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Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma

New findings show the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit among previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma (N Engl J Med 2023; doi: 10.1056/NEJMoa2206834). Futibatinib targets a particular genetic alteration-FGFR2 fusion-which is found in approximately 14 percent of bile duct cancers. This multinational, open-label, single-group, Phase II study included 103 patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma, as well as disease progression after one or more previous lines of systemic therapy, excluding FGFR inhibitors.


Study participants received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary endpoint of this research was objective response (partial or complete response); secondary endpoints included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. "A total of 43 of 103 patients (42%) had a response, and the median duration of response was 9.7 months," the study authors reported. "Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations." At a median follow-up of 17.1 months, the data showed a median progression-free survival of 9 months and overall survival of 21.7 months. In terms of safety, common treatment-related Grade 3 adverse events included hyperphosphatemia, an increased aspartate aminotransferase level, stomatitis, and fatigue.


AUTHOR COMMENTARY: "These results turn treatment for this group of patients on its head," noted John Bridgewater, PhD, Professor at the UCL Cancer Institute and University College London Hospitals NHS Foundation Trust. "Instead of treating them with the blunderbuss that is chemotherapy, which attacks healthy cells alongside the cancer, we can offer a personalized treatment that just targets a specific alteration within the cancer. The benefits that patients saw in the trial were remarkable. It's important that patients with bile duct cancer get their cancer tested to find out if they have this abnormality. We can't afford to miss one of these alterations: the difference they could make to treatment outcomes is dramatic."



Chemotherapy delivery time affects treatment outcomes of female patients with diffuse large B cell lymphoma

A recent analysis suggests that rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment in the afternoon can reduce toxicity, while improving efficacy and survival outcome, among female patients with diffuse large B cell lymphoma (JCI Insight 2023; Researchers performed chronotherapeutic analysis using two cohorts of patients with diffuse large B-cell lymphoma undergoing chemotherapy in the morning or afternoon. The study authors evaluated the effect of a morning or afternoon schedule of R-CHOP on survival and drug tolerability in a survival cohort (n=210) and an adverse event cohort (n=129), respectively. Data revealed that female patients who underwent treatment in the afternoon had a 12.5 times reduced mortality rate (25% to 2%), while the cancer recurrence after 60 months was decreased by 2.8 times (37% to 13%). The analysis found that chemotherapy side effects, such as neutropenia, were more common in female patients who received treatment in the morning.


The study authors observed no difference in treatment efficiency depending on the treatment schedule among male patients. On average, the dose intensity was reduced by about 10 percent in female patients treated in the morning compared with those who received treatment in the afternoon. This was mainly attributed to a higher incidence of adverse side effects. An analysis of approximately 14,000 healthy individuals was then conducted to better understand the cause of gender differences. The research team found that "sex-specific chronotherapeutic effects can be explained by the larger daily fluctuation of circulating leukocytes and neutrophils in female than in male patients."


AUTHOR COMMENTARY: "Because the time of the internal circadian clock can vary greatly depending on the individual's sleep-wake patterns, we are currently developing a technology to estimate the time of the circadian clock from the patient's sleep pattern," said study author Jae Kyoung Kim, from the Seoul National University College of Medicine. "We hope that it can be used to develop an individualized anti-cancer chronotherapy."



Postoperative restrictive opioid protocols and durable changes in opioid prescribing and chronic opioid use

A recent study revealed that placing a 3-day limit on opioid prescriptions to treat surgical pain after hospital discharge reduces the number of patients who become chronic opioid users without compromising pain relief or recovery (JAMA Oncol 2023; doi:10.1001/jamaoncol.2022.6278). The research team found that this approach also reduces the amount of opioids circulating in the community. Study participants included all patients who underwent surgery from August 1, 2018, to July 31, 2019.


"In this prospective cohort study with a case-control design, a restrictive opioid prescription protocol (ROPP) specifying an opioid supply of three or fewer days after discharge from surgery along with standardized patient education was implemented across all surgical services at a tertiary-care comprehensive cancer center," the study authors explained.


The analysis included 4,068 patients with 2,017 in the pre-ROPP group and 2,051 in the post-ROPP group. Both clinical providers and patients were educated about the protocol in advance. The Pharmacy Department reported 95 percent compliance with the new restrictive opioid protocol. The data showed that, during the pre-protocol period, 3.9 days was the mean duration of opioid prescriptions written at discharge. During the protocol, that number dropped to 1.9 days, with a 45 percent decrease in the volume of opioids prescribed, according to the study authors. Patient requests for refills dropped from 20.9 percent pre-protocol to 17.9 percent post-protocol.


The research team also found that patients who converted to chronic use of opioids after surgery decreased in both opioid-naive cancer patients (11.3% pre-protocol to 4.5% post-protocol) and non-cancer patients (6.1% pre-protocol to 2.7% post-protocol). They used New York State's system of tracking opioid prescriptions, focusing on how many new prescriptions the patients filled 3 months after discharge when post-surgical pain would no longer be an issue.


AUTHOR COMMENTARY: "Current state regulations allow us to prescribe literally unlimited opioids for acute pain, because our patients have a cancer diagnosis," said Emese Zsiros, MD, PhD, the Shashi Lele, MD, Endowed Chair and Director of Research, Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center. "When it comes to end-of-life care and cancer-related pain management, we fully support the use of opioids as necessary; however, many of our patients are opioid-naive at the time of surgery and are also long-term survivors. Thus, reducing the conversion to chronic opioid use could potentially further extend their lives. Implementing a restrictive protocol across a cancer center is not only feasible but decreases the circulating opioids in the community and the conversion to chronic opioid use among our cancer patients."