Selecting First-Line Chemotherapy Protocols for Metastatic Pancreatic Cancer
Does the chemotherapy protocol NALIRIFOX (fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin) confer survival benefit as a first-line treatment in patients with metastatic pancreatic cancer, especially in reference to the other accepted chemotherapy protocols used for the condition? A systematic review and meta-analysis published in JAMA allowed comparison between NALIRIFOX and the protocols FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) and GEM-NABP (gemcitabine with nab-paclitaxel).
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The study examined results of phase 3 clinical trials that tested these protocols as first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) and included in their reports overall survival and progression-free survival. There have been few direct comparisons of these protocols. The NAPOL3 trial showed the superiority of NALIRIFOX over GEM-NABP in metastatic PDAC, but NALIRIFOX and FOLFIRINOX, because they are so similar, are unlikely to be directly compared in a study on efficacy and tolerability.
In the seven trials included in the meta-analysis, 383 patients with metastatic PDAC were treated with NALIRIFOX, 433 with FOLFIRINOX, and 1,756 with GEM-NABP. Median follow-up was 18.8 months overall, with a significantly shorter follow-up for NALIRIFOX (16.2 months versus 20.3 months for GEM-NABP and 18.8 months for FOLFIRINOX).
NALIRIFOX and FOLFIRINOX showed superior progression-free and overall survival compared with GEM-NABP. Using NALIRIFOX as the reference, GEM-NABP had worse progression-free survival (5.7 months versus 7.4 months; hazard ratio [HR], 1.45), with no statistical significance observed for differences with FOLFIRINOX (7.3 months versus 7.4 months; HR, 1.21). In addition, GEM-NABP had poorer overall survival compared with NALIRIFOX (10.4 months versus 11.1 months; HR, 1.18), while no difference was observed between FOLFIRINOX and NALIRIFOX (11.7 months versus 11.1 months; HR, 1.06). There were no statistically significant differences in overall response rate (ORR) among the three chemotherapy protocols: NALIRIFOX 41.8%, FOLFIRINOX 31.6%, and GEM-NABP 35.0%.
NALIRIFOX had the most favorable toxicity profile compared to the other two regimens, with a lower incidence of hematologic effects and peripheral neuropathy, both of which can lead to discontinuation of the other regimens. For example, the platelet count decreased by 1.6% with NALIRIFOX versus 11.8% with FOLFIRINOX and 10.8% with GEM-NABP. NALIRIFOX did have a higher rate of diarrhea compared with GEM-NABP (20.3% versus 15.7%).
Treatment of metastatic PDAC is challenging, as the results of this study show. The most used regimens have only moderate efficacy, with progression-free survival and overall survival of less than 1 year. Because it has fewer toxic effects, GEM-NABP is preferred, whereas FOLFIRINOX has been reserved for carefully selected patients. The question then arises, how does the newer regimen, NALIRIFOX, compare with the very similar FOLFIRINOX? Its tolerable toxicity profile and high ORR are encouraging, but the high cost of liposomal irinotecan may limit use of NALIRIFOX. Patient selection should be based on the regimens' toxicity profiles. Liposomal irinotecan, and therefore NALIRIFOX, should be avoided in patients at risk of grade 3 or greater diarrhea. But it should be the choice for patients who need tumor shrinkage and in whom peripheral neuropathy could compromise adherence. (Nichetti, F., et al. (2024). NALIRIFOX, FOLFIRINOX, and gemcitabine with nab-paclitaxel as first-line chemotherapy for metastatic pancreatic cancer: A systematic review and meta-analysis. JAMA Network Open, 7(1), Article e2350756. Retrieved February 2024 from https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2813517)
Released: February 2024
Nursing Drug Handbook
© 2024 Wolters Kluwer
Lamotrigine Prevents Depressive Episodes in Bipolar I Disorder in Females of Childbearing Age
A meta-analysis using patient-level data from four randomized, placebo-controlled trials showed that maintenance lamotrigine delayed relapse or recurrence of mood episodes in females of childbearing age who had bipolar I disease. It produced this effect largely by preventing depressive episodes in these patients.
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The meta-analysis investigated data from studies of patients with bipolar I disorder, differing in whether they included patients who had experienced a current or recent depressive episode, manic episode, or either. After trial with open-label lamotrigine (up to 16 weeks), those who responded to that treatment were randomized to a double-blind maintenance phase. Of the 717 females of childbearing age included in the open-label phase, 287 responded to the initial treatment and were assigned to 100 to 400 mg/day lamotrigine (n = 153) or placebo (n = 134) for up to 76 weeks.
The primary outcome was median time to intervention for any mood episode, which was 323 days with lamotrigine treatment and 127 days with placebo, with the hazard ratio (HR) significantly favoring lamotrigine (HR, 0.69). In the lamotrigine group, 65/152 patients (43%) had interventions for a mood episode, compared with 73/133 patients (55%) in the placebo group. On further analysis, it was shown that lamotrigine delayed time to intervention for any depressive episode (HR, 0.59) with no treatment difference shown for manic episodes (HR, 0.91). It was found that 38/152 (25%) participants had a depressive episode requiring intervention compared with 50/133 (38%) participants in the placebo group. The median time to a depressive episode could not be estimated for the lamotrigine group; the lower level was 137 days, but the upper limit was not reached.
In the open-label phase, 2/717 patients (less than 1%) experienced serious risk-related adverse events; 127 (18%) experienced adverse events leading to study withdrawal or permanent discontinuation of the study drug during that phase, with similar incidence in both arms. Adverse events leading to permanent discontinuation or withdrawal from the study in the double-blind phase occurred in 12/152 patients (8%) in the lamotrigine arm and 18/133 (14%) in the placebo arm.
Given the high incidence of unplanned pregnancies among females of childbearing age with bipolar 1 disorder, treatment decisions should always consider the possibility of pregnancy in this group. Lamotrigine has a more favorable safety profile during pregnancy; its use is also associated with a lower risk of ovulatory dysfunction, hyperandrogenism, and polycystic ovary syndrome than valproate. In addition, the efficacy of lamotrigine in delaying depressive symptoms has important clinical implications for the treatment of bipolar disorder in females of childbearing age, who are more likely than males to have a predominant depressive polarity. (Vieta, E., et al. (2024). Lamotrigine efficacy, safety, and tolerability for women of childbearing age with bipolar I disorder: Meta-analysis from four randomized, placebo-controlled maintenance studies. Eur Neuropsychopharmacol, 78, 81–92. Retrieved February 2024 from https://www.sciencedirect.com/science/article/pii/S0924977X23006715)
Released: February 2024
Nursing Drug Handbook
© 2024 Wolters Kluwer
Oral Simnotrelvir Effectively Treats Mild to Moderate COVID-19
In a Chinese study, early administration of simnotrelvir plus ritonavir shortened time to resolution of symptoms among adult patients with mild to moderate coronavirus disease 2019 (COVID-19). Vaccination can lessen the effects of COVID-19 in high-risk groups but is less effective in preventing infections caused by SARS-CoV2 variants. More drug options are needed to accelerate the resolution of symptoms among patients who, despite vaccination, develop mild to moderate COVID-19. In this phase 2/3 double-blind, randomized, placebo-controlled trial, patients with mild to moderate COVID-19 infection were randomized within 3 days of symptom onset to 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days.
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The study enrolled 1,208 patients, defining the intent-to-treat population as all patients who received at least one dose of the trial drug or placebo and had a diagnosis of SARS-CoV2 infection confirmed by RCT-PCR, no concomitant influenza infection, and at least one COVID-related symptom at baseline. They were followed to determine time to sustained resolution of symptoms, defined as absence of 11 COVID-related symptoms for 2 consecutive days. Symptom severity was scored on a 4-point scale, from 0 (no symptoms) to 3 (severe symptoms). The most frequent COVID-19 symptoms at baseline were sore or dry throat (76.2%), cough (73.4%), stuffy or runny nose (55.9%), headache (52.9%), and fever (52.9%).
Among patients who received the first dose of treatment within 72 hours of symptom onset, time to sustained resolution of symptoms (symptom score, 0) was significantly shorter with simnotrelvir plus ritonavir than placebo (180.1 hours versus 216.0 hours; median difference, −35.8 hours). In the subgroup of patients with risk factors for severe COVID-19, the median time to sustained resolution was even longer: −60.4 hours. Among patients who had sustained resolution of symptoms by day 14, symptom rebound occurred in 1/425 patients (0.2%) in the simnotrelvir plus ritonavir group and in 2/420 patients (0.5%) in the placebo group.
The median time to sustained alleviation of symptoms (symptom score of 1 or less) was also significantly shorter in the simnotrelvir group than the placebo group (120.4 hours versus 168.3 hours; median difference, −47.9 hours). Simnotrelvir plus ritonavir treatment significantly accelerated the alleviation of respiratory symptoms (median difference, −41.4 hours).
The baseline viral load was similar in the two groups. By day 3, the mean additional change in viral load with simnotrelvir as compared with placebo was −1.10 log10 copies/mL; by day 5, it was −1.51 log10 copies/mL. The most pronounced antiviral effect occurred at day 5. Of the 750 patients who had respiratory samples available, viral rebound occurred in 18/379 participants (4.7%) on simnotrelvir and 18/371 patients (4.9%) in the placebo group. No patients had both viral and symptom rebound. (Cao, B., et al. (2024). Oral simnotrelvir for adult patients with mild-to-moderate Covid-19. New Engl J Med, 390, 230–241. Retrieved February 2024 from https://www.nejm.org/doi/full/10.1056/NEJMoa2301425?query=featured_home)
Released: February 2024
Nursing Drug Handbook
© 2024 Wolters Kluwer
Testosterone Therapy in Older Males and Fracture Risk
Among middle-aged and older males with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo; the fracture incidence was numerically higher among males who received testosterone than among those who received placebo. This finding was reported in an issue of the New England Journal of Medicine, in a paper detailing the results of a subtrial of the TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men). TRAVERSE was a double-blind, randomized, placebo-controlled trial conducted at 316 sites in the United States that assessed the cardiovascular safety of testosterone treatment in older males with hypogonadism.
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Testosterone is required for a healthy skeletal system in males; males need sufficient exposure to achieve peak bone mass and strength during early adulthood and to prevent accelerated bone resorption during aging. It has been shown to increase bone mineral density on dual-energy X-ray absorptiometry, leading to improved bone strength and microarchitecture, so it would seem to follow that its use would reduce fracture risk in older males with hypogonadism. But this study did not demonstrate that.
The study randomized 5,204 males with preexisting cardiovascular disease or at high risk of CV disease, symptoms of hypogonadism, and two morning serum testosterone concentrations lower than 300 mg/dL (10.4 nmol/L) to low-dose testosterone or placebo for up to 4 years. Median age of participants was 64; 80% were White, with mean body mass index of 35; about 70% had diabetes. Importantly, less than 1% took osteoporosis medications. The fracture subtrial was designed separately from the CV trial. Participants were assigned to a transdermal 1.62% testosterone gel, dosage adjusted to maintain a serum testosterone concentration of 350 to 750 mg/dL, or to placebo. At every visit, participants were asked if they had experienced a fracture since the previous visit. If so, medical records were obtained and examined by an independent judge. The main fracture endpoint was the time to the first clinical fracture; other endpoints included time to first non-high-impact fracture, time to clinical fracture in patients not taking osteoporosis medications, and fracture-free survival.
Testosterone treatment in this trial did NOT result in a lower incidence of clinical fracture; rather, a numerically higher fracture incidence was seen in participants using testosterone than among those using placebo. Clinical fractures occurred in 91/2,601 participants (3.50%) in the testosterone group and in 64/2,603 participants (2.46%) in the placebo group after a median follow-up of 3.19 years. The most common sites of fractures were ribs, wrist, and ankle.
This trial had limitations. The incidence of fracture was lower than estimated for statistical power; in addition, it's possible that participants, most of whom had obesity or diabetes, conditions that suppress sex hormone-binding globulin, did not have hypogonadism but pseudohypogonadism (that is, low serum testosterone but normal free testosterone). In decision making about testosterone treatment for males with low serum testosterone levels because of aging or obesity, the potential increase in future risk should be taken into consideration. Males at high risk for fracture because of bone fragility should receive osteoporosis treatment independent of testosterone treatment. Further trials need to have enough power to further characterize the fracture risk in this population. (Grossmann, M., & Anawalt, B. D. (2024). Breaking news — Testosterone treatment and fractures in older men. New Engl J Med, 390, 267–268 Retrieved February 2024 from https://www.nejm.org/doi/full/10.1056/NEJMe2313787; Snyder, P. J., et al. (2024). Testosterone treatment and fractures in men with hypogonadism. New Engl J Med, 390, 203–211. Retrieved February 2024 from https://www.nejm.org/doi/full/10.1056/NEJMoa2308836.)
Released: February 2024
Nursing Drug Handbook
© 2024 Wolters Kluwer