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Aim: To investigate the outcomes of cabozantinib in patients with unresectable hepatocellular carcinoma (uHCC), focusing on dose setting and modification. Methods: We retrospectively analyzed 34 Japanese patients who received cabozantinib for uHCC. Trough concentrations (Ctrough) of cabozantinib were also measured weekly for 6 weeks in the 18 patients. Results: Sixteen patients received ≥40 mg (high‐dose group), and 18 patients received 20 mg (low‐dose group). Dose escalations were performed in 27.8% of the patients in the low‐dose group. Although median duration of the first dose reduction or interruption in the low‐dose group was twice that in the high‐dose group (28 vs. 14 days, p < 0.001), there were no significant differences in the relative dose intensity (RDI) during 6 weeks, progression free survival (PFS), and overall survival (p = 0.162, p = 0.950, p = 0.817, respectively) between the two groups. Patients who received RDI during 6 weeks ≥33.4% showed a trend toward longer median PFS (p = 0.054). Each serum aldolase value during the 6 weeks was significantly correlated with the Ctrough at any point (r = 0.500, p < 0.001). In multivariate analyses, aldolase ≥8.7 U/L within 2 weeks was significantly associated with the very early dose reduction or interruption (odds ratio 20.0, p = 0.002). Conclusions: An initial dose of 20 mg cabozantinib could be a safe option in Japanese patients. The serum aldolase value could be useful for making appropriate dose modifications of cabozantinib. [ABSTRACT FROM AUTHOR]

Background/Aim: Olaparib, a poly (ADP-ribose) polymerase inhibitor, is widely used as maintenance therapy for ovarian cancer. Dose modification, such as dose reduction and treatment interruption, are frequently performed to manage adverse events (AEs) of olaparib. By identifying patients at high risk for dose modification before administration, interventions related to appropriate control of AEs can be implemented. This study aimed to evaluate risk factors of olaparib dose modification and its clinical usefulness. Patients and Methods: Sixty patients with ovarian cancer who received olaparib were included in this retrospective cohort study. Associations between patients’ characteristics and dose modification were evaluated by multivariate logistic regression analysis. We also examined whether risk factors of dose modification were associated with treatment discontinuation due to AEs. Results: Twenty-five (41.7%) patients required dose modification. Patients who required dose modification were significantly older (p=0.018) and tended to be more underweight (p=0.078) than those who did not require dose modification. In multivariate analysis, increasing age was significantly associated with dose modification (odds ratio=1.056; 95% confidence interval=1.002-1.112; p=0.034). The optimal cutoff of age as a risk factor for dose modification, calculated from receiver operating characteristic curves, was 65.0 years. Patients aged 65.0 years and older were significantly more likely to discontinue olaparib owing to AEs (p=0.0437). Conclusion: Age is a risk factor of olaparib dose modification due to AEs. Older patients, who frequently require dose modification, are more likely to discontinue olaparib, suggesting that strict management of AEs is particularly necessary in this patient group. [ABSTRACT FROM AUTHOR]

Abstract Aim To investigate the outcomes of cabozantinib in patients with unresectable hepatocellular carcinoma (uHCC), focusing on dose setting and modification. Methods We retrospectively analyzed 34 Japanese patients who received cabozantinib for uHCC. Trough concentrations (Ctrough) of cabozantinib were also measured weekly for 6 weeks in the 18 patients. Results Sixteen patients received ≥40 mg (high‐dose group), and 18 patients received 20 mg (low‐dose group). Dose escalations were performed in 27.8% of the patients in the low‐dose group. Although median duration of the first dose reduction or interruption in the low‐dose group was twice that in the high‐dose group (28 vs. 14 days, p

Pharmacies are currently unable to stock proper oral dosage forms for pediatric populations. This leads to manipulation of medications or the need to compound specialized medications, which can be a time-consuming process. Using Semisolid Extrusion (SSE) additive manufacturing (AM), specialized medications can be produced in an expedited process from off-the shelf medication in a hospital or outpatient pharmacy setting. In this study, tablets with a desired dose of 5 mg of metoprolol tartrate derived from commercial Seloken™ 50 mg tablets were 3D printed in a hospital setting. Validation testing was done on five batches, highlighting tablets with a high uniformity in mass and dimension, drug content, acceptable microbial assays, and prolonged release during in-vitro analysis. The average drug content found for the tablets was within ±6% of 5 mg for all batches produced. Comparisons were done between the SSE tablets and capsules produced in an external compounding facility, highlighting several positive aspects of SSE-produced tablets beyond simply shortening the production timeline. The SSE tablets printed in this study are characterized by their smaller size, enhanced prolonged release properties, and more uniform drug content across the tested samples. Additionally, interviews with pharmaceutical professionals were conducted to determine the positive aspects of SSE and further improvements to bring this technique as seamlessly as possible into the pharmacy. This study underscores the feasibility of employing SSE in the production of specialized medications within a hospital environment. Furthermore, it highlights the methodological advantages SSE offers over existing production standards, demonstrating its potential to improve pharmaceutical manufacturing in healthcare settings.

Background: Anti-programmed cell death (PD)-1 and anti-PD-L1 medications inhibit the PD-1 and PD-L1 interaction and have been shown to be effective in treating several forms of advanced cancers. Since the approval of these agents, standard dosing protocols have been utilized. However, a small population of patients in the community setting has received dose-modified PD-1 and PD-L1 inhibitors secondary to a lack of tolerability. Data from this study suggests possible benefit with different dosing strategies. Objectives: The purpose of this retrospective study is to assess the efficacy and tolerability in terms of time to progression and adverse effects in patients receiving dose-modified PD-1 and PD-L1 inhibitors in Food and Drug Administration (FDA)-labeled indications. Methods: This single-institution retrospective chart review was conducted in an outpatient community setting on patients with cancer that received nivolumab, pembrolizumab, durvalumab, or atezolizumab for an FDA indication at one of the Houston Methodist Hospital infusion clinic site between September 1, 2017 and September 30, 2019. Data collection included demographics, adverse effects, dosing, treatment delay, and number of immunotherapy cycles administered per patient. Results: This study included 221 patients, who received either nivolumab (n = 81), pembrolizumab (n = 93), atezolizumab (n = 21), or durvalumab (n = 26). There were 11 patients who experienced a dose reduction and 103 patients who experienced a treatment delay. Of the patients with a treatment delay, the median time to progression was 197 days, and for patients with a dose reduction, the median time to progression was 299 days. Conclusion: The results of this study found that the immunotherapy associated adverse effects led to dosing and frequency changes for tolerance with continued therapy. Our data suggests that there could be potential benefits of dose modifications to immunotherapy treatment, but further large studies are needed to assess the efficacy of specific immunotherapy dose modifications on both outcomes and adverse effects. [ABSTRACT FROM AUTHOR]

Background: FOLFIRINOX, used in metastatic pancreatic cancer (MPC), is highly efficacious but also toxic. Various dose modifications for FOLFIRINOX have been introduced to reduce toxicity. However, these studies lack a unified pattern for 'planned' dose modification, and the 'actually administered' dose varied more. Objective: To map a 10-year trend for 'planned' and 'actual' doses of FOLFIRINOX and investigate the clinical outcomes according to dose modification. Data sources and methods: A comprehensive systematic literature search was conducted from January 2011 to September 2021. All studies for FOLFIRINOX as first-line treatment in MPC were considered. Selected studies were firstly classified according to prospective versus retrospective research, secondly standard versus modified FOLFIRINOX, and thirdly 'planned' versus 'actual' dose. For evidence-mapping for the trend of dose modification, we developed a web-based interactive bubble-plot program (www.RDI-map.com). Objective response rate (ORR) and hematologic toxicity were set as endpoints for the comparison of clinical outcomes according to dose modification. Results: A total of 37 studies were identified for evidence-mapping (11 prospective and 26 retrospective studies). There were 12 different types of 'planned' dose modification in FOLFIRINOX ranging 75–100% oxaliplatin, 75–100% irinotecan, 0–100% 5-fluorouracil (5-FU) bolus, and 75–133% 5-FU continuous injection. The 'actual' dose further decreased to 54–96%, 61–88%, 0–92%, and 63–98%, respectively. For the standard versus modified FOLFIRINOX, the ORR was 28.2% (95% CI: 22.5–33.9%) and 33.8% (95% CI: 30.3–37.3%), respectively (p = 0.100), and the incidence of febrile neutropenia was 11.6% (95% CI: 0–16.0%) and 5.5% (95% CI: 0–8.9%), respectively (p = 0.030). Conclusions: RDI-map.com enables multifactorial evidence-mapping for practical FOLFIRINOX dose reduction. The pattern of dose modification was not consistent across studies, and there was a significant gap between the 'planned' and 'actual' doses. Modified FOLFIRINOX showed similar efficacy to the standard regimen with reduced incidence of febrile neutropenia. [ABSTRACT FROM AUTHOR]

The prognosis of chronic myelogenous leukemia (CML-CP) in chronic phase has improved dramatically since the introduction of imatinib. In addition to imatinib, second- and third-generation tyrosine kinase inhibitors (TKIs) and a novel allosteric inhibitor, asciminib, are now available. During long-term TKI therapy, the optimal selection of TKI therapy for individual patients requires the understanding of specific patterns of toxicity profile to minimize chronic toxicity and the risk of adverse events, including pulmonary arterial hypertension, pleural effusion, and cardiovascular events. Given the high efficacy of TKI therapy, dose modifications of TKI therapy reduce the risk of toxicities and improves quality of life during therapy. In this review article, we summarize the characteristics and adverse event profile of each TKI and dose modifications in patients with CML-CP and discuss future perspectives in the treatment of CML-CP. [ABSTRACT FROM AUTHOR]

Background: A survival advantage with apalutamide (APA) combined with androgen deprivation therapy for metastatic castration-sensitive prostate cancer (mCSPC) has been demonstrated in the clinical trial, irrespective of race. However, the incidence of APA-induced skin rash in the Japanese subpopulation is higher than that in the global population. In the present study, we investigated the predictive value of APA dose per body weight for the incidence of skin rash., Methods: A total of 128 patients with mCSPC treated with APA between January 2018 and December 2022 were retrospectively reviewed. A receiver operating characteristic analysis was performed to identify the optimal APA cutoff dose. In addition to comparing the status of APA-induced skin rash, the progression-free survival (PFS) was compared after propensity score matching., Results: The optimal cutoff dose predicting the occurrence of skin rash was 3.33 mg/kg. Our cutoff value significantly stratified the 2 groups in time to occurrence of APA-induced skin rash and discontinuation of APA due to skin rash (P = .005 and P = .009, respectively). The incidence of a ≥G3 skin rash in patients receiving ≥3.33 mg/kg was significantly higher than in others (6.5% vs. 19.7%, P = .037). There was no significant difference in the PFS between patients administered <3.33 mg/kg and those administered ≥3.33 mg/kg., Conclusions: Our data suggest that the drug dosage per body weight may predict the incidence and severity of APA-induced skin rash. Further large-scale prospective studies are needed to validate the predictive value of drug dosage per body weight and identify the optimal cutoff value., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: A head-to-head comparison between enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) revealed similar survival benefits for castration-resistant prostate cancer (CRPC) in the ENABLE study for PCa. Considering that a dose reduction of ENZ and ABI has demonstrated sufficient inhibitory ability of androgen receptor (AR) signaling, we analyzed the efficacy of modified doses of these agents in the ENABLE study for PCa., Methods: This investigator-initiated, multicenter, randomized controlled trial that was conducted in Japan analyzed the prespecified survival endpoints, prostate-specific antigen (PSA) response rate ( ≥50% decline from baseline), and safety profile in patients treated with modified doses (ENZ ≤ 120 mg/day, ABI ≤ 750 mg/day) compared with those treated with a standard dose (ENZ 160 mg/day, ABI 1000 mg/day) as a starting dose., Results: In total, 92 patients in each arm were treated and analyzed; 16 patients were treated with a modified dose in both the ENZ and ABI arms, respectively. Moreover, 32 patients treated with modified doses showed a significantly better time to PSA progression (TTPP) and overall survival (OS) compared with the 152 patients treated with a standard dose (HR 0.47, 95%CI 0.27-0.83, p = 0.0379, and HR 0.35, 95%CI 0.19-0.63, p = 0.0162). Despite a significantly longer TTPP in the modified ABI group than in the standard ABI group (HR 0.29, 95%CI 0.14-0.62, p = 0.0248), no significant difference was observed in the TTPP between the modified and standard ENZ groups (p = 0.5366). Furthermore, similar adverse event rates and grades were observed in each treatment dose group., Conclusions: The modified doses of ABI showed better TTPP than the standard dose of ABI and may be a potential treatment option for CRPC patients; however, its mechanism is still unclear, although its ability to suppress AR signaling is equivalent to that of a standard dose., (© 2024 Wiley Periodicals LLC.)

The ECHELON-1 trial demonstrated the effectiveness of brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment regimen in classical Hodgkin lymphoma. However, peripheral neuropathy (PN) is common with this regimen, occurring in up to two-thirds of patients. While standard prescribing information recommends BV dose modification at the onset of grade 2 PN, management strategies for PN are not well-defined. Most commonly, clinicians dose reduce or discontinue BV, vinblastine, or both. We review evidence-based and practical approaches for managing peripheral neuropathy, emphasizing early detection and dose modification., Competing Interests: Declaration of Competing Interest Jeremy Abramson declares support for the present manuscript (no payments made)– Seagen; grants or contracts from any entity – Seagen, Merck, Mustang Bio, Cellectis, Bristol Myers Squibb, Genentech/Roche; consulting fees – Bristol Myers Squibb, AstraZeneca, AbbVie, Genentech/Roche, Kite Pharma/Gilead, Seagen, Interius, BeiGene, Cellectar, Lilly, Incyte, Caribou Biosciences, Takeda, Janssen, Epizyme, Century Therapeutics, MorphoSys, Mustang Bio, Ono Pharma, Kymera; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events – Genmab, Bristol Myers Squibb, AstraZeneca, Regeneron, AbbVie. Robert Stuver declares no conflicts related to this manuscript. Alex Herrera declares grants or contracts from any entity – Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, Karyopharm, Kite Pharma, Gilead Sciences, AstraZeneca, ADC Therapeutics; consulting fees – Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, Karyopharm, ADC Therapeutics, Takeda, Tubulis, Regeneron, Genmab, Pfizer, Caribou Biosciences, Adicet Bio, AbbVie, Allogene. Emily Patterson declares no conflicts related to this manuscript. Yi-Ping Wen declares no conflicts related to this manuscript. Alison Moskowitz declares grants or contracts from any entity – Leukemia Lymphoma Society – Career Development Program, Incyte, Merck, Secura Bio, Bristol Myers Squibb, Syndax, Seagen, Genentech, Kite Pharma, Gilead Sciences, AstraZeneca, ADC Therapeutics; consulting fees – Bristol Myers Squibb, Genentech, Merck, Seagen, AstraZeneca, ADC Therapeutics, Takeda, Genmab, Pfizer, Caribou Biosciences, Adicet Bio, AbbVie, Allogene Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events – Affimed, Bio Ascend, Canadian Heme Conference, Janpix, Physician Education Resource, Academic Medical Education, BP, Great Debates & Updates, Harborside Press, Imbrium Therapeutics, International Symposium on Hodgkin Lymphoma, Kyowa Hakko Pharma, Medscape, Merck Sharp & Bohue, Ahompr, Seagen, Takeda, Tessa, Triangle Insights Group, UpToDate, WebMD; participation on a data safety monitoring board or advisory board – Affimed, Janpix, Seagen, Kyowa Hakko Pharma., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Elderly patients with extensive-disease small-cell lung cancer (ED-SCLC) have a high risk of chemotherapy toxicity due to multiple comorbidities and poor performance status. Although dose modification is often used to avoid toxicity in elderly patients with ED-SCLC, there is little data on the effect of initial dose-reduced chemotherapy on survival outcomes. Methods and Patients: We retrospectively reviewed 100 elderly patients (≥70 years) with ED-SCLC who received first-line etoposide plus platinum chemotherapy between January 2006 and December 2020. Results: The median age was 74 years. Eighty-nine patients (89%) had a history of smoking, and 38 (38%) had chronic lung disease. Thirty-four patients (34%) received dose-reduced etoposide plus platinum in the first cycle. The dose-reduced group had significantly higher age, lower body mass index, and poor Eastern Cooperative Oncology Group Performance Score. There were no significant differences in survival outcomes between the dose-reduced and full-dose chemotherapy (median overall survival [OS], 4.9 vs. 6.5 months, p = 0.440; median progression-free survival [PFS], 3.7 vs. 4.6 months, p = 0.272). In multivariate analyses, DR in the first cycle (hazard ratio 0.519, 95% CI: 0.269–1.000, p = 0.050) was significantly associated with OS. Following a subgroup analysis of 59 patients who received minimum four cycles, no significant differences in survival outcomes between the two groups (median OS, 10.9 vs. 9.4 months, p = 0.817; median PFS, 6.3 vs. 6.5 months, p = 0.902) were noted. Conclusions: The dose-reduced chemotherapy with first-line etoposide plus platinum had non-inferior survival outcomes compared to the full-dose chemotherapy in elderly patients with ED-SCLC. [ABSTRACT FROM AUTHOR]

Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used as a first-line treatment option for patients with chronic myeloid leukemia (CML). Currently, dose modification due to adverse events (AEs) is common in patients treated with dasatinib. This study compared the outcomes of two sequential prospective trials that enrolled patients with newly diagnosed chronic phase of CML (CP-CML) and initiated dasatinib at a starting dose of 100 mg daily. In the PCR-DEPTH study, CP-CML patients who started dasatinib 100 mg daily were enrolled and followed up, while in the DAS-CHANGE study, when patients achieved early molecular response with any grade of AEs were enrolled and treated with dasatinib 80 mg once daily. A total of 102 patients (PCR-DEPTH) and 90 patients (DAS-CHANGE) were compared. Although the median value of the relative dose intensity (RDI) of dasatinib was significantly higher in PCR-DEPTH than in DAS-CHANGE (99.6 % vs. 80.1 %, p <0.001), the MMR rate at 12months showed a trend toward superiority in DAS-CHANGE compared to PCR-DEPTH (77.1 % vs 65.2 %, p = 0.084). The frequencies of MR4.0 at 24 and 36 months were higher in DAS-CHANGE than in PCR-DEPTH (44.4 % vs 28.8 %, p = 0.052 and 63.6 % vs 40.3 %, p= 0.013, respectively). RDIs were not different according to the MMR, MR4.0 or MR4.5 in analyses using a pooled population. Our results suggest that early dose reduction of dasatinib does not compromise efficacy in patients achieving EMR at 3 months and could be an interventional strategy for improving long term outcomes. • Early dose reduction of dasatinib to 80 mg maintains efficacy in newly diagnosed chronic myeloid leukemia patients. • The DAS-CHANGE study showed higher rates of MR4.0 compared to the PCR-DEPTH study. • Median relative dose intensity was significantly lower in DAS-CHANGE compared to PCR-DEPTH. • Early dose reduction can be an effective strategy for improving long-term outcomes. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to characterize real-world utilization of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) in women with ovarian cancer (OC). Methods: This retrospective observational study of claims data from US MarketScan® Commercial/Medicare Supplemental databases included women with OC initiating olaparib, niraparib, or rucaparib from January 1, 2017, to May 31, 2019. Patients were observed from first outpatient prescription until at least 30 days' follow-up. Clinical events of interest (CEIs), based on adverse reactions in PARPi prescribing information, were identified from claims using ICD-9/10 codes. Other outcomes included dose modification, persistence, adherence, healthcare resource utilization (HCRU), and cost. Results: Overall, 303, 348, and 162 women with OC received olaparib, niraparib, and rucaparib, respectively. During follow-up, risk of any CEI was higher with niraparib versus olaparib (odds ratio 3.36 [95% confidence interval 2.00–5.65]) and niraparib versus rucaparib (2.09 [1.10–3.95]), with no significant difference between rucaparib and olaparib (1.61 [0.93–2.79]). PARPi dose decreases were observed in 21.1%, 35.1%, and 30.2% of olaparib-, niraparib-, and rucaparib-treated patients, respectively. Persistence (no treatment gaps of more than 90 days) was significantly higher (P < 0.05) with olaparib (62.2%) versus niraparib (35.9%) and rucaparib (48.7%); adherence (medication possession ratio, MPR ≥ 80%) was 80.2% versus 38.6% and 63.2%, respectively (P < 0.001). Inpatient admissions and outpatient service use were higher with niraparib and rucaparib versus olaparib, reflected in mean (± standard deviation) total medical costs (excluding pharmacy) of $5393 ± 8828 for olaparib, $7732 ± 14,054 for niraparib, and $6868 ± 7929 for rucaparib. Conclusion: Differences between the licensed PARPi were observed in the risk of experiencing a CEI, likelihood of dose modifications, ability to receive continuous PARPi therapy, HCRU, and costs. [ABSTRACT FROM AUTHOR]

Abstract Background Palbociclib improves outcomes for women with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3. Methods This analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving palbociclib plus fulvestrant or placebo plus fulvestrant. Results A total of 311 (35.5%) patients with HR+/HER2− ABC required a palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction. Conclusions A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management. Trial registration These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409 ; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427 ; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135 ; registration date September 13, 2013.

Pharmacies are currently unable to stock proper oral dosage forms for pediatric populations. This leads to manipulation of medications or the need to compound specialized medications, which can be a time-consuming process. Using Semisolid Extrusion (SSE) additive manufacturing (AM), specialized medications can be produced in an expedited process from off-the shelf medication in a hospital or outpatient pharmacy setting. In this study, tablets with a desired dose of 5 mg of metoprolol tartrate derived from commercial Seloken™ 50 mg tablets were 3D printed in a hospital setting. Validation testing was done on five batches, highlighting tablets with a high uniformity in mass and dimension, drug content, acceptable microbial assays, and prolonged release during in-vitro analysis. The average drug content found for the tablets was within ±6% of 5 mg for all batches produced. Comparisons were done between the SSE tablets and capsules produced in an external compounding facility, highlighting several positive aspects of SSE-produced tablets beyond simply shortening the production timeline. The SSE tablets printed in this study are characterized by their smaller size, enhanced prolonged release properties, and more uniform drug content across the tested samples. Additionally, interviews with pharmaceutical professionals were conducted to determine the positive aspects of SSE and further improvements to bring this technique as seamlessly as possible into the pharmacy. This study underscores the feasibility of employing SSE in the production of specialized medications within a hospital environment. Furthermore, it highlights the methodological advantages SSE offers over existing production standards, demonstrating its potential to improve pharmaceutical manufacturing in healthcare settings., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Jonas Lindh reports financial support was provided by Sweden's Innovation Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background/aim: Olaparib, a poly (ADP-ribose) polymerase inhibitor, is widely used as maintenance therapy for ovarian cancer. Dose modification, such as dose reduction and treatment interruption, are frequently performed to manage adverse events (AEs) of olaparib. By identifying patients at high risk for dose modification before administration, interventions related to appropriate control of AEs can be implemented. This study aimed to evaluate risk factors of olaparib dose modification and its clinical usefulness., Patients and Methods: Sixty patients with ovarian cancer who received olaparib were included in this retrospective cohort study. Associations between patients' characteristics and dose modification were evaluated by multivariate logistic regression analysis. We also examined whether risk factors of dose modification were associated with treatment discontinuation due to AEs., Results: Twenty-five (41.7%) patients required dose modification. Patients who required dose modification were significantly older (p=0.018) and tended to be more underweight (p=0.078) than those who did not require dose modification. In multivariate analysis, increasing age was significantly associated with dose modification (odds ratio=1.056; 95% confidence interval=1.002-1.112; p=0.034). The optimal cutoff of age as a risk factor for dose modification, calculated from receiver operating characteristic curves, was 65.0 years. Patients aged 65.0 years and older were significantly more likely to discontinue olaparib owing to AEs (p=0.0437)., Conclusion: Age is a risk factor of olaparib dose modification due to AEs. Older patients, who frequently require dose modification, are more likely to discontinue olaparib, suggesting that strict management of AEs is particularly necessary in this patient group., Competing Interests: The Authors have no conflicts of interest to declare., (Copyright 2024, International Institute of Anticancer Research.)

Extracorporeal veno-venous membrane blood oxygenation (V-V ECMO) is used in acute respiratory distress syndrome (ARDS) which is a common complication of COVID-19. This technique requires cannulation of the venous bed and is applied in patients without heart failure. V-V ECMO is composed of system of cannulas (inflow and outflow), an oxygenator, a centrifugal pump, pressure and flow detectors. Simultaneously mechanical ventilation is applied, optimally with the use of positive end expiratory pressure (PEEP). The care of the patient treated with this method requires particular supervision by properly trained medical team. Possible complications of V-V ECMO are: bleeding from injection sites, clotting, haemolysis, hypoxaemia, air embolism, inflammation, endothelial dysfunction and exacerbation of immunity disorders. V-V ECMO is an effective therapy which greatly increases the chance of survival. [ABSTRACT FROM AUTHOR]

From the medical point of view, it is important to individualize the therapeutic treatment to the patient. Drugs that work perfectly in a particular population can be lethal to an individual patient, for example in a situation where he is allergic to a given active substance. Importantly, this issue is also important from the legal perspective, because the applicable legal regulations impose an obligation on the doctor to provide the patient with services in accordance with the current medical knowledge. This obligation includes the need to individualize therapy, in particular pharmacotherapy, because the effectiveness and safety of the pharmacotherapy used is not an absolute concept. That is why the individual dosage of drugs is so important. The dosing data in the SmPC is not relevant to all patient populations treated and therefore requires modification. [ABSTRACT FROM AUTHOR]

Summary: Background Gemcitabine plus cisplatin is regarded as the standard first-line therapy for patients with advanced biliary tract cancer (BTC); however, no standard chemotherapy has yet been recommended after treatment failure. Modified FOLFIRINOX (mFOLFIRINOX) appears to be a better-tolerated regimen, which leads to improved survival in metastatic pancreatic cancer that has histological and molecular similarities with BTC. We assessed the efficacy and safety of mFOLFIRINOX as salvage therapy in advanced BTC patients who were refractory to previous chemotherapy. Methods A total of 15 consecutive patients with documented unresectable locally advanced or metastatic BCT who received the mFOLFIRINOX regimen were included in the study. Patients were intravenously administrated with oxaliplatin (65 mg/m2), leucovorin (400 mg/m2), irinotecan (150 mg/m2), and continuous infusion of fluorouracil (2400 mg/m2) over 46 h. The objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were recorded. Results At least three cycles of mFOLFIRINOX regimen were delivered to 15 patients with a median number of 6.0 cycles (IQR 5.5–11.0). The median duration of treatment was 3.8 months (IQR 2.9–8.5). Four patients (26.7%) achieved an ORR, and 12 patients (80.0%) had a DCR. The median PFS and OS were 6.7 months (95%CI 2.3–11.1) and 13.2 months (95%CI 7.3–19.1), respectively. Five patients (33.3%) had treatment-related grade 3/4 AEs. The most common grade 3/4 AE was neutropenia (n = 3, 20.0%), while there was no occurrence of febrile neutropenia. Conclusion Treatment with mFOLFIRINOX has promising efficacy and favorable tolerance as salvage therapy in patients with refractory advanced BCT. [ABSTRACT FROM AUTHOR]

Abstract Background Oxaliplatin, irinotecan, 5-fluorouracil, and l-leucovorin (FOLFIRINOX) has become one of the first-line treatment options for advanced pancreatic cancer (PC). However, the relatively high rate of grade 3 or 4 adverse events associated with the standard dosage of FOLFIRINOX limits its widespread use in clinical practice. In this study, we were to evaluate the efficacy and safety of a modified FOLFIRINOX regimen as a first-line chemotherapy for Chinese patients with metastatic PC. Methods Patients with histologically confirmed primary metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2 were recruited to receive the modified FOLFIRINOX regimen (intravenous infusion of oxaliplatin, 65 mg/m2; irinotecan, 150 mg/m2; l-leucovorin, 200 mg/m2; and 5-fluorouracil, 2400 mg/m2, repeated every 2 weeks). The treatment was continued for 12 cycles unless the patient had progressive disease (PD), stable disease (SD) with symptom deterioration, unacceptable adverse events, or requested to terminate the treatment prematurely. The primary endpoint was objective response rate (ORR). Results Sixty-five patients were enrolled from July 2012 to April 2017 in three institutions, and they all received at least one cycle of chemotherapy, with a median of 8 cycles (range 1–12 cycles). No complete response was observed. Twenty-one (32.3%) patients had partial responses, and 27 (41.5%) had SD. The ORR and disease control rate of the study cohort was 32.3% and 73.8%. The estimated median overall survival and progression-free survival were 11.60 (95% confidence interval [CI] 8.76–14.44) and 5.77 (95% CI 5.00–6.54) months. Major grade 3 or 4 adverse events included neutropenia (12.3%) and diarrhea (6.2%). No treatment-related death was observed. Conclusions Modified FOLFIRINOX was well-tolerated and might be a promising option as first-line therapy for Chinese patients with metastatic PC. Trial registration ClinicalTrials.gov, NCT02028806. Registered 7 January 2014, https://clinicaltrials.gov/ct2/show/NCT02028806

Background: FOLFIRINOX chemotherapy displays significant survival improvements in patients with pancreatic cancer. However, toxicities have hampered enthusiasm for the use of FOLFIRINOX in full dose. In order to increase the tolerability, many researchers focused on the modification of FOLFIRINOX. On the other hand, hyperthermia (HT) has been considered as an effective ancillary treatment for cancer therapy. Up to now, there is no report evaluating combining deep regional hyperthermia (DRHT) with modified-FOLFIRINOX for pancreatic cancer patients. Methods: In this study, we conducted a retrospective review of pancreatic cancer patients treated with the combination of new form modified-FOLFIRINOX and DRHT (BSD2000). Patients underwent chemotherapy that included low-dose irinotecan (70–130 mg/m2), oxaliplatin (65–70 mg/m2) on day 1 and 5-FU (2400 mg/m2 as a 46 h continuous infusion, no bolus) or capecitabine (CAP) (1000 mg/m2 twice daily on days 1–10) or tegafur, gimeracil and oteracil potassium (TS-1) (80–120 mg/d twice daily on days 1–10), 2-week schedule. Generally, DRHT treatment was performed weekly, 45 min for each time during chemotherapy. Results: The patients receiving mFOLFIRINOX as the first line chemotherapy combining with DRHT, obtained an improvement in OS and PFS, 17 months (95% CI 1.97–32.03 months) and 4 months (95% CI 0–8.29 months) respectively. Overall, this combination regimen was safe; 17.6% patients suffered from grade 3/4 toxicities. Conclusions: In conclusion, we conducted a retrospective study combining mFOLFIRINOX and DRHT, which was well tolerated. The efficacy in the treatment of pancreatic cancer was encouraging, but further studies would be required to prove its merit, compared with conventional treatment.

Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506). Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis. Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74). An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes. [ABSTRACT FROM AUTHOR]

Controlling adverse events (AEs) through dose reduction can enhance drug adherence and treatment response. Currently, there is no guide for sorafenib dosing. The aim of this study was to evaluate whether sorafenib dosing could affect treatment outcomes. A total of 782 hepatocellular carcinoma (HCC) patients treated with sorafenib were evaluated for sorafenib dosing and its modifications via medical records at baseline and regular follow‐up. Study outcomes included progression‐free survival (PFS), overall survival (OS), sorafenib duration, cumulative dose, AEs and drug discontinuation. The median patient survival was 7.7 months. Overall, 242 (30.9%) patients underwent dose reduction and 121 (17.5%) discontinued sorafenib due to AEs. In multivariate analysis, dose reduction was identified to be independently predictive of PFS and OS. The 800‐to‐400 mg/day group provided significantly better PFS than the 800 mg/day‐maintained group or the 800‐to‐600 mg/day group. Likewise, the 800‐to‐400 mg/day group resulted in a significantly better OS than other dosing. However, dose reduction to 200 mg/day led to significantly worse PFS and OS. Hand‐foot skin reaction and drug discontinuation due to AEs were higher in the 800‐to‐600 mg/day group than the 800‐to‐400 mg/day group. The 800‐to‐400 mg/day group had significantly longer treatment duration and higher cumulative dose than the 800 mg/day‐maintained group. Sorafenib dose reduction can improve HCC survival and increase patient tolerance and adherence coupled with longer duration and higher cumulative dose. Dose reduction from 800 to 400 mg/day than to 600 mg/day is recommended when clinically warranted. However, dose reduction to 200 mg/day is not recommendable. What's new? Although sorafenib, a kinase inhibitor drug, is effective in the treatment of advanced liver cancer, a large fraction of patients discontinue treatment because of adverse events. Here the authors evaluated the effect of drug dosing on treatment outcome in a large cohort study in South Korea. They found that proper sorafenib dose reduction helped control adverse events, leading to increased patient adherence coupled with longer duration and ultimately improved patient survival. They propose that proper dose modifications are a key determinant of successful sorafenib treatment. [ABSTRACT FROM AUTHOR]

Purpose: Neutropenia is the most common toxicity of CDK4/6 inhibitors, causing frequent dose interruptions. However, CDK4/6 inhibitor-induced neutropenia shows a benign clinical course in contrast to that caused by chemotherapy. Here, we investigated the safety of a new dose scheme for palbociclib, which avoids dose delays or reductions due to afebrile grade 3 neutropenia. Methods: A consecutive cohort of ER(+)/HER2(−) advanced breast cancer patients who received palbociclib between 2017 and 2018 was analyzed. The patients were classified into Group 1 (patients who maintained palbociclib dose with afebrile grade 3 neutropenia), Group 2 (patients who experienced any dose modification with afebrile grade 3 neutropenia), and Group 3 (patients without afebrile grade 3 neutropenia). The primary endpoint was febrile neutropenia incidence; other toxicities were compared with those of the PALOMA-2 trial. Results: Among the 107 patients, 54.2%, 22.4%, and 23.4% were classified into Groups 1, 2, and 3, respectively. There was no febrile neutropenia in Groups 1 and 2 during palbociclib treatment. Group 1 showed higher incidence of thrombocytopenia (all-grade, 32.8%; grade 3–4, 8.6%) than Group 2 and the PALOMA-2 data, but there was no bleeding related to thrombocytopenia. Group 1 showed higher incidence of all-grade non-hematologic adverse events than Group 2; only one grade 3 non-hematologic toxicity was observed in Group 1. There were no treatment-related hospitalizations or deaths in Group 1. Conclusions: Thus, omitting palbociclib dose modification with afebrile grade 3 neutropenia is safe and tolerable without febrile neutropenia events. This scheme could be useful to avoid unnecessary reductions in palbociclib doses in future practice. [ABSTRACT FROM AUTHOR]

We present a technique for adding dose modifications into seamless Phase II and Phase II/III trials featuring dose selection at an interim analysis. The method is convenient to apply and can be used either in a fully prespecified, structured way or as a response to new considerations that emerge at interim. Strong control of the familywise error rate regarding false declarations of efficacy versus control is maintained. Two examples are given. One illustrates how the method could potentially "save" a trial performed in a Phase II context. The other is a seamless Phase II/III trial that uses an adaptive exploration strategy for an assumed nonmonotonic dose-response curve. It can result in greatly improved efficiency over a standard "promote the winner" rule. [ABSTRACT FROM AUTHOR]

Background: Palbociclib improves outcomes for women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3.Methods: This analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving palbociclib plus fulvestrant or placebo plus fulvestrant.Results: A total of 311 (35.5%) patients with HR+/HER2- ABC required a palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction.Conclusions: A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management.Trial Registration: These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135; registration date September 13, 2013. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Purpose: While general guidelines (such as CONSORT or Consensus on Exercise Reporting Template) exist to enhance the reporting of exercise interventions in the field of exercise science, there is inadequate detail facilitating the standardized reporting of resistance training adherence in the oncology setting. The purpose of this study was to apply a novel method to report resistance training dose, adherence, and tolerance in patients with cancer. Methods: A total of 47 prostate cancer patients (70.1 ± 8.9 yr, body mass index, 28.6 ± 4.0) with bone metastatic disease completed an exercise program for 12 wk. We assessed traditional metrics of adherence (attendance and loss to follow-up), in addition to novel proposed metrics (exercise-relative dose intensity, dose modification, and exercise interruption). Total training volume in kilograms (repetitions × sets × training load (weight)) was calculated for each patient. Results: Attendance assessed from traditional metrics was 79.5% ± 17.0% and four patients (9%) were lost to follow-up. The prescribed and actual cumulative total dose of resistance training was 139,886 ± 69,150 kg and 112,835 ± 83,499 kg, respectively, with a mean exercise-relative dose intensity of 77.4% ± 16.6% (range: 19.4% –99.4%). Resistance training was missed (1–2 consecutive sessions) or interrupted (missed ≥3 consecutive sessions) in 41 (87%) and 24 (51%) participants, respectively. Training dose was modified (reduction in sets, repetitions, or weight) in 40 (85%) of patients. Importantly, using attendance as a traditional metric of adherence, these sessions would have all counted as adherence to the protocol. Conclusions: Traditional reporting metrics of resistance training in exercise oncology may overestimate exercise adherence. Our proposed metrics to capture resistance training dose, adherence, and tolerance may have important applications for future studies and clinical practice. [ABSTRACT FROM AUTHOR]

Background: Rates of adverse events with sorafenib were higher in the DECISION trial in radioactive iodine-refractory, advanced differentiated thyroid cancer (DTC) than in trials of sorafenib for other tumor types. One possible explanation is that sarcopenia, a known predictive factor of toxicity in patients with cancer, is more common in patients with DTC due to hormone suppressive therapy. Methods: This retrospective exploratory analysis was performed to assess whether the risk of early toxicity leading to dose modification (DMT) with sorafenib was higher in patients with sarcopenia compared with those without sarcopenia. The data set comprised patients from the phase III DECISION trial with a computed tomography scan available to determine muscle mass. The skeletal muscle (SM) cross-sectional area was used to determine the SM index and define sarcopenia. The end points were changes in body composition, DMT, early DMT (within 1 month), severe toxic events (STEs), and early STEs. Results: Overall, 365 patients were eligible for this analysis; baseline characteristics were well balanced between patients receiving sorafenib (n = 180) versus placebo (n = 185). Using a sarcopenia definition of an SM index less than the median sex-specific SM index, approximately half of the patients receiving sorafenib were at risk of sarcopenia (89/180; 49.4%), with wide geographical variation. At 6 months, the mean weight, body mass index, and lean body mass of patients receiving sorafenib were lower than at baseline and significantly lower than for patients receiving placebo (all p < 0.0001). Most DMTs and STEs occurred in the first month of treatment. There was a nonsignificant trend for more early DMTs in patients with sarcopenia compared with those without sarcopenia (55.3% vs. 44.7%, respectively; p = 0.2273). Conclusions: These results show a significant effect of sorafenib on muscle mass. However, there was no association between sarcopenia and DMT or early DMT, in contrast to observations in hepatocellular and renal cell carcinoma. [ABSTRACT FROM AUTHOR]

BACKGROUND: The treatment of rheumatoid arthritis is based on the use of disease-modifying antirheumatic drugs (DMARDs). Tocilizumab can be used as monotherapy or in combination with conventional synthetic DMARDs for the treatment of moderate-to-severe active rheumatoid arthritis. Subcutaneous (SC) and intravenous forms of the drug are available, but the SC form is more widely used. OBJECTIVE: To understand the real-world dose modification patterns of SC tocilizumab in the treatment of patients with rheumatoid arthritis in the United States. METHODS: Data were obtained from the Truven (now IBM) MarketScan and Optum Clinformatics databases. Patients were included if they had ≥1 pharmacy claims for SC tocilizumab and met other inclusion criteria. The mean, standard deviation, and median values were reported for the continuous variables, and frequency was reported for the categorical variables. Kaplan-Meier analysis was used to analyze the time to first dose modification. Logistic regression modeling was used to identify predictors of the likelihood of dose modification. RESULTS: The study included 1266 patients in the Truven database and 512 patients in the Optum database who had commercial or Medicare Advantage or supplemental insurance. Of the patients who started treatment with biweekly SC tocilizumab (48% each in the Truven and Optum databases), 37% in Truven and 40% in Optum had dose escalation to a weekly dose. Of those who started weekly SC tocilizumab (43% in the Truven and 49% in the Optum databases), 3% (Truven) and 4% (Optum) had dose reduction. The remaining patients started alternative SC tocilizumab doses. Overall, 60% and 68% of patients in the Truven and Optum cohorts, respectively, initiated or escalated to the higher weekly dose of tocilizumab; the mean time to dose escalation was 126 days and 112 days, respectively. In the Truven cohort, corticosteroid use, age, and anemia were the main predictors for dose escalation. In the Optum cohort, female patients had increased odds of dose escalation compared with male patients. CONCLUSION: The dosing trends observed in this study show that physicians have taken advantage of the option to increase SC tocilizumab dosing, but only a few providers chose to reduce the dose. This trend in dose modification may increase the costs related to SC tocilizumab therapy. [ABSTRACT FROM AUTHOR]

• Of the 470 chemotherapy protocols in the EviQ database, 119 (25%) recommend a platinum drug. • Cisplatin, carboplatin, and oxaliplatin are recommended in the treatment of 24 different cancers. • Dose reductions of a platinum drug are recommended for six specific side effects. • Further development of platinum drugs, via drug design or drug delivery, is warranted by bioinorganic chemists. A cross-sectional descriptive study in Australia was undertaken to examine the current clinical guidelines on the use of platinum-based drugs in cancer treatment. From the Australian EviQ system, data from each chemotherapy protocol was collected with respect to recommended drugs for specific cancer types, drug doses, and dose modifications. Only three drugs have marketing approval: cisplatin, carboplatin, and oxaliplatin, and they are recommended in 119 of the 470 (25%) chemotherapy protocols. The platinums are indicated for the treatment of 24 specific types of cancer (excluding metastatic and non-metastatic variants): head and neck, gynaecological, respiratory, upper gastrointestinal, urogenital, colorectal, and breast cancers, and lymphomas, sarcomas, and multiple myelomas. The recommended doses for cisplatin are between 10 and 100 mg/m2, for carboplatin the recommended doses are between 1.5 and 8 area under the curve (AUC), and for oxaliplatin the recommended doses are between 85 and 130 mg/m2. A patient may be prescribed a dose reduction of between 25 and 100% when they experience any one of six specific side effects: low platelet levels, low absolute neutrophil count, renal impairment, peripheral neuropathy, mucositis & stomatitis, and diarrhoea. Overall, the results indicate that platinums remain an integral part of chemotherapy and reinforces the need for chemists to continue to develop new platinum drugs and drug delivery strategies, especially for reducing drug side effects. [ABSTRACT FROM AUTHOR]

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Abstract Purpose To determine the relationship between chemotherapy dose modification (dose adjustment or treatment delay), overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) who receive carboplatin and paclitaxel. Methods Women with stages III and IV EOC and PPC treated on the Gynecologic Oncology Group phase III trial, protocol 182, who completed eight cycles of carboplatin with paclitaxel were evaluated in this study. The patients were grouped per dose modification and use of granulocyte colony stimulating factor (G-CSF). The primary end point was OS; Hazard ratios (HR) for PFS and OS were calculated for patients who completed eight cycles of chemotherapy. Patients without dose modification were the referent group. All statistical analyses were performed using the R programming language and environment. Results A total of 738 patients were included in this study; 229 (31%) required dose modification, 509 did not. The two groups were well-balanced for demographic and prognostic factors. The adjusted hazard ratios (HR) for disease progression and death among dose-modified patients were: 1.43 (95% CI, 1.19–1.72, P < 0.001) and 1.26 (95% CI, 1.04–1.54, P = 0.021), respectively. Use of G-CSF was more frequent in dose-modified patients with an odds ratio (OR) of 3.63 (95% CI: 2.51–5.26, P < 0.001) compared to dose-unmodified patients. Conclusion Dose-modified patients were at a higher risk of disease progression and death. The need for chemotherapy dose modification may identify patients at greater risk for adverse outcomes in advanced stage EOC and PPC. Highlights • Chemotherapy dose modification is common in ovarian cancer treatment. • Patients requiring dose modification are more likely to require growth factor. • Dose modified patients are at a higher risk of worse treatment outcome. [ABSTRACT FROM AUTHOR]

Background Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methods All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e. as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables. Results Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose ∼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day. ClinicalTrials.gov ID NCT01847274. [ABSTRACT FROM AUTHOR]

Background: The investigation of exercise training in metastatic breast cancer has received minimal attention. This study determined the feasibility and safety of aerobic training in metastatic breast cancer.Methods: Sixty-five women (age, 21-80 years) with metastatic (stage IV) breast cancer (57% were receiving chemotherapy, and >40% had ≥ 2 lines of prior therapy) were allocated to an aerobic training group (n = 33) or a stretching group (n = 32). Aerobic training consisted of 36 supervised treadmill walking sessions delivered thrice weekly between 55% and 80% of peak oxygen consumption (VO2peak ) for 12 consecutive weeks. Stretching was matched to aerobic training with respect to location, frequency, duration, and intervention length. The primary endpoint was aerobic training feasibility, which was a priori defined as the lost to follow-up (LTF) rate (<20%) and attendance (≥70%). Secondary endpoints were safety, objective outcomes (VO2peak and functional capacity), and patient-reported outcomes (PROs; quality of life).Results: One of the 33 patients (3%) receiving aerobic training was LTF, whereas the mean attendance rate was 63% ± 30%. The rates of permanent discontinuation and dose modification were 27% and 49%, respectively. Intention-to-treat analyses indicated improvements in PROs, which favored the attention control group (P values > .05). Per protocol analyses indicated that 14 of 33 patients (42%) receiving aerobic training had acceptable tolerability (relative dose intensity ≥ 70%), and this led to improvements in VO2peak and functional capacity (P values < .05).Conclusions: Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of patients with metastatic breast cancer. The acceptable feasibility and promising benefit for select patients warrant further evaluation in a dose-finding phase 1/2 study. Cancer 2018;124:2552-60. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a plasma cell neoplasm that affects elderly individuals with two-thirds of patients over 65 years at diagnosis. However, data available are derived from clinical trials conducted in younger patients. Fewer studies investigated treatment options in the elderly. This review summarizes the clinical outcomes and toxicities associated with therapeutic regimens in older patients including doublet, triplet and high dose therapyin newly diagnosed patients and relapsed patients with MM. We highlight the importance of an approach tailored to individuals, incorporates the geriatric frailty assessment, considers comorbiditiess and commits to early recognition and management of toxicities ranging from myelosuppression to polypharmacy. To date, no trial has prospectively investigated a tailored treatment paradigm in older patients based on frailty and/or comorbidities. As the population ages, the proportion of MM patients with advanced age will grow. Studies are indicated to determine optimal treatment approaches in this increasingly heterogeneous geriatric population. [ABSTRACT FROM AUTHOR]

Introduction: Targeted therapies have revolutionized the treatment of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC). However, as for many oncology drugs, the dose of targeted therapies may need to be adjusted over time, leading to drug wastage when a dose modification is needed but the dose cannot be split or saved. This has been shown to be the case for palbociclib and has led to concerns among payers. This study described palbociclib dosing patterns and estimated the economic burden of the drug wastage associated with palbociclib dose modifications in postmenopausal women with HR+/HER2- mBC.Methods: A large US claims database was used to identify postmenopausal women with HR+/HER2- mBC who received a palbociclib-based therapy during one of their first three lines of therapy for mBC between February 2015 (palbociclib approval) and December 2015. Dosing patterns (dosing modifications and sequences) were reported; a dose modification was defined as an increase/decrease of at least 25 mg daily compared to the preceding dose. Estimates of drug wastage costs were based on days with overlap in prescription fills for different palbociclib doses.Results: A total of 473 postmenopausal palbociclib-treated women with HR+/HER2- mBC were included (first line 214; second line 157; third line 120). Over an average duration of line of therapy of approximately 4 months, dose modification was observed in 17.8%, 31.2%, and 35.0% of patients in first, second, and third line. Average overlap in prescription fills was 9.2, 9.9, and 5.4 days in first, second, and third line. This potential drug wastage resulted in an average cost of $4376, $4740, and $2592 per patient in first, second, and third line.Conclusions: This study showed that drug wastage due to palbociclib dose modification results in substantial costs. Treatment options with more flexible dosing may help reduce the costs of drug wastage.Funding: Novartis Pharmaceuticals Corporation. [ABSTRACT FROM AUTHOR]

Introduction: The median overall survival (mOS) in metastatic pancreatic cancers (PCs) hovers between 6 months to 11 months.Materials and Methods: The study is a retrospective analysis of metastatic PC patients who were evaluated from August 2013 to August 2016 in the Department of Gastrointestinal (GI) Medical Oncology, Tata Memorial Hospital (TMH).Results: Out of 218 patients, 24 patients (11%) were not planned for chemotherapy and referred to the Department of Palliative Care for further supportive care. One hundred and fifty-three patients received palliative chemotherapy in TMH with median age of 56 years (range: 23-79), male (60.1%), and nonresident in Maharashtra (60.1%). Regimens used most commonly were gemcitabine-nab-paclitaxel in 60 patients (39.2%), gemcitabine-erlotinib in 25 patients (16.3%), and modified FOLFIRINOX in 21 patients (13.7%). A total of 58 patients (43%; n = 135) had Grade 3/4 toxicities. As of cutoff date for the analysis of outcomes, 139 patients (90.8%) patients had ceased first-line chemotherapy, due to radiologically proven progressive disease (PD) in 89 patients (64%), repeated Grades 3 and 4 adverse events in 26 patients (18.7%), and clinically PD in 18 patients (12.9%). With a median follow-up of 278 days, the mOS was 217 days (95% confidence interval [CI]: 175-258), and the median event-free survival was 125 days (95% CI: 107-122).Conclusion: Dose modifications for chemotherapy are required commonly when treating metastatic PC, with common reasons for dose reduction being toxicities, Eastern Cooperative Oncology Group performance status >=2, and low albumin levels. Studies evaluating logistic and financial aspects of treating metastatic PC with chemotherapy in India are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Since the widespread implementation of adding palbociclib to endocrine therapy in clinical practice, myelosuppression is becoming increasingly recognized as a toxicity that may lead to dose modification. We aimed to characterize toxicities observed with palbociclib resulting in dose modifications and prescriber preferences in modifying palbociclib dosage in response to treatment-related toxicities outside the context of a clinical trial.Methods: We conducted a single institution, retrospective study of treatment-related adverse events (AEs) resulting in modifications in dose and schedule and the methods by which dose modifications occurred in patients with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer receiving palbociclib and endocrine therapy.Results: From 2/2015 to 10/2016, 100 patients were identified for inclusion in this study. Treatment with palbociclib and endocrine therapy resulted in dose modifications in 38.0% of patients due to AEs with 18.4% requiring subsequent dose changes. Most palbociclib dose modifications occurred during the first 2 cycles. Grade 3-4 neutropenia accounted for 54.8% events of palbociclib dose modification. Most providers (65.8%) dose reduced palbociclib from 125 mg to 100 mg as their preferred method of dose modification, while others dose reduced from 125 mg to 75 mg (10.5%) and altered the schedule to 125 mg every other day (7.9%). A comparable rate of palbociclib dose modifications and subsequent dose changes were identified in an age ≥ 65 subgroup. In this group, dose adjustments were most commonly from grade 3-4 neutropenia, occurred mainly during cycle 1, and were most frequently addressed by dose reduction from 125 to 100 mg.Conclusions: Neutropenia remains the predominant cause for palbociclib dose modification and most modifications occur within the first two cycles. Older age (≥ 65) does not affect palbociclib tolerance. Our findings provide context outside of a clinical trial that inform ongoing studies evaluating the safety and feasibility of palbociclib-based therapies. [ABSTRACT FROM AUTHOR]

Dose reductions or interruptions may be required to manage treatment-associated adverse events among patients with myelodysplastic syndromes (MDS) treated with lenalidomide; such modifications are recommended to sustain therapy and maximize treatment duration. The aim of this retrospective case-control study was to determine the relationship between lenalidomide dose modification (DM), duration of lenalidomide therapy (DOT), and patient outcomes in patients with MDS. Those patients with database follow-up >20 months (n = 305) were more likely to have received erythropoiesis-stimulating agents (ESAs) ( P = 0.004), had longer median DOT ( P < 0.001), and higher rate of DM ( P < 0.001) versus those with shorter follow-up (n = 306). Multivariate analysis indicated that lenalidomide DM (odds ratio [OR] 1.08) and prior ESA treatment (OR 2.40) were significantly associated with longer follow-up; transfusion dependence before lenalidomide initiation was associated with a significantly shorter follow-up (OR 0.60). These data suggest that effective management of lenalidomide treatment using dose reduction and/or delay is associated with longer DOT, which can improve patient outcomes. [ABSTRACT FROM AUTHOR]