Diversity of oncopharmacogenetic profile within Spanish population.

Consensus guidelines for genotype-guided fluoropyrimidine dosing based on variation in the dihydropyrimidine dehydrogenase (DPYD) gene before treatment have been firmly established. The prior pharmacogenetic report avoids the serious toxicity that inevitably occurred in a non-negligible percentage of the treated patients. The precise description of the allelic distribution of the variants of interest in our reference populations is information of great interest for the management of the prescription of these antineoplastic drugs. We characterized the allelic distribution of the UGT1A1*28 variant (rs3064744), as well as the DPYD*2A (rs3918290) variant, c.1679T>G (rs55886062), c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in series of 5251 patients who are going to receive treatment with irinotecan and fluoropyrimidines, representative of Valencian, Aragonese and Western Andalusian populations.

A phase 1 study of mebendazole with bevacizumab and irinotecan in high-grade gliomas.

BACKGROUND: High-grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole is an anti-helminthic benzimidazole that has demonstrated efficacy in numerous in vitro cancer models, and is able to cross the blood-brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of mebendazole in combination with bevacizumab and irinotecan in children and young adults with HGG. OBJECTIVE: To determine the maximally tolerated dose of mebendazole when given in combination with bevacizumab and irinotecan in children with HGG; to describe the progression-free survival (PFS) and overall survival (OS) for this group. DESIGN/METHOD: Patients between 1 and 21 years of age with HGG were enrolled in a 3 + 3 design to escalating doses of mebendazole in combination with bevacizumab (10 mg/kg/dose) and irinotecan (150 mg/m2 /dose). Subjects were eligible upfront after completion of radiation or at the time of progression. Mebendazole was taken orally twice per day continuously, and bevacizumab and irinotecan were given intravenously on Days 1 and 15 of 28-day cycles. RESULTS: Between 2015 and 2020, 10 subjects were enrolled at mebendazole doses of 50 mg/kg/day (n = 3), 100 mg/kg/day (n = 4), and 200 mg/kg/day (n = 3). One subject assigned to 100 mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, one subject had anaplastic astrocytoma, and one subject had a spinal HGG. All subjects received radiation. There were no dose-limiting toxicities. The most frequent G3/4 adverse events were neutropenia (n = 3) and lymphopenia (n = 4). The overall response rate was 33%, with two subjects achieving a partial response and one subject achieving a complete response sustained for 10 months. The mean PFS and OS from the start of study treatment were 4.7 and 11.4 months, respectively. CONCLUSION: Mebendazole was safe and well tolerated when administered with bevacizumab and irinotecan at doses up to 200 mg/kg/day. Further studies are needed to determine the efficacy of this treatment.

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.

Evaluation of the risk factors for the failure of a single prophylactic dose of anticholinergic drugs for irinotecan-induced cholinergic symptoms.

OBJECTIVE: Irinotecan (IRI) is an anticancer drug that is frequently used to treat colorectal, gastric, and pancreatic cancers. Its side effects include cholinergic symptoms, such as diarrhea, abdominal pain, nausea, and hyperhidrosis. Anticholinergic medicines are frequently used for treatment or prophylaxis; however, the risk factors for the failure of a single prophylactic anticholinergic administration remain unclear. Moreover, an appropriate anticholinergic drug for prophylaxis remains unknown. Thus, we aimed to identify the risk factors associated with the failure of a single prophylactic dose of anticholinergic drugs for IRI-induced cholinergic symptoms and to evaluate the usefulness of multiple prophylactic doses of anticholinergic drugs. MATERIALS AND METHODS: Patients who underwent IRI treatment for colorectal, gastric, or pancreatic cancer and received prophylactic anticholinergic drugs for IRI-induced cholinergic symptoms (n = 135) were retrospectively evaluated. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for failure of a single prophylactic dose of anticholinergic drugs. We also evaluated the efficacy of multiple prophylactic anticholinergic drug administration. RESULTS: Based on univariate and multivariate analyses, colorectal cancer, female sex, and prophylactic use of scopolamine butyl bromide were identified as risk factors for failure of a single prophylactic dose of anticholinergic drugs. The efficacy of multiple prophylactic doses was confirmed to be 95% of the patients who had a single prophylactic failure due to temporary effect but symptom appearance after a certain period of time (wearing-off). CONCLUSION: We determined that colorectal cancer, female sex, and prophylactic use of scopolamine butyl bromide were risk factors associated with the failure of a single prophylactic dose of anticholinergic drugs, and that multiple prophylactic doses for wearing-off can be a promising method.

Irinotecan-gut microbiota interactions and the capability of probiotics to mitigate Irinotecan-associated toxicity.

BACKGROUND: Irinotecan is a chemotherapeutic agent used to treat a variety of tumors, including colorectal cancer (CRC). In the intestine, it is transformed into SN-38 by gut microbial enzymes, which is responsible for its toxicity during excretion. OBJECTIVE: Our study highlights the impact of Irinotecan on gut microbiota composition and the role of probiotics in limiting Irinotecan-associated diarrhea and suppressing gut bacterial ß-glucuronidase enzymes. MATERIAL AND METHODS: To investigate the effect of Irinotecan on the gut microbiota composition, we applied 16S rRNA gene sequencing in three groups of stool samples from healthy individuals, colon cancer, and Irinotecan treated patients (n = 5/group). Furthermore, three Lactobacillus spp.; Lactiplantibacillus plantarum (L. plantarum), Lactobacillus acidophilus (L. acidophilus), Lacticaseibacillus rhamnosus (L. rhamnosus) were used in a single and mixed form to in-vitro explore the effect of probiotics on the expression of ß-glucuronidase gene from E. coli. Also, probiotics were introduced in single and mixed forms in groups of mice before the administration of Irinotecan, and their protective effects were explored by assessing the level of reactive oxidative species (ROS) as well as studying the concomitant intestinal inflammation and apoptosis. RESULTS: The gut microbiota was disturbed in individuals with colon cancer and after Irinotecan treatment. In the healthy group, Firmicutes were more abundant than Bacteriodetes, which was the opposite in the case of colon-cancer or Irinotecan treated groups. Actinobacteria and Verrucomicrobia were markedly present within the healthy group, while Cyanobacteria were noted in colon-cancer and the Irinotecan-treated groups. Enterobacteriaceae and genus Dialister were more abundant in the colon-cancer group than in other groups. The abundance of Veillonella, Clostridium, Butryicicoccus, and Prevotella were increased in Irinotecan-treated groups compared to other groups. Using Lactobacillus spp. mixture in mice models significantly relieved Irinotecan-induced diarrhea through the reduction of both ß-glucuronidase expression and ROS, in addition to guarding gut epithelium against microbial dysbiosis and proliferative crypt injury. CONCLUSIONS: Irinotecan-based chemotherapy altered intestinal microbiota. The gut microbiota participates greatly in determining both the efficacy and toxicity of chemotherapies, of which the toxicity of Irinotecan is caused by the bacterial ß-glucuronidase enzymes. The gut microbiota can now be aimed and modulated to promote efficacy and decrease the toxicity of chemotherapeutics. The used probiotic regimen in this study lowered mucositis, oxidative stress, cellular inflammation, and apoptotic cascade induction of Irinotecan.

Multicenter Retrospective Analysis of Original versus Modified FOLFIRINOX in Metastatic Pancreatic Cancer: Results of the NAPOLEON Study.

INTRODUCTION: Original FOLFIRINOX (oFFX) is more toxic than other regimens for patients with metastatic pancreatic cancer (mPC); therefore, a modified FFX (mFFX) regimen with a reduced dosage has been used in Japanese clinical practice. However, very few studies have compared these two regimens. METHODS: This study was conducted as part of a multicenter retrospective study of 318 patients with mPC across 14 centers in Japan (NAPOLEON study). To control for potential bias and confounders, we conducted a propensity score-adjusted analysis of patient characteristics and clinical outcomes. RESULTS: oFFX and mFFX were administered to 48 and 54 patients. More patients with younger age and poorer performance status were included in the oFFX group. The overall survival (OS; median, 11.6 vs. 11.3 months; hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.60-1.40; p = 0.67), progression-free survival (PFS) (median, 6.3 vs. 5.7 months; HR, 0.85; 95% CI, 0.56-1.28; p = 0.44), and overall response rate (29 vs. 26%, p = 0.71) were not significantly different for the oFFX and mFFX groups. Thrombopenia and liver dysfunction were significantly more frequent with oFFX than with mFFX. The median received dose intensity of CPT-11 was higher with oFFX than with mFFX (299 vs. 270 mg/m2/week, p < 0.01). The propensity score-adjusted analysis revealed no statistically significant differences in OS and PFS between the two groups. CONCLUSION: In our data, there was no significant difference in efficacy between mFFX and oFFX, and mFFX has fewer adverse events.

Pogostemon cablin (Blanco) Benth granule revealed a positive effect on improving intestinal barrier function and fecal microbiota in mice with irinotecan-induced intestinal mucositis.

Pogostemon cablin (Blanco) Benth (PCB), a medicinal and edible homologous Chinese herb, has a protective effect on the structure and function of intestine. In this study, we aimed to investigate the effect of PCB granule (PCBG) on the improvement of irinotecan-induced intestinal mucositis and the regulation of intestinal microorganisms in mice. Our results demonstrated that PCBG supplementation significantly improved diarrhea symptoms caused by irinotecan, as evidenced by inhibiting weight loss, reversing intestinal atrophy, protecting against splenomegaly and balancing oxidative stress. Furthermore, compared with the model group, PCBG restored the intestinal morphology and improved intestinal barrier dysfunction by promoting the expression of tight junction proteins and mucin. Moreover, high-throughput sequencing analysis revealed that PCBG improved the flora disorder caused by irinotecan and regulated microbial community structure, such as decreasing the relative abundance of Bacteroides as well as increasing the relative abundance of Lactobacillus. Meanwhile, the disordered microbial functions in intestinal mucositis mice were recovered more closely to the controls by PCBG. Finally, we found that a robust correlation between the specific microbiota and intestinal mucositis-related index. In summary, these findings revealed the beneficial effects of PCBG on the intestinal barrier and gut microbiota of irinotecan-induced intestinal mucositis, which may be one of the potential strategies to reduce the clinical side effects of irinotecan.

Survival of Patients with Colorectal Liver Metastases after Transarterial Chemoembolization Using Irinotecan-Eluting Microspheres: A Single-Center Retrospective Analysis Comparing RECIST 1.1 and Choi Criteria.

PURPOSE: To evaluate the factors that affected overall survival and hepatic progression-free survival using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Choi criteria in patients with colorectal liver metastases treated with transarterial chemoembolization (TACE) using irinotecan-eluting microspheres (IEMs) who failed at least 1 line of systemic chemotherapy. MATERIALS AND METHODS: A single-institution retrospective analysis was performed including patients with unresectable liver metastases from a colorectal primary malignancy and treated with IEM-TACE. Radiologic hepatic progression-free survival was measured using the RECIST 1.1 and Choi criteria. RESULTS: The median patient age was 61.5 years, with 80 (67%) men. A total of 328 IEM-TACE procedures were performed during the study period. One hundred eighteen patients who failed at least 1 line of systemic chemotherapy before TACE demonstrated a median overall survival of 12.7 months. Overall survival was higher in patients who had previous primary resection (P < .05), prior ablation (P < .05), or completed the scheduled TACE treatments (P < .05) but was adversely affected by the presence of extrahepatic disease (P < .05) and larger preprocedural tumor burden (P < .01). Prior systemic chemotherapy lines (P = .98) and microsphere size (P = .34) did not affect survival. Partial radiologic response to treatment using the Choi criteria (n = 28, P < .01) correlated significantly with survival, a correlation not seen with the RECIST 1.1 measurements (n = 5, P = .13). CONCLUSIONS: A partial response to treatment of unresectable colorectal liver metastases treated by TACE with IEMs measured using the Choi criteria correlated significantly with improved survival, while RECIST 1.1 measurements did not.

Genetic variations in ABC transporter genes as a predictive biomarker for toxicity in North Indian lung cancer patients undergoing platinum-based doublet chemotherapy.

ATP-binding cassette (ABC) transporters are expressed in various human tissues and play a vital role in the efflux of various chemotherapeutic drugs. The current study has assessed genetic variants of ABCB1, ABCC1, ABCC2, and ABCG2 genes in 407 lung cancer patients undergoing platinum-based doublet chemotherapy. The association of ABCB1 (C1236 T, C3435 T, and G2677 T/A), ABCC1 (G3173 A and G2168 A),ABCC2 (G4544 A), and ABCG2 (C421 A) polymorphisms with chemotherapy-induced adverse events were assessed, and statistical analysis was conducted. Our data showed that patients harboring heterozygous (GA) genotype for ABCC1 G3173 A had an increased risk of developing leukopenia (odds ratio [OR] = 1.88, p = 0.04) and anemia (adjusted odds ratio [AOR] = 2.70, p = 0.03). For ABCC2 G4544 A polymorphism, patients harboring one copy of the mutant (GA) allele showed an increased risk of developing anemia (OR = 4.24, p = 0.03). After adjusting with various confounding factors, the heterozygous (GA) genotype showed a 5.63-fold increased risk of developing anemia (AOR = 5.63, p = 0.03). The ABCB1 G2677 A (OR = 0.37, p = 0.008) and ABCC1 G3173 A (OR = 0.54, p = 0.04) polymorphism showed a lower incidence of developing nephrotoxicity. In ABCG2 C421 A polymorphism, patients harboring heterozygous (CA) genotype had a lower incidence of having diarrhea (OR = 0.25, p = 0.04). An increased risk of having diarrhea was observed in the heterozygous genotype (GA) for ABCC1 G3173 A polymorphism (AOR = 2.78, p = 0.04). An increased risk of liver injury was found in the patients carrying heterozygous genotype of the ABCC1 G3173 A (OR = 2.06, p = 0.02) and ABCB1 C1236 T (OR = 1.85, p = 0.01). This study demonstrates the role of polymorphic variations in ABCB1, ABCC1, ABCC2, and ABCG2 in predicting hematological, nephrotoxicity, gastrointestinal, and hepatotoxicity.

Liposomal irinotecan with fluorouracil and leucovorin after gemcitabine-based therapy in Japanese patients with metastatic pancreatic cancer: additional safety analysis of a randomized phase 2 trial.

BACKGROUND: Nanoliposomal irinotecan (nal-IRI) was recently authorized in Japan for unresectable pancreatic cancer after disease progression following chemotherapy. Physicians now consider certain aspects of nal-IRI safety profile as slightly different from conventional irinotecan. This report aims to explore additional aspects of the nal-IRI safety in Japanese phase 2 study. METHODS: We analyzed the incidence, time to first onset, and time to resolution for adverse events that require special attention and other selected toxicities in the nal-IRI combination group (n = 46). RESULTS: Leukopenia/neutropenia (76.1%/71.7%), diarrhea (58.7%) and hepatic dysfunction (41.3%) were the most commonly reported treatment-emergent adverse events, with a median time to onset of 21.0 days (range: 8, 97), 9.0 days (1, 61) and 22.0 days (2, 325), respectively, and a median time to resolution of 8.0 days (95% confidence intervals: 8, 9), 4.0 days (4, 8) and 40.0 days (9, -), respectively. Eight patients experienced Grade ≥ 3 diarrhea and their symptoms were well controlled by dose modification except one patient who had drug withdrawal. The median time to resolution for Grade ≥ 3 and Grade ≤ 2 diarrhea was 17.5 days (95% confidence intervals: 1, 31) and 4 days (3, 7), respectively. Anorexia occurred in 28/46 patients (60.9%) with a median time to onset of 4.0 days (range: 2, 132) and a median time to resolution of 12.0 days (95% confidence intervals: 6, 26). CONCLUSIONS: We explored safety profile of nal-IRI combination regimen recognized as effective and tolerable treatment for Japanese unresectable pancreatic cancer patients. Although the treatment-emergent adverse events occurred were controllable, patients with prolonged toxicities should be closely managed.

Design, synthesis, and biological evaluation studies of novel carboxylesterase 2 inhibitors for the treatment of irinotecan-induced delayed diarrhea.

Human carboxylesterase 2 (hCES2A), one of the most important serine hydrolases distributed in the small intestine and colon, plays a crucial role in the hydrolysis of various prodrugs and esters. Accumulating evidence has demonstrated that the inhibition of hCES2A effectively alleviate the side effects induced by some hCES2A-substrate drugs, including delayed diarrhea caused by the anticancer drug irinotecan. Nonetheless, there is a scarcity of selective and effective inhibitors that are suitable for irinotecan-induced delayed diarrhea. Following screening of the in-house library, the lead compound 01 was identified with potent inhibition on hCES2A, which was further optimized to obtain LK-44 with potent inhibitory activity (IC50 = 5.02 ± 0.67 µM) and high selectivity on hCES2A. Molecular docking and molecular dynamics simulations indicated that LK-44 can formed stable hydrogen bonds with amino acids surrounding the active cavity of hCES2A. The results of inhibition kinetics studies unveiled that LK-44 inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a Ki value of 5.28 µM. Notably, LK-44 exhibited low toxicity towards HepG2 cells according to the MTT assay. Importantly, in vivo studies showed that LK-44 significantly reduced the side effects of irinotecan-induced diarrhea. These findings suggested that LK-44 is a potent inhibitor of hCES2A with high selectivity against hCES1A, which has potential as a lead compound for the development of more effective hCES2A inhibitors to mitigate irinotecan-induced delayed diarrhea.

Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil.

Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial ß-oxidation (CPT1α) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism.

Eosinophil plays a crucial role in intestinal mucositis induced by antineoplastic chemotherapy.

Mucositis is a major clinical complication associated with cancer treatment and may limit the benefit of chemotherapy. Leukocytes and inflammatory mediators have been extensively associated with mucositis severity. However, the role of eosinophils in the pathophysiology of chemotherapy-induced mucositis remains to be elucidated. Here, using GATA-1-deficient mice, we investigated the role of eosinophils in intestinal mucositis. There was marked accumulation of eosinophils in mice given irinotecan and eosinophil ablation inhibited intestinal mucositis. Treatment with Evasin-4, a chemokine receptor antagonist, reduced the recruitment of eosinophils and decreased irinotecan-induced mucositis. Importantly, Evasin-4 did not interfere negatively with the antitumour effects of irinotecan. Evasin-4 was of benefit for mice given high doses of irinotecan once Evasin-4-treated mice presented delayed mortality. Altogether, our findings suggest that Evasin-4 may have significant mucosal-protective effects in the context of antineoplastic chemotherapy and may, therefore, be useful in combination with anticancer treatment in cancer patients.

RESILIENT part 1: a phase 2 dose-exploration and dose-expansion study of second-line liposomal irinotecan in adults with small cell lung cancer.

BACKGROUND: RESILIENT (NCT03088813) is a phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with small cell lung cancer and disease progression on/after first-line platinum-based therapy. Here, we present results from RESILIENT part 1. METHODS: This open-label, single-arm, safety run-in evaluation with dose-exploration and dose-expansion phases included patients ≥18 years old with Eastern Cooperative Oncology Group performance status of 0/1; those with asymptomatic central nervous system metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: During dose exploration, 5 patients received intravenous liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received intravenous liposomal irinotecan at 70 mg/m2 . Of these 25 patients (median age [range], 59.0 [48.0-73.0] years, 92.0% with metastatic disease), 10 experienced grade ≥3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20.0%) and neutropenia (16.0%), and 3 had serious treatment-related TEAEs, of whom 2 died. ORR was 44.0% (95% confidence interval [CI]: 24.40-65.07; 1 complete response, 10 partial responses) and median (95% CI) PFS and OS were 3.98 (1.45-4.24) months and 8.08 (5.16-9.82) months, respectively. CONCLUSION: Overall, no new safety signals were identified with liposomal irinotecan, and antitumor activity was promising. RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan, is ongoing. LAY SUMMARY: Small cell lung cancer (SCLC) is an aggressive disease with few treatment options after platinum-based therapy. Administering 1 option, irinotecan, as a "liposomal" formulation, may extend drug exposure and improve outcomes. The RESILIENT part 1 trial assessed the safety and efficacy of liposomal irinotecan in 25 adults with SCLC after disease progression despite platinum-based therapy. No new safety concerns were reported. The most common moderate-to-severe side effects were diarrhea (20% of patients) and neutropenia (16%). Tumors responded to treatment in 44% of patients. Average survival was 8.08 months, and time to disease progression was 3.98 months. Liposomal irinotecan trials are ongoing.

Integration of DNA sequencing with population pharmacokinetics to improve the prediction of irinotecan exposure in cancer patients.

BACKGROUND: Irinotecan (CPT-11) is an anticancer agent widely used to treat adult solid tumours. Large interindividual variability in the clearance of irinotecan and SN-38, its active and toxic metabolite, results in highly unpredictable toxicity. METHODS: In 217 cancer patients treated with intravenous irinotecan single agent or in combination, germline DNA was used to interrogate the variation in 84 genes by next-generation sequencing. A stepwise analytical framework including a population pharmacokinetic model with SNP- and gene-based testing was used to identify demographic/clinical/genetic factors that influence the clearance of irinotecan and SN-38. RESULTS: Irinotecan clearance was influenced by rs4149057 in SLCO1B1, body surface area, and co-administration of 5-fluorouracil/leucovorin/bevacizumab. SN-38 clearance was influenced by rs887829 in UGT1A1, pre-treatment total bilirubin, and EGFR rare variant burden. Within each UGT1A1 genotype group, elevated pre-treatment total bilirubin and/or presence of at least one rare variant in EGFR resulted in significantly lower SN-38 clearance. The model reduced the interindividual variability in irinotecan clearance from 38 to 34% and SN-38 clearance from 49 to 32%. CONCLUSIONS: This new model significantly reduced the interindividual variability in the clearance of irinotecan and SN-38. New genetic factors of variability in clearance have been identified.

A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects With Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer.

OBJECTIVES: To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. METHODS: A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. RESULTS: Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). CONCLUSIONS: Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01836432.

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer.

BACKGROUND: Standard chemotherapy is associated with low response rates and short progression-free survival among patients with pretreated metastatic triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody-drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors. METHODS: We conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous anticancer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall survival. Post hoc analyses determined the response rate and duration, which were assessed by blinded independent central review. RESULTS: The 108 patients with triple-negative breast cancer had received a median of 3 previous therapies (range, 2 to 10). Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7). CONCLUSIONS: Sacituzumab govitecan-hziy was associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions. (Funded by Immunomedics; IMMU-132-01 ClinicalTrials.gov number, NCT01631552.).

Conversion therapy, palliative chemotherapy and surgery, which of these is the best treatment for locally advanced and advanced pancreatic cancer?

A retrospective study was conducted to analyze which translational therapy, palliative chemotherapy and surgery is the best treatment for locally advanced and advanced pancreatic cancer, and to screen out the dominant population for the best treatment. A total of 83 patients with pancreatic cancer, including locally advanced and advanced pancreatic cancer, who had lost the opportunity for radical surgery and were admitted to Zhejiang Provincial People's Hospital between January 2015 and July 2021 were collected. A total of 39 patients received palliative chemotherapy, 25 patients received conversion therapy and 19 patients tried surgery at the first visit. We conducted survival follow-up and prognostic evaluation of 83 patients. The median overall survival (mOS) and median progression-free survival (mPFS) of 25 pancreatic cancer patients who received conversion therapy were longer than those of pancreatic cancer patients who received palliative chemotherapy (mOS: 16 months vs. 9 months, P = 0.001; mPFS: 11 months vs. 7.5 months, P = 0.038) and surgery (mOS: 16 months vs. 9 months, P = 0.018; mPFS: 11 months vs. 5.5 months, P < 0.001). Multivariate and Kaplan-Meier analysis showed that age, distant metastasis, and the degree of CA199 declined after chemotherapy were independent factors affecting overall survival (OS) of pancreatic cancer patients who received conversion therapy. Conversion therapy can improve OS and progression-free survival in patients with locally advanced or advanced pancreatic cancer to a certain extent. Some patients with advanced pancreatic cancer have surprising results after receiving conversion therapy.

DPYD polymorphisms c.496A>G, c.2194G>A and c.85T>C and risk of severe adverse drug reactions in patients treated with fluoropyrimidine-based protocols.

AIMS: Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)-related adverse events (AE). Guidelines recommend FP dosing adjusted to genotype-predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798 and rs56038477). We evaluated the relationship between three further DPYD polymorphisms: c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265) and the risk of severe AEs. METHODS: Consecutive FP-treated adult patients were genotyped for "standard" and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0-2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining two tested polymorphisms). RESULTS: Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhoea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n = 127) than in controls (n = 376) [OR = 5.20 (95% CI 1.88-14.3), Bayesian OR = 5.24 (95% CrI 3.06-9.12)]. Odds tended to be higher in c.2194G>A variant carriers (n = 58) than in controls (n = 432) [OR = 1.88 (0.95-3.73), Bayesian OR = 1.90 (1.03-3.56)]. c.85T>C did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls). CONCLUSION: DPYD c.496A>G and possibly c.2194G>A variants might need to be considered for inclusion in the DPYD genotyping panel.

Comparison of safety and efficacy of fluorouracil + oxaliplatin + irinotecan (FOLFOXIRI) and modified FOLFOXIRI with bevacizumab for metastatic colorectal cancer: data from clinical practice.

PURPOSE: The efficacy of fluorouracil + oxaliplatin + irinotecan with bevacizumab (FOLFOXIRI + BV) has been verified for metastatic colorectal cancer (mCRC). In clinical practice, the original (O-FOLFOXIRI + BV) and modified dose settings (M-FOLFOXIRI + BV) are adopted for Asian patients. We aimed to compare the real-world efficacy and safety of these two regimens. METHODS: This retrospective cohort study reviewed clinical data of all consecutive mCRC patients treated with FOLFOXIRI + BV at a cancer centre in Japan. One hundred patients were divided into two groups: one that received O-FOLFOXIRI + BV (group O, n = 30) and another that received M-FOLFOXIRI + BV (group M, n = 70). Progression-free survival (PFS) was set as the primary endpoint, with overall survival (OS), overall response rate (ORR), and safety as secondary endpoints. RESULTS: PFS was superior in group M (median PFS; 8.7 vs. 11.5 months, P = 0.098). The use of O-FOLFOXIRI + BV emerged as an independent risk factor of poor PFS (hazard ratio = 2.155, P = 0.012). Both ORR (43.3 vs. 65.7%, P = 0.047) and OS (median OS; 17.9 vs. 27.0 months, P = 0.127) were more favourable in group M. Grade ≥ 3 adverse events were more frequently observed in group O (90 vs. 74.3%, P = 0.108), whereas dose intensity was higher in group M because a shorter duration was required for cytotoxic drug administration (2.9 vs. 2.6 weeks/course, P = 0.051) in the induction term. CONCLUSION: We found that M-FOLFOXIRI + BV had more favourable efficacy and safety than O-FOLFOXIRI + BV, which may be a better fit for Asian patients and can be potentially used as an alternative for upfront chemotherapy for mCRC.