Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

INTRODUCTION AND OBJECTIVE: Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. RESULTS: A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). CONCLUSION: TDM reduced the proportion of patients with subtherapeutic exposure levels by ~ 50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥ 20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

[A rapidly enlarging neck mass]. / Een snelgroeiende zwelling in de hals.

The differential diagnosis of a rapidly enlarging neck mass consists of many different benign ((haemorrhagic) cyst) and malignant (anaplastic thyroid cancer (ATC) and lymphoma) causes. ATC is a rare disease with a median survival of 6 months. As early diagnosis and management are key for fast-growing cancers, in our centre we have implemented a dedicated short-stay in-hospital fast-track diagnostic work-up for patients with a rapid growing mass in the neck. The goal of this track is to have a fast diagnostic and therapeutic plan for this disease. Based on three clinical cases we discuss our experience with this fast-track diagnostic work-up for rapidly growing mass in the neck and illustrate the additional value in this clinical entity.

Individualized Dosing Patterns in the Treatment of Older Patients with Gastrointestinal Stromal Tumors: Results of a Registry-Based Observational National Cohort Study Including 871 Patients.

BACKGROUND: While the effectiveness of tyrosine kinase inhibitors (TKIs) seems similar in older patients with gastrointestinal stromal tumors (GIST) compared with younger patients, toxicities in older patients treated with TKIs more often lead to discontinuation of treatment. OBJECTIVE: To better understand the age-related pharmacology and pharmacodynamic differences in patients with GIST treated with TKIs, the primary aim of this study was to evaluate TKI dosing patterns in older patients with GIST, while the secondary aims were to evaluate differences in imatinib trough plasma concentrations between age groups and to compare the overall survival (OS) in patients with and without dose reductions in all treatment lines in a palliative setting. METHODS: Patients (18 years of age or older) with histologically proven GIST diagnosed between January 2009 and June 2021 and treated with one or more lines of TKIs were selected from the Dutch GIST Registry (DGR) database. Age groups were divided into younger patients (age <70 years) and older patients (age ≥70 years). All imatinib trough plasma concentrations of blood withdrawals taken from initiation of imatinib until a maximum of 1 year of treatment with imatinib were collected. Reasons for first adjustment of treatment were classified as adverse event, dose modification, progressive disease and other reasons. The next treatment steps after first adjustment of treatment were defined as dose escalation, dose reduction, dose interruption, or end of treatment. The association of dose reduction and OS was analyzed using the landmark approach. RESULTS: Overall, 871 patients were included in this study, including 577 younger patients and 294 older patients. Older patients more often had an adverse event as the reason for first adjustment of treatment with both imatinib (45.6%; p < 0.001) and sunitinib (58.6%; p = 0.224) compared with younger patients (19.5% and 42.7%, respectively). Adjustment of imatinib and sunitinib after starting on a standard dose because of an adverse event most often resulted in dose reduction in both age groups. Median trough plasma concentrations of all samples taken within the first year after initiation of imatinib were higher in older patients (1228 ng/mL, interquartile range [IQR] 959-1687) compared with younger patients (1035 ng/mL [IQR 773-1377]; p < 0.001). No significant differences were seen between OS in patients with or without dose reduction in all treatment lines (imatinib: p = 0.270; sunitinib: p = 0.547; and regorafenib: p = 0.784). CONCLUSION: Older patients showed higher imatinib trough plasma concentrations compared with younger patients and also had earlier and more often adverse events as the reason for first adjustment of treatment with imatinib followed by dose reduction. However, in a landmark analysis, patients with imatinib dose reductions had no poorer outcomes compared with patients not requiring a dose reduction.

Representation of older patients in the safety analysis of protein kinase inhibitor registration studies.

INTRODUCTION: Older patients (≥65 years old) make up the majority of the cancer population. Older patients seem to experience more adverse events (AEs) from protein kinase inhibitors (PKIs) in clinical practice. Yet they are underrepresented in clinical trials. We aimed to evaluate whether age-related safety differences were described at authorization of PKIs. Representation of older patients in registration studies was also evaluated. MATERIALS AND METHODS: European Public Assessment Reports (EPARs) of PKIs authorized between 2010 and 2015 were evaluated for the description of age-related safety- and pharmacokinetic differences. The International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use (ICH) E7 guideline was applied to EPARs to assess the representation of older patients. Study results were presented descriptively. RESULTS: Eighteen PKIs with 19 EPARs were analyzed. Age-related safety differences were described in 14 out of 19 EPARs, and age-related pharmacokinetic differences in 1 out of 19 EPARs. More than 100 older patients were included in half of the studies. Older patients were not excluded solely by age, although other inclusion and exclusion criteria negatively influenced enrollment of older patients. None of the PKIs met all criteria from the ICH E7 guideline. DISCUSSION: Age-related safety differences are described for most PKIs. Older patients were underrepresented in PKI registration studies. Adequate representation of older patients in clinical trials for PKIs is vital, since they make up most of the cancer population.

End-of-life care for patients with advanced ovarian cancer in the Netherlands: A retrospective registry-based analysis.

OBJECTIVE: Patients with advanced ovarian cancer have a poor prognosis and can experience debilitating symptoms in the last phase of life. Several analyses, mainly performed in the United States (US), show high rates of chemotherapy administration and hospital visits near the end-of-life in this patient category. No large European studies are available, while the organisation of palliative care differs between the US and Europe. We aimed to analyse the intensity of inpatient care near the end-of-life in the Netherlands and perform a cross-study comparison with previous reports. METHODS: All patients with ovarian cancer that died in 2016 and 2017 were identified from the Vektis database, a data warehouse including all insurance declarations in the Netherlands. For the last 6 months of life the following parameters of aggressive care were extracted: administration of chemotherapy, emergency room (ER) visits, surgical procedures, hospital and intensive care unit (ICU) admissions. The intensity of inpatient care was compared to previously reported European and US data. RESULTS: Data on medical care use was available for 1775 patients. During the last 6 months of life, half of the ovarian cancer patients were admitted to hospital. Chemotherapy administration near the end-of-life was infrequent: 12% in the last month of life. Surgery and ICU admissions in the final 6 months of life were rare (<10%). Our cohort showed the lowest percentages of all five indicators of aggressive care reported thus far. CONCLUSION: Aggressive medical care use in the final 6 months of life in this Dutch cohort of ovarian cancer patients was lower than in other previously reported cohorts.

State of the art and future directions in the systemic treatment of medullary thyroid cancer.

PURPOSE OF REVIEW: Systemic treatment is the only therapeutic option for patients with progressive, metastatic medullary thyroid cancer (MTC). Since the discovery of the rearranged during transfection (RET) proto-oncogene (100% hereditary, 60-90% sporadic MTC), research has focused on finding effective systemic therapies to target this mutation. This review surveys recent findings. RECENT FINDINGS: Multikinase inhibitors are systemic agents targeting angiogenesis, inhibiting growth of tumor cells and cells in the tumor environment and healthy endothelium. In the phase III EXAM and ZETA trials, cabozantinib and vandetanib showed progression-free survival benefit, without evidence of prolonged overall survival. Selpercatinib and pralsetinib are kinase inhibitors with high specificity for RET; phase I and II studies showed overall response rates of 73% and 71% in first line, and 69% and 60% in second line treatment, respectively. Although resistance mechanisms to mutation-driven therapy will be a challenge in the future, phase III studies are ongoing and neo-adjuvant therapy with selpercatinib is being studied. SUMMARY: The development of selective RET-inhibitors has expanded the therapeutic arsenal to control tumor growth in progressive MTC, with fewer adverse effects than multikinase inhibitors. Future studies should confirm their effectiveness, study neo-adjuvant strategies, and tackle resistance to these inhibitors, ultimately to improve patient outcomes.

Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer.

BACKGROUND: This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer (BC). PATIENTS AND METHODS: Patients with advanced BC treated with palbociclib from 2017 to 2020 were included. The Kaplan-Meier method was used to calculate time to next treatment (TTNT) and overall survival (OS) for patients with or without dose reductions. These clinical outcomes were also compared in subgroup analyses for older patients (≥70 years) and younger patients (<70 years) and for patients discontinuing palbociclib early (<4 administrations). RESULTS: A total of 598 patients with advanced BC were included, with a median age of 64 years. Palbociclib dose reductions occurred in 33% of all patients. Early discontinuation of palbociclib without dose reductions occurred in 23% of the patients. Patients who required a palbociclib dose reduction were older (median age 67 years vs. 63 years). Patients with dose reductions had a significantly higher TTNT of 16.9 vs. 11.4 months (p < 0.001) and median OS of 29.7 vs. 21.9 months (p = 0.003) compared to patients without dose reductions. The TTNT in older patients was significantly longer (16.9 vs. 11.6 months, p = 0.013) than younger patients, but OS was similar (20.7 vs. 26.7 months, p = 0.051). CONCLUSION: Palbociclib dose reductions occurred in real-world practice similarly to the PALOMA-3 trial. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS.

Clinical benefit of systemic therapies for recurrent ovarian cancer-ESMO-MCBS scores.

BACKGROUND: Licensed systemic treatment options for platinum-sensitive recurrent ovarian cancer are platinum-based chemotherapy and maintenance treatment with bevacizumab and poly (ADP-ribose) polymerase inhibitors. For platinum-resistant disease, several non-platinum options are available. We aimed to assess the clinical benefit of these treatments according to the European Society of Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). MATERIALS AND METHODS: A PubMed search was carried out including all studies evaluating systemic treatment of recurrent epithelial ovarian cancer, from 1990 onwards. Randomised trials with an adequate comparator and design showing a statistically significant benefit of the study arm were independently scored by two blinded observers using the ESMO-MCBS. RESULTS: A total of 1127 papers were identified, out of which 61 reported results of randomised trials of sufficient quality. Nineteen trials showed statistically significant results and the studied treatments were graded according to ESMO-MCBS. Only three treatments showed substantial benefit (score of 4 on a scale of 1-5) according to the ESMO-MCBS: platinum-based chemotherapy with paclitaxel in the platinum-sensitive setting and the addition of bevacizumab to chemotherapy in the platinum-resistant setting. The WEE1 inhibitor adavosertib (not licensed) also scores a 4, based on a recent small phase II study. Assessment of quality-of-life data and toxicity using the ESMO-MCBS showed to be complex, which should be taken into account in using this score for clinical decision making. CONCLUSION: Only a few licensed systemic therapies for recurrent ovarian cancer show substantial clinical benefit based on ESMO-MCBS scores. Trials demonstrating overall survival benefit are sparse.

Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer.

Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.

Effectiveness and toxicity of lenvatinib in refractory thyroid cancer: Dutch real-life data.

OBJECTIVE: The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial. METHODS: From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies. RESULTS: A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04). CONCLUSIONS: PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.

Clinical benefit of controversial first line systemic therapies for advanced stage ovarian cancer - ESMO-MCBS scores.

BACKGROUND: The magnitude of clinical benefit scale (MCBS) was introduced by the European Society of Medical Oncology (ESMO) to quantify the clinical benefit of therapeutic regimens and to prioritise therapies. It distinguishes curative from palliative treatments and ranks their benefit based on overall survival (OS), progression free survival (PFS), quality of life (QoL) and toxicity. Objective of this study on the first line treatment of ovarian cancer was to evaluate the evidence for the current standard of care using the ESMO-MCBSv1.1 with an emphasis on controversial therapeutic options: intraperitoneal chemotherapy, dose-dense paclitaxel and bevacizumab. METHODS: Phase III trials, published since 1992, investigating first line systemic treatment of Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIB-IV epithelial ovarian cancer were included. Since most studies included patients with FIGO stage IV disease or incomplete debulking, all treatments were judged to be palliative. Treatments were graded 5 to 1 on the ESMO-MCBSv1.1, where grades 5 and 4 represent a high level of clinical benefit. RESULTS: 55 studies met the inclusion criteria. ESMO-MCBS scores were calculated for eleven studies that showed a statistically significant benefit of the experimental treatment. Intraperitoneal (ip) cisplatin scored a 4 and 3, but two other studies were negative and therefore not scored on the ESMO-MCBS. Dose-dense paclitaxel showed substantial clinical benefit in one study (score 4), but three studies were negative. Addition of bevacizumab also scored a 4 in one study subgroup including high-risk patients but a 2 in another trial with a larger study population. CONCLUSION: Based on ESMO-MCBS scores, dose-dense paclitaxel and intraperitoneal chemotherapy cannot be recommended as standard treatment. Bevacizumab should be considered only in the high-risk population. The ESMO-MCBSv1.1. helps to summarise reported studies on controversial treatment regimens, and identifies their weaknesses.

Molecular imaging in ovarian cancer.

Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer.

Lung lesions increase the risk of reduced meat quality of slaughter pigs.

Lung lesions of about 1000 pigs (nN) were scored in the slaughter line. Carcass weight, back fat thickness, loin muscle depth, pHi and PQMi were measured on 460 pigs. Twenty-four hours after slaughter pHu, PQMu, brightness, redness, yellowness and drip loss were measured on 59 carcasses. A score for lung lesions was assessed at batch level, based on observations of all pigs in that batch, i.e. about 130. Pigs systematically selected from batches scoring more than 25% lung lesions had a lower pH of LD muscle (P≤0.0003) and a six fold higher risk for P(ale)S(oft)E(xudative) traits (P≤0.050) compared to batches scoring less than 5%.

Volume control in treatment-resistant congestive heart failure: role for peritoneal dialysis.

Chronic congestive heart failure (HF) has a rising prevalence and increasing impact on health care systems. Current treatment consists of diuretics, renin-angiotensin-aldosterone system blockers, and restriction of salt and fluids. This strategy is often hampered by a drop in effective circulating volume and hence renal perfusion and function, triggering harmful counter regulatory mechanisms. Slow ultrafiltration by peritoneal dialysis (PD) might be an effective treatment strategy to relieve fluid overload without compromising cardiac output and thereby renal function. In this review, we discuss the (patho)physiological mechanisms of the cardiorenal interaction and the current literature on PD strategies in congestive HF.