Preoperative Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

Prevention of allergic reactions during oxaliplatin desensitization through inhibition of Bruton tyrosine kinase.

BACKGROUND: Acute infusion reactions to oxaliplatin, a chemotherapeutic used to treat gastrointestinal cancers, are observed in about 20% of patients. Rapid drug desensitization (RDD) protocols often allow the continuation of oxaliplatin in patients with no alternative options. Breakthrough symptoms, including anaphylaxis, can still occur during RDD. OBJECTIVE: Our aim was to evaluate whether pretreatment with acalabrutinib, a Bruton tyrosine kinase inhibitor, can prevent anaphylaxis during RDD in a patient sensitized to oxaliplatin. METHODS: A 52-year-old male with locally advanced gastric carcinoma developed anaphylaxis during his fifth cycle of oxaliplatin. As he required 6 additional cycles to complete his curative-intent treatment regimen, he underwent RDD to oxaliplatin but still developed severe acute reactions. The risks and benefits of adding acalabrutinib before and during RDD were reviewed, and the patient elected to proceed. RESULTS: With acalabrutinib taken before and during the RDD, the patient was able to tolerate oxaliplatin RDD without complication. Consistent with its mechanism of action, acalabrutinib completely blocked the patient's positive skin prick response to oxaliplatin. Acalabrutinib did not alter the percentage of circulating basophils (1.24% vs 0.98%) before the RDD but did protect against basopenia (0.74% vs 0.09%) after the RDD. Acalabrutinib was associated with a drastic reduction in the ability of basophils to upregulate CD63 in vitro following incubation with oxaliplatin (0.11% vs 2.38%) or polyclonal anti-human IgE antibody (0.08% vs 44.2%). CONCLUSIONS: Five doses of acalabrutinib, 100 mg, orally twice daily starting during the evening 2 days before and continuing through RDD allowed a sensitized patient to receive oxaliplatin successfully and safely.

Phase I trial of apatinib and paclitaxel+oxaliplatin+5-FU/levoleucovorin for treatment-naïve advanced gastric cancer.

Chinese guidelines recommend POF (paclitaxel, oxaliplatin, and 5-FU/levoleucovorin) as first-line treatment for advanced gastric cancer (AGC). Apatinib can augment the antitumor effect of paclitaxel, oxaliplatin, or fluorouracil in preclinical studies of AGC. A phase I clinical trial was conducted to evaluate the anticancer activity and maximum tolerated dose (MTD) of apatinib plus POF in treatment-naïve patients with AGC and to establish a recommended phase II dose. Participants received escalating doses of daily oral apatinib (250, 375, 500, 625, 750, and 850 mg) plus POF every 2 weeks using a conventional "3 + 3" study design. Among 21 treated patients, one experienced a dose-limiting toxicity (grade 3 skin ulceration at 850 mg). No MTD was reached. Apatinib 750 mg plus POF was recommended for phase II study. The most common grade 3-4 adverse events (AEs) were neutropenia (33.3%), mucositis (14.3%), and hand-foot syndrome (14.3%). Median progression-free and overall survival were 10.4 months (95% CI: 6.3, 14.6) and 18.4 months (95% CI: 9.8, 28.2), respectively. Apatinib up to 850 mg coadministered with POF was well tolerated with manageable AEs. The safety and anticancer activity of this regimen warrants its further investigation as first-line treatment for AGC in a larger study.

Differential presentation of hypersensitivity reactions to carboplatin and oxaliplatin: Phenotypes, endotypes, and management with desensitization.

BACKGROUND: Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. METHODS: Seventy-nine patients presenting with DHRs to oxaliplatin (N = 46) and carboplatin (N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. RESULTS: Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p < .05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes. CONCLUSION: Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin-reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols.

Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients - a randomized controlled trial. (OxaNeuro).

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors' quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN. METHODS: The OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months. The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy. DISCUSSION: If readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT05404230 Protocol version: 1.2, April 25th. 2023.

Association of oxaliplatin-containing adjuvant duration with post-treatment fall-related injury and fracture in patients with stage III colon cancer: a population-based retrospective cohort study.

PURPOSE: Oxaliplatin-containing adjuvant chemotherapy yields a significant survival benefit in stage III colon cancer and is the standard of care. Simultaneously, it causes dose-dependent peripheral neuropathy that may increase the risk of fall-related injury (FRI) such as fracture and laceration. Because these events carry significant morbidity and the global burden of colon cancer is on the rise, we examined the association between treatment with a full versus shortened course of adjuvant chemotherapy and post-treatment FRI and fracture. METHODS: In this overlap propensity score weighted, retrospective cohort study, we included patients aged ≥ 18 years with resected stage III colon cancer diagnosed 2007-2019 and treated with oxaliplatin-containing adjuvant chemotherapy (oxaliplatin plus a fluoropyrimidine; capecitabine [CAPOX] or 5-fluorouracil and leucovorin [FOLFOX]). Propensity score methods facilitate the separation of design from analysis and comparison of baseline characteristics across the weighted groups. Treatment groups were defined as 50% (4 cycles CAPOX/6 cycles FOLFOX) and > 85% (7-8 cycles CAPOX/11-12 cycles FOLFOX) of a maximal course of adjuvant chemotherapy to approximate the treatment durations received in the IDEA collaboration. The main outcomes were time to any FRI and time to fracture. We determined the subdistribution hazard ratios (sHR) estimating the association between FRI/fracture and treatment group, accounting for the competing risk of death. RESULTS: We included 3,461 patients; 473 (13.7%) received 50% and 2,988 (86.3%) received > 85% of a maximal course of adjuvant therapy. For post-treatment FRI, median follow-up was 4.6 years and total follow-up was 17,968 person-years. There were 508 FRI, 301 fractures, and 692 deaths. Treatment with > 85% of a maximal course of therapy conferred a sHR of 0.84 (95% CI 0.62-1.13) for post-treatment FRI and a sHR of 0.72 (95% CI 0.49-1.06) for post-treatment fracture. CONCLUSION: For patients with stage III colon cancer undergoing treatment with oxaliplatin-containing adjuvant chemotherapy, any potential neuropathy associated with longer durations of treatment was not found to result in greater rates of FRI and fracture. Within the limits of this retrospective study, our findings suggest concern about FRI, while mechanistically plausible, ought not to determine treatment duration.

Prolonged administration of the granisetron transdermal delivery system reduces capecitabine plus oxaliplatin regimen induced nausea and vomiting.

OBJECTIVE: To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy. DESIGN: Open-label, prospective, multi-center phase II trial. SETTING: Three institutions. PARTICIPANTS: Fifty-four patients scheduled to receive CapeOX chemotherapy. INTERVENTIONS: Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone. MAIN OUTCOME MEASURES: The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life. RESULTS: The complete control rate for delayed CINV over the entire period (25-480 h) was 72.7% (95% CI 0.57-0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69-0.95). No serious adverse events related to the antiemetic regimen were reported. CONCLUSION: Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX. TRIAL REGISTRATION: ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021.

Real-world efficacy and safety of capecitabine with oxaliplatin in patients with advanced adenocarcinoma of the ampulla of Vater.

BACKGROUND: Adenocarcinoma of the ampulla of Vater (AoV) is one of the rare periampullary cancers, and due to its anatomical location, it is categorized into various histologic subtypes. Its rarity and diversity pose challenges in treatment decision-making for patients with advanced AoV carcinoma. This study investigated the efficacy and safety of the combined regimen of capecitabine and oxaliplatin (CAPOX) in a real-world clinical setting. METHODS: This investigation encompassed patients with advanced AoV carcinoma who underwent CAPOX treatment. Histologic phenotypes were identified through a combination of histopathological analysis and protein expression markers, including MUC1, CDX2, CK20, and MUC2. The correlation between histopathological determinants and survival outcomes was explored, in addition to an evaluation of the safety profile of CAPOX therapy. RESULTS: From January 2010 to June 2023, 42 patients received CAPOX. Of these, 14 patients (33.3%) had not received any prior palliative chemotherapy, while 28 patients (66.7%) had undergone one prior line of chemotherapy. At a median follow up of 9.0 months, the median progression-free survival (PFS) was 4.38 months (95% CI, 2.78-5.69) and the median overall survival (OS) was 9.57 months (95% CI 7.56-11.6). The objective response and disease control rates were 38.1% and 61.9%, respectively. Patients who received CAPOX as a second-line treatment had poorer PFS (HR = 2.62; 95% CI, 1.49-4.90, p = 0.003) and OS (HR = 2.82, 95% CI, 1.47-5.38, p = 0.001) compared to those who received CAPOX as a first-line chemotherapy. There were no statistically significant differences in PFS (p = 0.185) and OS (p = 0.097) between groups based on histologic subtypes. Neutropenia (14.3%) emerged as the predominant grade 3-4 toxicity. Notably, treatment cessation occurred in select instances owing to grade 3 fatigue (9.5%) and peripheral neuropathy (9.5%). CONCLUSIONS: This study confirmed the therapeutic efficacy and safety of CAPOX in a real-world setting, consistent with prior phase II trial results. While CAPOX proved feasible for advanced AoV carcinoma regardless of histologic subtype, its reduced effectiveness in second-line settings necessitates further research to determine its optimal palliative use.

Safety of first-line systemic therapy in patients with metastatic colorectal cancer: a network meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis. METHODS: The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens. RESULTS: A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs. CONCLUSION: In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.

Digital subtraction angiography-guided pancreatic arterial infusion of GEMOX chemotherapy in advanced pancreatic adenocarcinoma: a phase II, open-label, randomized controlled trial comparing with intravenous chemotherapy.

BACKGROUND: Advanced pancreatic adenocarcinoma lacks effective treatment options, and systemic gemcitabine-based chemotherapy offers only marginal survival benefits at the cost of significant toxicities and adverse events. New therapeutic options with better drug availability are warranted. This study aims to evaluate the safety and efficacy of digital subtraction angiography (DSA)-guided pancreatic arterial infusion (PAI) versus intravenous chemotherapy (IVC) using the gemcitabine and oxaliplatin (GEMOX) regimen in unresectable locally advanced or metastatic pancreatic cancer (PC) patients. MATERIALS AND METHODS: This study prospectively enrolled 51 eligible treatment-naive patients with unresectable PC to receive GEMOX treatment via PAI or IVC (1:1 ratio randomization) from December 2015 to December 2019. Cycles were repeated monthly, and each process consisted of two treatments administered bi-weekly. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-year survival, 6-month survival, tumor-site subgroup survival, and incidences of adverse events were compared. RESULTS: The median OS of the PAI and IVC groups were 9.93 months and 10.07 months, respectively (p = 0.3049). The median PFS of the PAI and IVC groups were 5.07 months and 4.23 months (p = 0.1088). No significant differences were found in the ORR (11.54% vs. 4%, p = 0.6312), DCR (53.85% vs. 44%, p = 0.482), and 1-year OS rate (44% vs. 20.92%, p = 0.27) in PAI and IVC groups. The 6-month OS rate was significantly higher in the PAI group (100%) than in the IVC group (83.67%) (p = 0.0173). The median OS of patients in PAI group with pancreatic head and neck tumors were significantly higher than those of body and tail tumors (12.867 months vs. 9 months, p = 0.0214). The incidences of hematologic disorders, liver function disorders, and digestive disorders in the IVC group were higher than in the PAI group (p < 0.05). CONCLUSION: GEMOX PAI therapy presented a higher 6-month OS rate and fewer adverse events than IVC in advanced pancreatic adenocarcinoma patients. Those with pancreatic head and neck tumors may yield a superior treatment outcome from PAI treatment. TRIAL REGISTRATION NUMBER: NCT02635971. DATE OF REGISTRATION: 21/12/2015.

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group.

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005.

Plasma neurofilament light chain levels in chemotherapy-induced peripheral neurotoxicity according to type of anticancer drug.

BACKGROUND AND PURPOSE: A real-time biomarker in chemotherapy-induced peripheral neurotoxicity (CIPN) would be useful for clinical decision-making during treatment. Neurofilament light chain (NfL) can be detected in blood in the case of neuroaxonal damage. The aim of the study was to compare the levels of plasma NfL (pNfL) according to the type of chemotherapeutic agent and the severity of CIPN. METHODS: This single-center prospective observational longitudinal study included patients treated with paclitaxel (TX; n = 34), brentuximab vedotin (BV; n = 29), or oxaliplatin (PT; n = 19). All patients were assessed using the Total Neuropathy Score-clinical version and Common Terminology Criteria for Adverse Events before, during, and up to 6-12 months after the end of treatment. Nerve conduction studies (NCS) were performed before and after chemotherapy discontinuation. Consecutive plasma samples were analyzed for NfL levels using a Simoa® analyzer. Changes in pNfL were compared between groups and were eventually correlated with clinical and NCS data. Clinically relevant (CR) CIPN was considered to be grade ≥ 2. RESULTS: Eighty-two patients, mostly women (59.8%), were included. One third of the patients who received TX (29.4%), BV (31%), or PT (36.8%) developed CR-CIPN, respectively, without differences among them (p = 0.854). Although pNfL significantly increased during treatment and decreased throughout the recovery period in all three groups, patients receiving TX showed significantly greater and earlier changes in pNfL levels compared to the other agents (p < 0.001). CONCLUSIONS: A variable change in pNfL is observed depending on the type of agent and mechanism of neurotoxicity with comparable CIPN severity, strongly implying the need to identify different cutoff values for each agent.

Curcumin relieves oxaliplatin-induced neuropathic pain via reducing inflammation and activating antioxidant response.

Oxaliplatin (OXA) has shown high effectiveness in the treatment of cancers, but its anticancer clinical effects often induce neurotoxicity leading to neuropathic pain. Oxidative damage and NLRP3 inflammasome play important roles in neuropathic pain development. Here, neuropathic pain mouse model was constructed by continuous intraperitoneal injection of OXA. OXA administration induced mechanical pain, spontaneous pain, thermal hyperalgesia and motor disability in mice. The spinal cord tissues of OXA mice exhibited the suppressed antioxidative response, the activated NLRP3 inflammasome mediated inflammatory responses, and the increased GSK-3ß activity. Next, we injected curcumin (CUR) intraperitoneally in OXA mice for seven consecutive days. CUR-treated mice showed increased mechanical pain thresholds, reduced number of spontaneous flinches, increased paw withdrawal latency, and restored latency to fall. While in the spinal cord, CUR treatment inhibited the NLRP3 inflammasome mediated inflammatory response, increased Nrf2/GPX4-mediated antioxidant responses, and decreased mitochondrial oxidative generation. Additionally, CUR combined with GSK-3ß through four covalent bonds and reduced GSK-3ß activity. In conclusion, our findings suggest that CUR treatment inhibits GSK-3ß activation, increases Nrf2 mediated antioxidant responses, inhibits oxidative damage and inflammatory reaction, and alleviates OXA-induced neuropathic pain.

Incidence and risk factors for developing chemotherapy-induced neuropathic pain in 500 cancer patients: A file-based observational study.

OBJECTIVE: To define the incidence and risk factors for developing chemotherapy-induced neuropathic pain (CINP). METHODS: Retrospective, file-based analysis on cancer patients who received any type of conventional chemotherapy and for whom neurological evaluation was asked to reveal the extent of chemotherapy-induced peripheral neurotoxicity (CIPN) with or without CINP. CINP was assessed by means of the PI-NRS and Douleur Neuropathique-4 questionnaire. The total neuropathy score-clinical version graded the severity of CIPN. RESULTS: The medical files of 500 chemotherapy-treated cancer patients were reviewed. Any grade chronic CIPN was disclosed in 343 (68.6%) patients and CINP in 127 (37%) of them, corresponding to an overall percentage of 25.4% among all 500 included patients. The logistic regression analysis identified as independent predictors for CINP development the presence of uncomplicated diabetes (OR: 2.17; p = .039) and grade 2-3 chronic CIPN (OR: 1.61; p < .001) as also the administration of combined paclitaxel plus cisplatin (reference variable), compared to oxaliplatin (OR: 0.18; p = .001) and taxanes (OR: 0.16; p < .001). The increased severity of acute OXAIPN was associated with CINP (OR: 4.51; p < .001). OXA-treated patients with persistent CINP presented a worst likelihood to improve after chemotherapy discontinuation, than patients receiving combined paclitaxel plus cisplatin (OR: 50; p < .001). CONCLUSION: The incidence of CINP in our cohort was comparable to previous reports, with severities fluctuating upwards during chemotherapy and declined post-chemotherapy. Uncomplicated diabetes, the combined paclitaxel plus cisplatin treatment and the increased severity of acute oxaliplatin neurotoxicity mostly increase the risk for developing CINP. OXA-treated patients present less possibilities to recover from CINP after chemotherapy discontinuation, than other chemotherapies.

Cilostazol improves the prognosis after hepatectomy in rats with sinusoidal obstruction syndrome.

BACKGROUND AND AIM: Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. MATERIAL AND METHODS: Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS + CZ (MCT + CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48 h after MCT administration. Postoperative survival rates were evaluated (n = 9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. RESULTS: The cumulative 10-day postoperative survival rate was significantly higher in the SOS + CZ group than in the SOS group (88.9% vs 33.3%, P = 0.001). Total SOS scores were significantly lower in the SOS + CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS + CZ group than in the SOS group on POD 1 (86.1 ± 8.2% vs 63.8 ± 9.3%, P = 0.003). CONCLUSION: Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.

Bone loss over time and risk of osteoporosis in advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer has a high risk of developing osteoporosis. However, the impact of osteoporosis has not been well-studied. This study aimed to evaluate bone loss over time and risk of osteoporosis in patients with advanced pancreatic cancer. METHODS: We retrospectively examined consecutive patients with unresectable pancreatic cancer who had evaluable computed tomography before treatment and at 1-year follow-up. Bone mineral density at the first lumbar vertebra was measured on computed tomography, and osteoporosis was defined as bone mineral density < 135 Hounsfield units. The prevalence and risk factors for osteoporosis, changes in bone mineral density over time and incidence of bone fractures were analyzed. RESULTS: Three hundred eighty patients were included. Osteoporosis was associated with older age, female sex, low body mass index and poor performance status at baseline. A consistent decrease in bone mineral density was observed over time regardless of age, sex or disease status, resulting in an increase in the prevalence of osteoporosis over time (47% at baseline, 79% at 1 year, 88% at 2 years, 89% at 3 years, 95% at 4 years and 100% at 5 years). Changes in bone mineral density from baseline were greater in patients with locally-advanced pancreatic cancer, in those who received modified FOLFIRINOX or S-IROX for more than 3 months, and in those who received radiation therapy. Incident fractures developed in 45 patients (12%) during follow-up. CONCLUSIONS: Osteoporosis and osteoporotic fractures were highly prevalent in patients with advanced pancreatic cancer. This study highlights the importance of screening for osteoporosis in such patients.

Motor disorders related to oxaliplatin-induced peripheral neuropathy: long-term severity and impact on quality of life.

PURPOSE: Sensory chemotherapy-induced peripheral neuropathy (CIPN) is well-recognized, but motor CIPN remains understudied. This secondary analysis focused on the long-term severity and impact of motor disorders, their relation to sensory CIPN, neuropathic pain, psychological distress, and health-related quality of life (HRQoL) after oxaliplatin-based chemotherapy in colorectal cancer (CRC) survivors. METHODS: Data from a multicenter, cross-sectional study were re-analyzed to explore motor CIPN among CRC survivors up to 5 years post-chemotherapy, with no longitudinal follow-up. Questionnaires assessed sensory and motor CIPN (QLQ-CIPN20), neuropathic pain (DN4), anxiety and depression (HADS), and HRQoL (QLQ-C30). RESULTS: Among 405 CRC survivors, 31.1% had sensory CIPN as previously described. When categorizing the 405 CRC survivors based on the years since their last oxaliplatin-based chemotherapy, the motor scores derived from the QLQ-CIPN20 showed no significant difference between years (p = 0.08). Motor CIPN scores correlated with female gender, higher oxaliplatin dose intensity, sensory CIPN, and neuropathic pain. Motor CIPN also linked to decreased HRQoL and increased psychological distress. CONCLUSION: The study underscores the detrimental impact of motor disorders on CRC survivors post-oxaliplatin-based chemotherapy. Oncologists should prioritize assessing and managing motor manifestations alongside sensory symptoms to enhance post-cancer quality of life. TRIAL REGISTRATION: NCT02970526 (2016-11-22). https://classic. CLINICALTRIALS: gov/ct2/show/NCT02970526?term=NCT02970526&draw=2&rank=1 .

Low skeletal muscle radiodensity is a risk factor for adjuvant chemotherapy discontinuation in colorectal cancer.

BACKGROUND: Previously, we reported SMR (skeletal muscle radiodensity) as a potential prognostic marker for colorectal cancer. However, there have been limited studies on the association between SMR and the continuation of adjuvant chemotherapy in colorectal cancer. METHODS: In this retrospective study, 143 colorectal cancer patients underwent curative surgery and adjuvant chemotherapy using the CAPOX regimen. Patients' SMRs were measured from preoperative CT images and divided into low (bottom quarter) and high (top three quarters) SMR groups. We compared chemotherapy cycles, capecitabine and oxaliplatin doses, and adverse effects in each group. RESULTS: The low SMR group had significantly fewer patients completing adjuvant chemotherapy compared to the high SMR group (44% vs. 68%, P < 0.01). Capecitabine and oxaliplatin doses were also lower in the low SMR group. Incidences of Grade 2 or Grade 3 adverse effects did not differ between groups, but treatment discontinuation due to adverse effects was significantly higher in the low SMR group. Logistic regression analysis revealed Stage III disease (odds ratio 18.09, 95% CI 1.41-231.55) and low SMR (odds ratio 3.26, 95% CI 1.11-9.56) as factors associated with unsuccessful treatment completion. Additionally, a higher proportion of low SMR patients received fewer than 2 cycles of chemotherapy (50% vs. 12%). CONCLUSION: The low SMR group showed higher treatment incompletion rates and received lower drug doses during adjuvant chemotherapy. Low SMR independently contributed to treatment non-completion in colorectal cancer patients.

Rechallenges without desensitization following platinum-based chemotherapy reactions.

BACKGROUND: There is increasing interest in non-desensitization protocols as a potential way to reintroduce chemotherapy following hypersensitivity reactions (HSR). OBJECTIVE: To provide insight into the potential utility of non-desensitization reintroduction, particularly at institutions where allergy consultation may not be available. METHODS: For 70 patients with platinum HSR who underwent rechallenge with standard (≤2 hours), extended (1-bag, 1-step, 4-6 hours), or titrated (4-to-5-bag and -step, 6-7.5 hours) infusions between 1/2014 and 7/2019, demographics and clinical characteristics were reviewed and initial and breakthrough reactions (BTR) were graded using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Tolerance (no BTR) and completion (dose completed despite BTR) were compared using Fisher's exact test. RESULTS: Patients (mean [standard deviation] age 57 [13] years, initial HSR grade 2 [1]), were rechallenged with standard (n = 8), extended (n = 23), or titrated (n = 22) infusions after oxaliplatin HSR; and standard (n = 5) or titrated (n = 12) after carboplatin HSR. Tolerance and completion were higher for extended versus (vs) standard (tolerance-87%-vs-8%, p < 0.005; completion-96%-vs-38%, p < 0.005) and titrated versus standard (tolerance-76%-vs-8%, p < 0.005; completion-79%-vs-38%, p < 0.05) infusions. CONCLUSIONS: Extended and titrated infusions may increase reintroduction safety compared to standard infusions. Further investigation into extended infusions may provide a safe alternative to standard infusions in patients who may not have access to desensitization at their institution.

αO-Conotoxin GeXIVA[1,2] Reduced Neuropathic Pain and Changed Gene Expression in Chronic Oxaliplatin-Induced Neuropathy Mice Model.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR)-specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models; however, the related mechanisms remain unclear. Here, we analyzed the preventive effect of GeXIVA[1,2] on neuropathic pain in the long-term oxaliplatin injection-induced CIPN model. At the end of treatment, lumbar (L4-L6) spinal cord was extracted, and RNA sequencing and bioinformatic analysis were performed to investigate the potential genes and pathways related to CIPN and GeXIVA[1,2]. GeXIVA[1,2] inhibited the development of mechanical allodynia induced by chronic oxaliplatin treatment. Repeated injections of GeXIVA[1,2] for 3 weeks had no effect on the mice's normal pain threshold or locomotor activity and anxiety-like behavior, as evaluated in the open field test (OFT) and elevated plus maze (EPM). Our RNA sequencing results identified 209 differentially expressed genes (DEGs) in the CIPN model, and simultaneously injecting GeXIVA[1,2] with oxaliplatin altered 53 of the identified DEGs. These reverted genes were significantly enriched in immune-related pathways represented by the cytokine-cytokine receptor interaction pathway. Our findings suggest that GeXIVA[1,2] could be a potential therapeutic compound for chronic oxaliplatin-induced CIPN management.