Evaluating the clinical benefit of pembrolizumab as a first-line agent in advanced solid tumors: A comprehensive review.

INTRODUCTION: The study evaluates the first-line application of pembrolizumab in metastatic non-small-cell lung cancer (mNSCLC), head and neck squamous cell cancer (HNSCC), gastric cancer, and renal cell carcinoma. Utilizing the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the American Society of Clinical Oncology Value Framework (ASCO-VF), the analysis incorporates data from pivotal KEYNOTE trials. METHODS: The study systematically assessed the clinical benefit of pembrolizumab in advanced solid malignancies through nine randomized controlled trials, one of which comprised two experimental arms. Data extraction from primary sources was conducted from PubMed, ASCO, and ESMO publications. Utilizing ESMO-MCBS and ASCO-VF forms, the evaluation focused on clinical benefit, toxicity, and bonus points, with discrepancies resolved through consensus discussions. RESULTS: Nine first-line indications for pembrolizumab received Food and Drug Administration approval for metastatic solid tumors between 2018 and 2023. Notable distinctions in ESMO-MCBS grades revealed seven trials with substantial clinical benefit (grades 5 to 4) and three with moderate to negligible benefit (grades 3 to 1). Bonus points, primarily based on the tail of the curve, were allocated to three trials for overall survival, one for progression-free survival, and one for a significant improvement in quality of life. CONCLUSIONS: Our evaluation of pembrolizumab across diverse cancers, especially in mNSCLC and HNSCC, revealed varied outcomes and challenges in clinical benefit interpretation. The assessment of clinical benefit, incorporating quantitative and qualitative endpoints, underscores the need to consider survivorship outcomes and patient perspectives for a comprehensive understanding.

Limited Sampling Strategy Using End of Infusion and Six-Hour Concentrations Overestimates Intravenous Busulfan Clearance Compared With Standard Six-Point Sampling in Hematopoietic Stem Cell Transplant Patients.

BACKGROUND: Therapeutic drug monitoring for busulfan (Bu) is important to improve outcomes of hematopoietic stem cell transplantation. However, standard therapeutic drug monitoring requires multiple samples and is inconvenient, labor-intensive, and costly. Accordingly, a limited sampling strategy (LSS) was evaluated, using 2-point sampling at end of infusion and at 6 hours, and the area-under-the-curve and Bu clearances (CLs) were compared with the results obtained from the standard sampling strategy (SSS) using 5-6 samples. METHOD: The analysis was based on retrospective clinical data from 202 patients receiving intravenous Bu before hematopoietic stem cell transplantation for malignant or nonmalignant conditions. Bu plasma concentrations were measured via liquid chromatography tandem-mass spectrometry, and pharmacokinetic parameters were calculated using the PKCNA package in R program. RESULT: A total of 502 doses were analyzed by applying SSS and LSS. Using the modified Bland-Altman plot, the mean percentage difference in CL between the SSS and LSS estimates of Bu 6-hourly regimen was -41% (Limits: -53% and -30%). In the once daily regimen, the mean difference in CL between the 2 strategies on the modified Bland-Altman plot was -22% (Limits: -66% and +22%). CONCLUSIONS: The Bu CL values estimated based on the BU concentration at end of infusion and at 6 hours postinfusion were significantly higher than the values obtained via the SSS.

Applications and challenges in therapeutic drug monitoring of cancer treatment: A review.

Most anticancer agents show wide variability in pharmacokinetics (PK) and have a narrow therapeutic index which makes fixed dosing suboptimal. To achieve the best therapeutic outcomes with these agents, many studies have postulated using PK or therapeutic drug monitoring (TDM)-guided dosing. However, multiple factors contribute to the variability in PKs making the application of TDM in practice challenging. Also, despite the known association with clinical outcomes, standard guidelines on PK-guided dosing are lacking for most agents. Understanding the factors that contribute to PK variability and their impact is essential for dose individualization. The purpose of this review is to discuss the factors that contribute to the PK variability of anticancer agents and the challenges faced in practice when individualizing doses for certain widely used agents. Searching the literature has identified several gaps and efforts are needed to ensure better targeting of cancer therapeutics.

Immune Checkpoint Inhibitors-Induced Endocrinopathies: Assessment, Management and Monitoring in a Comprehensive Cancer Centre.

OBJECTIVES: To determine the incidence, presentation, frequency and management of immune checkpoint inhibitors (ICI)-related endocrinopathies in a comprehensive cancer centre in Oman, particularly with programme death 1/programme death-ligand 1 (PD-1/PD-L1) inhibitors. BACKGROUND: A high number of patients treated with PD-1/PD-L1 inhibitors for the management of solid tumours developed endocrinopathies. METHODS: This is a retrospective study of patients admitted to Sultan Qaboos Comprehensive Cancer Care and Research Centre (SQCCCRC) from August 2021 to December 2022. All adults diagnosed with solid cancers and have received at least one dose of ICIs were included. Patients with incomplete data were excluded from the analysis. Data regarding the ICI-induced endocrinopathy were collected. RESULTS: A total of 139 patients were included in the study of which 58% were females. The median age of the cohort was 56 years. The incidence of endocrine-related adverse events was 28%. The mean time for the development of endocrine adverse events after treatment initiation was 4.1 ± 2.8 months. Of the patients who developed toxicity, 90% had hypothyroidism. Ten patients developed hyperthyroidism, two patients were diagnosed with secondary adrenal insufficiency/hypophysitis and one patient developed Type 1 diabetes mellitus (DM). Using univariable logistic regression weight and body mass index (BMI) significantly impacted the development of endocrine immune-related adverse events (irAEs). CONCLUSIONS: This is the first study from the Sultanate of Oman to assess PD-1/PDL-1 ICI-induced endocrinopathies. The most common endocrine adverse event is thyroid dysfunction, mainly hypothyroidism followed by hyperthyroidism. Hypophysitis, primary adrenal insufficiency and CIADM occur less frequently, but have a more significant effect on the patient's health. The treating physician should be aware of ICI-induced endocrinopathies, screening and treatment. Furthermore, our study showed that patients with a higher BMI have a greater risk of developing irAES. Further studies are needed to establish the predictors of endocrine irAEs.

The Prevalence and Patterns of Toxicity With Immune Checkpoint Inhibitors in Solid Tumors: A Real-World Experience From a Tertiary Care Center in Oman.

Introduction Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple cancers over the last decade. They work by employing the immune system and exhibiting activity over T cells resulting in immune upregulation. Despite their widespread use, they produce side effects that can limit their use. The immune-related adverse events (irAEs) can be sometimes significant. The irAEs caused by ICIs may occur at any time during the treatment and can vary in grade (G). We sought to study the prevalence and toxicity patterns of ICIs in Oman. Methods One hundred forty-one adult patients (≥18 years) who received at least one dose of nivolumab, pembrolizumab, atezolizumab, or durvalumab between 2016 and 2022 were included. The data were analyzed retrospectively using univariable and multiple-variable logistic regressions. The Wilcoxon rank-sum test and Cochran-Armitage trend test were also used to summarize the continuous and ordinal data. Results Out of the 141 patients, 80 patients (56.7%) received pembrolizumab, and 48 (34%) received nivolumab. Common irAEs included endocrine abnormalities, pneumonitis, and colitis. Thirty patients (21.3%) experienced varying irAE grade toxicity. Out of the 30, 23 patients (82%) developed grade 2 and 3 irAEs. Discussion Predictive analysis showed that male sex and lower hemoglobin (Hb) and bilirubin levels were all significant predictors (p < 0.05) when associated with irAE occurrence. The prevalence of irAEs was similar compared to other reports, literature reviews, or meta-analyses. Female sex has been mentioned previously also to be a predictive factor for endocrine-related toxicities.

Predictors of Hypersensitivity Reactions to Platinum-Based Chemotherapy in a Tertiary Care Hospital in Oman: A case control study.

Objectives: This study aimed to estimate the prevalence and evaluate risk factors of hypersensitivity reactions (HSRs) to platinum-based compounds (PBCs) in cancer patients. PBCs play an important role in cancer therapy. However, one of the drawbacks of PBCs is the occasional occurrence of HSRs, which can lead to serious consequences. Methods: This retrospective case control study was conducted from January 2013 to December 2020 at Sultan Qaboos University Hospital, Muscat, Oman and included patients who received any PBC for the management of non-haematological cancers. Data regarding demographic characteristics and diseases and treatment details were collected from the hospital's electronic database. The data were quantitatively described and Student's t-test and Wilcoxon Mann-Whitney tests were used to detect significant differences. Results: A total of 38 cases and 148 matched controls were studied. The prevalence of HSRs to PBCs in the cohort of this study was 4.7% (95% confidence interval: 3.33-6.37%), higher with carboplatin compared with cisplatin and oxaliplatin. The female gender (P = 0.032), concomitant taxanes (P = 0.002) and concurrent radiation (P <0.001) were significant predictors of HSRs to PBCs. The majority of the reactions were of mild to moderate severity, and the rechallenge rate after HSR development was 13%. Conclusion: HSRs to PBCs impact therapy decisions and understanding the risk factors is important to improve treatment outcomes in cancer patients.

Clinical and Cost Implications of Clinical Pharmacist Interventions on Antimicrobial Use at Sultan Qaboos University Hospital in Oman.

OBJECTIVE: To evaluate the clinical and financial impact of clinical pharmacists' interventions (CPIs) on antimicrobial use at a 500-bed multidisciplinary tertiary care hospital in Oman. METHODS: A retrospective analysis of CPIs related to antimicrobials use at Sultan Qaboos University Hospital (SQUH) from January to December 2018. Interventions were recorded using an electronic CPI form and were reviewed by two independent CPs. Data on the type and clinical significance of the interventions were extracted. Cost analysis was done using a previously defined cost avoidance model in addition to direct cost reduction estimation. Descriptive data were used to describe the results. RESULTS: In 2018, 26% of CPIs were related to antimicrobial use, with more than 60% of these interventions done on intensive care unit patients. The most common intervention type was adjusting the dosing regimen (42% of the total interventions), followed by deletion of the antimicrobial order in 34% of the cases. The most common clinical impact of CPIs was improving efficacy in 45% of the interventions, followed by preventing unnecessary exposure to the antimicrobials in around 30% of the interventions. The interventions were of major significance in 64% of the cases. This translated into a projected net cost saving of approximately $200,000 USD/year. CONCLUSIONS: CPs interventions on antimicrobial use had a positive impact on both the clinical and financial outcomes.

Pregnancy Outcomes in Systemic Lupus Erythematosus Women: A single tertiary centre experience.

OBJECTIVES: This study was conducted to assess pregnancy outcomes in women with systemic lupus erythematosus (SLE) in Oman. METHODS: A retrospective cohort study of 149 pregnancies in 98 women with SLE was conducted over 10 years to evaluate the impact of clinical and laboratory parameters in predicting adverse pregnancy outcomes. RESULTS: Mean maternal age was 30.6 ± 5 years ranging from 20-44 years, and the mean disease duration was 10 ± 5 years, ranging from 2-27 years. The most common maternal manifestations were joint pain in 36 (24.2%), lupus nephritis (LN) in 18 (12.08%), preeclampsia in 11 (7.4%), eclampsia in three (2%) and lupus flare in one pregnancy. The live birth rate was 139 (93.3%) with a mean gestational age of 36 ± 2 weeks ranging from 26-40 weeks. In total, 55 (39.6%) were preterm deliveries, six (4%) pregnancies ended in miscarriage, and four (2.7%) resulted in intrauterine fetal death. Intrauterine growth restriction was observed in 49 babies (35%). A significant association was found between hypertension (HTN) and miscarriage (P = 0.024) and preterm birth (P = 0.019). In addition, HTN was positively associated with preeclampsia (P = 0.004) and LN (P = 0.048). Antiphospholipid syndrome impacted preterm birth (P = 0.013) and postpartem haemorrhage (PPH) (P = 0.027) and was found to be a significant predictor for women developing deep vein thrombosis and pulmonary embolism (P <0.001 for both). CONCLUSION: Despite potential complications, most pregnancies complicated by SLE in Oman result in good outcomes. Adverse pregnancy outcomes, however, may still occur in women with SLE. In women with SLE, pregnancy planning, careful antenatal monitoring and efficient SLE treatment need to be undertaken for successful pregnancy outcomes.

Busulfan clearance does not predict the development of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a life-threatening complication following hematopoietic stem cell transplant (HSCT). Busulfan has a narrow therapeutic index and its concentration was found to correlate with VOD. Our primary objective was to assess the association between busulfan clearance and VOD in HSCT patients. In this retrospective analysis, we included patients who received their HSCT between 2003 and 2014 and followed at Sultan Qaboos University Hospital. All patients who received dose-targeted busulfan-containing conditioning were included. Target steady-state concentration (Css) was 800-900 ng/ml. VOD was assessed using modified Seattle criteria. The impact of busulfan clearance on VOD was analyzed using univariable logistic regression model. Seventy-three patients were included with a mean age of 15 years. Of those, 47% were transplanted for hematological malignancies and 53% for inherited hemoglobinopathies. Target Css was achieved in 85% of patients. The rate of VOD was 17%. There was no significant impact of busulfan clearance (p = 0.919) or area-under-the-concentration-time-curve (p = 0.275) on VOD. Targeting busulfan Css into narrow therapeutic range may have accounted for the findings. The risk of VOD might be related to other factors such as the genetic background, and more studies are required to investigate these factors.

Gestational Trophoblastic Disease at Sultan Qaboos University Hospital: Prevalence, Risk Factors, Histological Features, Sonographic Findings, and Outcomes.

OBJECTIVES: We sought to assess the prevalence of gestational trophoblastic diseases (GTD) among pregnant women at Sultan Qaboos University Hospital (SQUH) and compare our results with the international studies. We also sought to determine the risk factors, histological features, sonographic findings, and outcomes in women with GTD. METHODS: We conducted a retrospective cohort study of all women diagnosed with GTD and followed at SQUH between November 2007 and October 2015. We collected data on maternal demographics, risk factors, sonographic features, histological diagnosis, follow-up period, and chemotherapy treatment from the hospital information system. RESULTS: Sixty-four women with GTD were included in the study with a mean age of 31.0±7.5 years, mean gravidity 4.0, and parity 2.0. The prevalence of GTD was 0.3% (one in 386 births), and the most common risk factors were increased maternal age and multiparity. A partial hydatidiform mole was diagnosed in 54.7%, complete hydatidiform mole in 43.8%, and invasive mole in 1.6% of women. Eleven percent of women required chemotherapy. Typical ultrasound features for partial molar pregnancy were present in 54.7% of our sample, while snowstorm appearance was seen in 89.3% of those with complete mole. Negative beta-human chorionic gonadotropin was achieved 70 days after diagnosis in 41 women. CONCLUSIONS: The awareness of the risks and complications of GTD among physicians with close follow-up is paramount. There is a need to establish a national registry of GTD cases in Oman.

Therapeutic drug monitoring-guided dosing of busulfan differs from weight-based dosing in hematopoietic stem cell transplant patients.

Busulfan (Bu)-based preparative regimens in hematopoietic stem cell transplantation are commonly used. Previous studies have shown that Bu at a fixed dose of 3.2mg/kg/day (FBD) given intravenously decreases variability in drug pharmacokinetics and this decreases the dependency on therapeutic drug monitoring (TDM) of Bu. We compared the Bu dose given using TDM with the FBD of 3.2mg/kg/day. Seventy-three patients with acute leukemia, myelodysplasia, chronic myeloid leukemia, thalassemia major, and sickle cell disease were included. The mean age at transplant was 15years (range 2-55years) with 57% adults. Indication for transplantation was leukemia/myelodysplastic syndrome in 46% of the patients, while the remaining 54% were transplanted for inherited blood disorders. We found that the median FBD was lower than the median TDM dose by 39mg/day with a statistically significant difference (p<0.001) even after adjusting for the weight (median total FBD of 349mg, median TDM dose of 494mg, p<0.0001). Age and underlying condition (malignant vs. nonmalignant) were the main factors affecting Bu clearance (p<0.001 and p<0.07, respectively). TDM remains an important tool for the appropriate dosing of Bu in preparative regimens of hematopoietic stem cell transplantation, especially in populations with genetic admixture.