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Background: Constipation is a common side effect of opioid therapy. An observational study of opioid-induced constipation (OIC) in Japanese patients with cancer (OIC-J) included 212 patients with various tumor types. This post hoc analysis of OIC-J evaluated a subgroup of patients with gastrointestinal (GI) cancer. Methods: Patients were aged ≥ 20 years, starting strong opioid therapy, had an ECOG PS of ≤ 2, and must have had ≥ 3 bowel movements during the week before enrollment. OIC was evaluated for 2 weeks after opioid initiation using the Rome IV diagnostic criteria for colorectal disorders, as well as physician's diagnosis, number of spontaneous bowel movements, Bowel Function Index score, and patient's self-assessment. Relationships between baseline characteristics and OIC incidence, and the effects of OIC on quality of life (QOL) were also explored. Results: Fifty patients from OIC-J who had GI cancer [colon (50%), stomach (28%), and esophageal (22%)] were included. OIC incidence varied by which diagnostic criteria were used (46.0–62.0%) and occurred rapidly after initiating opioid therapy. The use of prophylactic laxatives reduced the overall incidence rate of OIC from 71.0% to 47.4%. No baseline characteristics, except comorbidities, were associated with OIC incidence. Change from baseline to day 15 in PAC-SYM total score was significantly greater for patients with OIC versus those without OIC (0.188 versus −0.362; P = 0.0011). Conclusions: This post hoc analysis suggests that OIC occurs rapidly in patients with GI cancer after initiating opioid therapy, and negatively impacts QOL. Early and effective intervention strategies may be particularly useful in this group. Additional Information: Coauthor Makio Gamoh is deceased. [ABSTRACT FROM AUTHOR]

d-19575 (glufosfamide: β- d-glucosylisophosphoramide mustard) is an alkylating agent in which isophosphoramide mustard, the cytotoxic metabolite of ifosfamide, is covalently linked to β- d-glucose. We have performed a phase I study to determine the safety profile, pharmacokinetics, and antitumor activity of d-19575 in Japanese patients with advanced solid tumors Patients were treated with escalating doses of d-19575 administered by a two-step (fast–slow) intravenous infusion over 6 h every 3 weeks. Thirteen patients received 43 treatment cycles (median 3; range 1–11) at d-19575 doses of 3,200, 4,500, or 6,000 mg/m2. Hematologic toxicities and other side effects were generally mild. The maximum tolerated dose of d-19575 was 6,000 mg/m2, at which two patients experienced dose-limiting toxicities (hypophosphatemia, hypokalemia, and metabolic acidosis each of grade 3). Pharmacokinetic analysis revealed a linear relation between the area under the concentration-versus-time curve (AUC) and dose. The AUC values for isophosphoramide mustard were substantially greater than those achieved by bolus administration or continuous infusion of ifosfamide in conventional therapy. One patient with gallbladder cancer previously treated with cisplatin and gemcitabine achieved a partial response lasting for >5 months, and eight patients achieved disease stabilization. Our results show that d-19575 can be safely administered by infusion over 6 h at 4,500 mg/m2 every 3 weeks. The safety profile and potential antitumor activity of d-19575 show that phase II studies of this drug are warranted. [ABSTRACT FROM AUTHOR]

Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown. A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue. In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19–0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor–β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB. A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted. • The relation of NSCLC tumour burden to PD-1/PD-L1 inhibitor efficacy was evaluated. • High tumour burden (HTB) was associated with resistance to ICI monotherapy. • HTB was not associated with treatment outcomes for cytotoxic chemotherapy. • HTB was associated with macrophage-related and protumourigenic gene expression. • Patients with HTB may require more aggressive treatment than ICI monotherapy. [ABSTRACT FROM AUTHOR]

Context: Many patients who have cancer consider opioid-induced constipation (OIC) to be a burdensome side effect of opioid treatment.Objectives: To evaluate patient-reported outcomes in Japanese patients with cancer pain and OIC.Methods: This prospective observational study evaluated OIC incidence for two weeks in patients with cancer after they initiated strong opioid therapy. Rome IV diagnostic criteria, a physician's diagnosis, spontaneous bowel movements, Bowel Function Index score, and patients' daily self-assessments were used. Changes from baseline in Patient Assessment of Constipation Symptoms and Patient Assessment of Constipation Quality of Life (PAC-QOL) scores were compared between patients with and without OIC. Patients and health care providers (HCPs) completed study-specific questionnaires regarding OIC burden, treatment satisfaction, and patient-provider communications.Results: Among 212 enrolled patients, the incidence of OIC was 47.6% by patients' self-assessments, with a cumulative incidence of 30.2% by Day 3 and 43.5% by Day 7. Patient Assessment of Constipation Symptoms and PAC-QOL overall scores from patients with OIC worsened significantly from baseline compared with patients without OIC by all diagnostic criteria, except for spontaneous bowel movement frequency for PAC-QOL. Patients and HCPs were generally satisfied with OIC treatment; however, 53.5% of patients and approximately 40.0% of HCPs reported that OIC affected pain management. Most patients and HCPs reported that OIC conditions were sufficiently or essentially communicated.Conclusion: After starting opioid therapy, patients recognized OIC onset and its impact on cancer pain management, highlighting the need for effective patient-provider communications, diagnosis, and treatment of OIC to improve QOL for patients with cancer receiving opioid analgesics. [ABSTRACT FROM AUTHOR]