 2.66 (1.18, 6.00). Including these two SNPs in a model with clinical characteristics led to an improved AUC for CIPN symptomatology (0.65 vs. 0.74, p = 0.04). CONCLUSIONS: Genetic and clinical characteristics were predictive of higher CIPN symptomatology in gynecologic cancer survivors, and combining these factors resulted in superior predictive power compared with a model with clinical factors only. Prospective validation and assessment of clinical utility are warranted.

Pembrolizumab plus lenvatinib with or without hepatic arterial infusion chemotherapy in selected populations of patients with treatment-naive unresectable hepatocellular carcinoma exhibiting PD-L1 staining: a multicenter retrospective study.

BACKGROUND: Not all patients with unresectable hepatocellular carcinoma (uHCC) benefit from treatment with immune checkpoint inhibitors and molecular-targeted agents. The aim of this retrospective study was to assess the efficacy and safety of pembrolizumab plus lenvatinib plus hepatic arterial infusion chemotherapy (HAIC) versus pembrolizumab plus lenvatinib in selected populations of patients with treatment-naive uHCC exhibiting programmed cell death ligand-1 (PD-L1) staining. METHODS: Consecutive patients with treatment-naive uHCC exhibiting PD-L1 staining who were treated with pembrolizumab plus lenvatinib plus HAIC (PLH) or pembrolizumab plus lenvatinib (PL) were retrospectively identified from our medical centres from 2018 to 2021. HAIC involved oxaliplatin, fluorouracil, and leucovorin (FOLFOX). Follow-up occurred every 3 weeks for 1 year and then every 6 weeks thereafter. The primary endpoints included overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the frequency of key adverse events (AEs). RESULTS: In total, 248 treatment-naive patients were retrospectively reviewed, 78 of whom were ineligible on the basis of the current criteria. Thus, 170 patients (PLH: n = 84, median age 52 years [range, 42-67]; PL: n = 86, 53 years [range, 43-69]) were eligible for the analysis. The median follow-up was 18.6 months (range, 1-26). At the final follow-up, the median OS was 17.7 months (95% confidence interval [CI], 15.2-18.3) in the PLH group versus 12.6 months (95% CI, 11.1-13.7) in the PL group (hazard ratio [HR] 0.52; 95% CI, 0.36-0.75; p = 0.001). A significant difference was also detected in the median PFS (10.9 months [95% CI, 8.7-11.4] for PLH vs. 6.8 months (95% CI, 5.2-7.4) for PL; HR 0.61, 95% CI, 0.43-0.85; p = 0.001). Significant differences in the rate of the key AEs were noted between groups (79.8% for PLH vs. 62.8% for PL, p = 0.015), but these AEs were controllable. CONCLUSIONS: Among selected populations of patients with treatment-naive uHCC exhibiting PD-L1 staining, the PLH regimen may substantially improve the survival benefits compared with the PL regimen with a controllable safety profile.

Platinum-based chemotherapy in early-stage triple negative breast cancer: A meta-analysis.

PURPOSE: The addition of platinum agents to anthracycline and taxane-based chemotherapy in early-stage triple negative breast cancer (TNBC) patients improves pathological complete response (pCR). Long-term outcomes, such as disease-free survival (DFS) and overall survival (OS), have not been well-established. METHODS: A systematic literature review identified studies using platinum-based treatment in TNBC patients in the neoadjuvant or adjuvant setting with reportable long-term outcomes. Hazard ratios (HR) from collected data were pooled in a meta-analysis using generic inverse-variance and random effects modeling. Subgroup analyses were conducted based on treatment setting and study design. RESULTS: Fourteen studies comprising 3518 patients met the inclusion criteria. Median follow up was 56.2 months. All studies reported DFS and 9 studies (64%) reported OS. DFS was significantly better in platinum-based treatment (HR 0.71, 95% confidence interval (CI) 0.56-0.89; p = 0.03). However, OS was no different (HR 0.98, 95% CI 0.75-1.27; p = 0.87). There was a non-significant difference between platinum exposure in the adjuvant compared to neoadjuvant setting for both DFS (HR 0.75 vs 0.62, p = 0.43) and for OS (HR 0.90 vs 1.10, p = 0.58). The addition of platinum was associated with more thrombocytopenia and all-grade neuropathy and non-significant increases in neutropenia and grade 3-4 neuropathy. CONCLUSIONS: Platinum-based treatment improves DFS but not OS. The reporting of toxicity was suboptimal, but in general adding platinum increased toxicity. The discordant effect of platinum-based treatment on DFS and OS suggest the potential development of platinum resistance and worse outcomes after recurrence. Platinum-based chemotherapy cannot be recommended in unselected patients with early TNBC.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.