Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology - an analysis of the closed cohorts of a multicentre prospective study.

BACKGROUND: Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS: We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS: For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS: Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.

Results of the first international quality control programme for oral targeted oncolytics.

AIMS: With the rising number of oral targeted oncolytics and growing awareness of the benefits of therapeutic drug monitoring (TDM) within the field of oncology, it is expected that the requests for quantifying concentrations of these drugs will increase. It is important to (cross-)validate available assays and ensure its quality, as results may lead to altered dosing recommendations. Therefore, we aimed to evaluate the performance of laboratories measuring concentrations of targeted oral oncolytics in a one-time international quality control (QC) programme. METHODS: Participating laboratories received a set of plasma samples containing low, medium and high concentrations of imatinib, sunitinib, desethylsunitinib, pazopanib, cabozantinib, olaparib, enzalutamide, desmethylenzalutamide and abiraterone, with the request to report their results back within five weeks after shipment. Accuracy was defined acceptable if measurements where within 85%-115% from the weighed-in reference concentrations. Besides descriptive statistics, an exploratory ANOVA was performed. RESULTS: Seventeen laboratories from six countries reported 243 results. Overall, 80.7% of all measurements were within the predefined range of acceptable accuracy. Laboratories performed best in quantifying imatinib and poorest in quantifying desethylsunitinib (median absolute inaccuracy respectively 4.0% (interquartile range (IQR) 1.8%-6.5%) and 15.5% (IQR 8.8%-34.9%)). The poorest performance of desethylsunitinib might be caused by using the stable-isotope-labelled sunitinib instead of desethylsunitinib as an internal standard, or due to the light-induced cis(Z)/trans(E) isomerization of (desethyl)sunitinib. Overall, drug substance and performing laboratory seemed to influence the absolute inaccuracy (F = 16.4; p < 0.001 and F = 35.5; p < 0.001, respectively). CONCLUSION: Considering this is the first evaluation of an international QC programme for oral targeted oncolytics, an impressive high percentage of measurements were within the predefined range of accuracy. Cross-validation of assays that are used for dose optimization of oncolytics will secure the performance and will protect patients from incorrect advices.

Referral patterns of GIST patients: data from a nationwide study.

BACKGROUND: This study compares the characteristics, referral and treatment patterns and overall survival (OS) of gastrointestinal stromal tumor (GIST) patients treated in reference and non-reference centers in the Netherlands. PATIENTS AND METHODS: This retrospective cohort study on patients diagnosed between 2016 and 2019, utilises data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Database. Patients were categorized into two groups: patients diagnosed in or referred to reference centers and patients diagnosed in non-reference centers without referral. RESULTS: This study included 1,550 GIST patients with a median age of 67.0 in reference and 68.0 years in non-reference centers. Eighty-seven per cent of patients were diagnosed in non-reference centers, of which 36.5% (493/1,352) were referred to a reference center. Referral rates were higher for high-risk (62.2% [74/119]) and metastatic patients (67.2% [90/134]). Mutation analysis was performed in 96.9% and 87.6% of these cases in reference and in non-reference centers (p < 0.01), respectively. Systemic therapy was given in reference centers versus non-reference in 89.5% versus 82.0% (p < 0.01) of high-risk and in 94.1% versus 65.9% (p < 0.01) of metastatic patients, respectively. The proportion of positive resection margins and tumor rupture did not differ between reference and non-reference centers. Median OS was not reached. CONCLUSION: A substantial amount of metastatic GIST patients in non-reference centers did not receive systemic treatment. This might be due to valid reasons. However, optimisation of the referral strategy of GIST patients in the Netherlands could benefit patients. Further research is needed to explore reasons for not starting systemic treatment in metastatic GIST patients.

Financial difficulties experienced by patients with gastrointestinal stromal tumours (GIST) in the Netherlands: data from a cross-sectional multicentre study.

PURPOSE: This study aims to (1) explore the prevalence of patient-reported financial difficulties among GIST patients, differentiating between those currently undergoing tyrosine kinase inhibitor (TKI) treatment and those who are not; (2) investigate associations between financial difficulties and sociodemographic and clinical characteristics, work, cancer-related concerns, anxiety and depression and (3) study the impact of financial difficulties on health-related quality of life. METHODS: A cross-sectional study was conducted among Dutch GIST patients diagnosed between 2008 and 2018, who were invited to complete a one-time survey between September 2020 and June 2021. Patients completed nine items of the EORTC item bank regarding financial difficulties, seven work-related questions, the Hospital Anxiety and Depression Scale, Cancer Worry Scale and EORTC QLQ-C30. RESULTS: In total, 328 GIST patients participated (response rate 63.0%), of which 110 (33.8%) were on TKI treatment. Patients currently treated with TKIs reported significantly more financial difficulties compared to patients not on TKIs (17.3% vs 8.7%, p = 0.03). The odds of experiencing financial difficulties was 18.9 (95% CI 1.7-214.7, p = 0.02) times higher in patients who were less able to work due to their GIST diagnosis. Patients who experienced financial difficulties had significantly lower global quality of life and functioning, and more frequently reported psychological symptoms as compared to patients who did not report financial difficulties. CONCLUSION: Even in a country where the costs of TKIs and follow-up care are covered by health insurance, financial difficulties can be present in GIST patients, especially in patients on TKI treatment, and may negatively influence the quality of life.

Therapeutic drug monitoring in anticancer agents: perspectives of Australian medical oncologists.

BACKGROUND: In the development of anticancer agents for solid tumours, body surface area continues to be used to personalise dosing despite minimal evidence for its use over other dosing strategies. With the development of tyrosine kinase inhibitors and other oral targeted anticancer agents, dosing using therapeutic drug monitoring (TDM) is now utilised in many health systems but has had limited uptake in Australia. AIM: To determine attitudes and barriers to the implementation of TDM among Australian oncologists. METHODS: A comprehensive questionnaire was developed by the Dutch Pharmacology Oncology Group from semistructured interviews of stakeholders. Seventy-nine questions across seven domains were developed with three free-text responses. This was rationalised to 17 questions with three free-text responses for Australian medical oncologists who identified limited experience with TDM. RESULTS: Fifty-seven responses were received, with 49 clinicians (86%) identifying limited experience of performing TDM in daily practice. Clinicians were positive (62-91% agree/strongly agree across seven questions) about the advantages of TDM. There was a mixed response for cost-effectiveness and scientific evidence being a barrier to implementation, but strong agreement that prospective studies were needed (75% agreed or strongly agreed); that national treatment guidelines would enable practice (80%) and that a 'pharmacology of oncolytics' education programme would be useful (96%) to provide knowledge for dose individualisation. CONCLUSION: Despite the limited experience of TDM in oncology in Australia, medical oncologists appear positive about the potential benefit to their patients. We have identified three barriers to implementation that could be targeted for increased adoption of TDM in oncology in Australia.

The influence of multidisciplinary team meetings on treatment decisions in advanced bladder cancer.

OBJECTIVES: To investigate the role of specialised genitourinary multidisciplinary team meetings (MDTMs) in decision-making and identify factors that influence the probability of receiving a treatment plan with curative intent for patients with muscle invasive bladder cancer (MIBC). PATIENTS AND METHODS: Data relating to patients with cT2-4aN0/X-1 M0 urothelial cell carcinoma, diagnosed between November 2017 and October 2019, were selected from the nationwide, population-based Netherlands Cancer Registry ('BlaZIB study'). Curative treatment options were defined as radical cystectomy (RC) with or without neoadjuvant chemotherapy, chemoradiation or brachytherapy. Multilevel logistic regression analyses were used to examine the association between MDTM factors and curative treatment advice and how this advice was followed. RESULTS: Of the 2321 patients, 2048 (88.2%) were discussed in a genitourinary MDTM. Advanced age (>80 years) and poorer World Health Organization performance status (score 1-2 vs 0) were associated with no discussion (P < 0.001). Being discussed was associated with undergoing treatment with curative intent (odds ratio [OR] 3.0, 95% confidence interval [CI] 1.9-4.9), as was the involvement of a RC hospital (OR 1.70, 95% CI 1.09-2.65). Involvement of an academic centre was associated with higher rates of bladder-sparing treatment (OR 2.05, 95% CI 1.31-3.21). Patient preference was the main reason for non-adherence to treatment advice. CONCLUSIONS: For patients with MIBC, the probability of being discussed in a MDTM was associated with age, performance status and receiving treatment with curative intent, especially if a representative of a RC hospital was present. Future studies should focus on the impact of MDTM advice on survival data.

The association of having a monitoring or blunting coping style with psychological distress, health-related quality of life and satisfaction with healthcare in gastrointestinal stromal tumour (GIST) patients.

BACKGROUND: There are two main coping styles regarding information seeking under medical threat; monitoring (information-seeking) and blunting (information-avoiding). The aim of this study is to (1) determine factors associated with a monitoring or blunting coping style in gastro-intestinal stromal tumour (GIST) patients and (2) investigate its association with psychological distress, cancer-related concerns, health-related quality of life and satisfaction with healthcare. METHODS: In a cross-sectional study, Dutch GIST patients completed the shortened version of the Threatening Medical Situations Inventory to determine their coping style, the Hospital Anxiety and Depression Scale, Cancer Worry Scale, EORTC QLQ-C30 and part of the EORTC QLQ-INFO25. RESULTS: A total of 307 patients were classified as blunters (n = 175, 57%) or monitors (n = 132, 43%). Coping style was not associated with tumour or treatment variables, but being a female (OR 2.5; 95%CI 1.5-4.1; p= <.001) and higher educated (OR 5.5; 95%CI 2.5-11.9, p= <.001) were associated with higher odds of being a monitor. Monitors scored significantly lower on emotional functioning (mean = 86.8 vs mean = 90.9, p=.044), which is considered a trivial difference, more often experienced severe fear of cancer recurrence or progression (53.0% vs 37.7%, p=.007), and had more concerns about dying from GIST in the future (60.6% vs 47.4%, p=.025). Compared to blunters, monitors were less satisfied with the received healthcare and information, and would have liked to receive more information. CONCLUSION: GIST patients with a monitoring coping style experience a higher emotional burden. Additionally, monitors exhibit a greater need for information. Although this need for information could potentially result in fears and concerns, recognising it may also create an opening for tailored communication and information.

The QT interval prolongation potential of anticancer and supportive drugs: a comprehensive overview.

Patients with cancer are prone to prolongation of the corrected QT interval (QTc) due to the use of anticancer drugs with QTc-prolonging potential in combination with electrolyte imbalances caused by, for example, gastrointestinal side-effects. However, most anticancer drugs were approved with little information on their QTc-prolonging potential and the added risk of torsade de pointes. The absence of this information on the drug label poses a considerable challenge to clinicians regarding the measures that need to be taken to safely start anticancer treatment. In this Review, we provide a comprehensive overview of the evidence for the QTc-prolonging properties of 205 anticancer drugs and 14 antiemetic drugs available from drug labels, assessment reports, and published studies. We classify the drugs as low-risk, moderate-risk, or high-risk for QTc prolongation. We also discuss the clinical relevance of these findings and include practical recommendations to guide clinicians to select the drugs with the least QTc-prolonging properties and to adequately monitor susceptible patients.

Exposure-toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer.

Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 µg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured Cmin at steady-state. The geometric mean (GM) Cmin at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM Cmin at the start dose was 1456 µg/L (95% CI: 1185-1789) vs 682 µg/L (95% CI: 572-812) (P < .001) for SGC and RCC patients, respectively. When dose-normalised to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (Cmin 971 µg/L [95% CI: 790-1193] vs 669 µg/L [95% CI: 568-788]) (P = .005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was between 20 to 30 mg for SGC and 40 mg for RCC patients. GM Cmin at BTD were comparable between the SGC and the RCC group, 694 µg/L (95% CI: 584-824) vs 583 µg/L (95% CI: 496-671) (P = .1). The observed cabozantinib exposure at BTD of approximately 600 µg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity.

Exposure-response analyses of cabozantinib in patients with metastatic renal cell cancer.

AIM: In the registration trial, cabozantinib exposure ≥ 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure-response relationship in patients with mRCC treated in routine care. METHODS: Cabozantinib trough concentrations (Cmin) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of Cmin > 750 ng/mL and median Cmin. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response. RESULTS: In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0-5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median Cmin was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average Cmin ≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with Cmin ≥ 750 ng/mL or ≥ 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. ≥ 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14-0.70, p = .004). CONCLUSION: In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy.

'I thought I had fibroids, and now I don't': a mixed method study on health-related quality of life in uterine sarcoma patients.

BACKGROUND: Uterine sarcomas are rare subtypes of primary urogenital tumours and need tailored treatment. This study aimed to examine the impact of diagnosis and treatment on health-related quality of life (HRQoL) in patients with uterine sarcoma and measures available to assess HRQoL in this group. METHODS: Thirteen patients with uterine sarcoma and 23 health care professionals were purposively sampled from sarcoma reference centers and participated in a semi-structured interview exploring HRQoL. Patients were also asked to review the EORTC QLQ-C30 and EORTC QLQ-EN24 for relevance. Data were analysed using thematic analysis and descriptive statistics. RESULTS: The most commonly reported physical health issues were related to sexual dysfunction and urological symptoms. Hormone-related issues and gastrointestinal symptoms were also identified. Cancer-generic issues such as functional problems, fatigue, pain, and treatment-related adverse effects were also reported. Regarding mental health, fears (about having sex, of recurrence, or of death), altered body-image, and dealing with lacking knowledge regarding sarcoma had an impact on HRQoL. Social health issues were related to the impact on relationships with others, limitations in undertaking activities, loss of independence, changes in work or study capacity, and financial difficulties. Most of the items of the EORTC QLQ-C30 and EORTC QLQ-EN24 questionnaires were rated as relevant. Questions about lack of knowledge about sarcoma, shock of diagnosis, and menopausal symptoms were lacking from existing measures. CONCLUSIONS: Uterine sarcoma patients experience a variety of concerns covering the physical, mental, and social domains of HRQoL that are in the main EORTC instruments, but not all of them. Combining cancer-generic, location- and sarcoma-specific items is recommended to assess HRQoL in this patient group. Trial registration NCT04071704.

Symptoms reported by gastrointestinal stromal tumour (GIST) patients on imatinib treatment: combining questionnaire and forum data.

PURPOSE: Treatment with the tyrosine kinase inhibitor (TKI) imatinib in patients with gastrointestinal stromal tumours (GIST) causes symptoms that could negatively impact health-related quality of life (HRQoL). Treatment-related symptoms are usually clinician-reported and little is known about patient reports. We used survey and online patient forum data to investigate (1) prevalence of patient-reported symptoms; (2) coverage of symptoms mentioned on the forum by existing HRQoL questionnaires; and (3) priorities of prevalent symptoms in HRQoL assessment. METHODS: In the cross-sectional population-based survey study, Dutch GIST patients completed items from the EORTC QLQ-C30 and Symptom-Based Questionnaire (SBQ). In the forum study, machine learning algorithms were used to extract TKI side-effects from English messages on an international online forum for GIST patients. Prevalence of symptoms related to imatinib treatment in both sources was calculated and exploratively compared. RESULTS: Fatigue and muscle pain or cramps were reported most frequently. Seven out of 10 most reported symptoms (i.e. fatigue, muscle pain or cramps, facial swelling, joint pain, skin problems, diarrhoea, and oedema) overlapped between the two sources. Alopecia was frequently mentioned on the forum, but not in the survey. Four out of 10 most reported symptoms on the online forum are covered by the EORTC QLQ-C30. The EORTC-SBQ and EORTC Item Library cover 9 and 10 symptoms, respectively. CONCLUSION: This first overview of patient-reported imatinib-related symptoms from two data sources helps to determine coverage of items in existing questionnaires, and prioritize HRQoL issues. Combining cancer-generic instruments with treatment-specific item lists will improve future HRQoL assessment in care and research in GIST patients using TKI.

Factors influencing the quality and functioning of oncological multidisciplinary team meetings: results of a systematic review.

BACKGROUND: Discussing patients with cancer in a multidisciplinary team meeting (MDTM) is customary in cancer care worldwide and requires a significant investment in terms of funding and time. Efficient collaboration and communication between healthcare providers in all the specialisms involved is therefore crucial. However, evidence-based criteria that can guarantee high-quality functioning on the part of MDTMs are lacking. In this systematic review, we examine the factors influencing the MDTMs' efficiency, functioning and quality, and offer recommendations for improvement. METHODS: Relevant studies were identified by searching Medline, EMBASE, and PsycINFO databases (01-01-1990 to 09-11-2021), using different descriptions of 'MDTM' and 'neoplasm' as search terms. Inclusion criteria were: quality of MDTM, functioning of MDTM, framework and execution of MDTM, decision-making process, education, patient advocacy, patient involvement and evaluation tools. Full text assessment was performed by two individual authors and checked by a third author. RESULTS: Seventy-four articles met the inclusion criteria and five themes were identified: 1) MDTM characteristics and logistics, 2) team culture, 3) decision making, 4) education, and 5) evaluation and data collection. The quality of MDTMs improves when the meeting is scheduled, structured, prepared and attended by all core members, guided by a qualified chairperson and supported by an administrator. An appropriate amount of time per case needs to be established and streamlining of cases (i.e. discussing a predefined selection of cases rather than discussing every case) might be a way to achieve this. Patient centeredness contributes to correct diagnosis and decision making. While physicians are cautious about patients participating in their own MDTM, the majority of patients report feeling better informed without experiencing increased anxiety. Attendance at MDTMs results in closer working relationships between physicians and provides some medico-legal protection. To ensure well-functioning MDTMs in the future, junior physicians should play a prominent role in the decision-making process. Several evaluation tools have been developed to assess the functioning of MDTMs. CONCLUSIONS: MDTMs would benefit from a more structured meeting, attendance of core members and especially the attending physician, streamlining of cases and structured evaluation. Patient centeredness, personal competences of MDTM participants and education are not given sufficient attention.

Preparing tomorrow's medical specialists for participating in oncological multidisciplinary team meetings: perceived barriers, facilitators and training needs.

INTRODUCTION: The optimal treatment plan for patients with cancer is discussed in multidisciplinary team meetings (MDTMs). Effective meetings require all participants to have collaboration and communication competences. Participating residents (defined as qualified doctors in training to become a specialist) are expected to develop these competences by observing their supervisors. However, the current generation of medical specialists is not trained to work in multidisciplinary teams; currently, training mainly focuses on medical competences. This study aims to identify barriers and facilitators among residents with respect to learning how to participate competently in MDTMs, and to identify additional training needs regarding their future role in MDTMs, as perceived by residents and specialists. METHODS: Semi-structured interviews were conducted with Dutch residents and medical specialists participating in oncological MDTMs. Purposive sampling was used to maximise variation in participants' demographic and professional characteristics (e.g. sex, specialty, training duration, type and location of affiliated hospital). Interview data were systematically analysed according to the principles of thematic content analysis. RESULTS: Nineteen residents and 16 specialists were interviewed. Three themes emerged: 1) awareness of the educational function of MDTMs among specialists and residents; 2) characteristics of MDTMs (e.g. time constraints, MDTM regulations) and 3) team dynamics and behaviour. Learning to participate in MDTMs is facilitated by: specialists and residents acknowledging the educational function of MDTMs beyond their medical content, and supervisors fulfilling their teaching role and setting conditions that enable residents to take a participative role (e.g. being well prepared, sitting in the inner circle, having assigned responsibilities). Barriers to residents' MDTM participation were insufficient guidance by their supervisors, time constraints, regulations hindering their active participation, a hierarchical structure of relations, unfamiliarity with the team and personal characteristics of residents (e.g. lack of confidence and shyness). Interviewees indicated a need for additional training (e.g. simulations) for residents, especially to enhance behavioural and communication skills. CONCLUSION: Current practice with regard to preparing residents for their future role in MDTMs is hampered by a variety of factors. Most importantly, more awareness of the educational purposes of MDTMs among both residents and medical specialists would allow residents to participate in and learn from oncological MDTMs. Future studies should focus on collaboration competences.

The impact of a 1-hour time interval between pazopanib and subsequent intake of gastric acid suppressants on pazopanib exposure.

Co-treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH-dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our study, we investigated whether a 1-hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady-state pazopanib trough concentration (Cmin ) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) Cmin levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM Cmin levels were lower in GAS users vs non-GAS users for both the 800 and 600 mg cohorts (23.7 mg/L [95% confidence interval [CI]: 21.1-26.7] vs 28.2 mg/L [95% CI: 25.9-30.5], P = .015 and 26.0 mg/L [95% CI: 22.4-30.3] vs 33.5 mg/L [95% CI: 30.3-37.1], P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non-GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub-analysis showed lower GM pazopanib Cmin in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non-users. Our research showed that a 1-hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.

Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer.

LESSONS LEARNED: Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d. Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined. BACKGROUND: Antitumor effects of MEK inhibitors are limited in KRAS-mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3-kinase-AKT pathway. Therefore, this phase I trial was initiated with the pan-HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild-type tumors. METHODS: Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy. RESULTS: Twenty-six patients were enrolled with colorectal cancer (n = 19), non-small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose-limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response. CONCLUSION: Afatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.

The relationship between sunitinib exposure and both efficacy and toxicity in real-world patients with renal cell carcinoma and gastrointestinal stromal tumour.

AIM: Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Because of the large interpatient pharmacokinetic variability and established exposure-response and exposure-toxicity relationships in clinical trial patients, therapeutic drug monitoring (TDM) seems promising for optimizing sunitinib exposure. We aimed to investigate the relationship between sunitinib exposure and treatment outcome in a real-world patient cohort. METHODS: We performed a retrospective observational cohort study in 53 patients with metastatic RCC and 18 patients with metastatic GIST treated with sunitinib and receiving TDM-guided dosing. Time on treatment - as a surrogate for progression-free survival - in patients who achieved adequate sunitinib exposure was compared with patients who did not. Additionaly, the median sunitinib exposure was compared in patients with or without sunitinib-induced toxicity leading to dose reduction. RESULTS: The median time on treatment in patients with RCC who achieved adequate sunitinib exposure (n = 39) was 32 weeks, compared to 15 weeks in patients who did not achieve adequate sunitinib exposure (n = 12) (P = 0.244). In 29 patients (41%) with toxicity leading to dose reduction, sunitinib sum plasma trough concentration (Ctrough ) until dose reduction was significantly higher compared to patients without toxicity leading to dose reduction (median 60 ng/mL vs 44 ng/mL; P < 0.001) and reduced to comparable levels after dose reduction (44 ng/mL; P = 0.488). CONCLUSION: In our real-world patient cohort, patients with sunitinib-induced toxicity requiring dose reduction had significantly higher sunitinib exposure compared to patients without toxicity. The threshold for toxicity, however, was lower compared to that previously described in clinical trials.

Patient and diagnostic intervals of survivors of sarcoma: Results from the SURVSARC study.

BACKGROUND: Patients diagnosed with sarcoma are hypothesized to experience a prolonged route to a cancer diagnosis. This route, the total interval, can be divided into a patient interval (the time from the appearance of symptoms to physician consultation) and diagnostic interval (time from the first consultation to diagnosis). In the current study, the authors investigated these intervals among survivors of sarcoma and identified factors associated with prolonged intervals. METHODS: A cross-sectional study was conducted among adult patients with sarcoma 2 to 10 years after diagnosis. Patients completed a questionnaire regarding their total interval, which was linked to clinical data from the Netherlands Cancer Registry. Descriptive statistics were used to describe intervals. Based on Dutch clinical guidelines, a diagnostic interval ≥1 month was considered to be prolonged and an interval ≥3 months was considered as very long. Multivariable regression analyses investigated associations between patient and tumor characteristics and interval length. RESULTS: A total of 1099 participants were included (response rate, 58%); approximately 60% reported a patient interval ≥1 month and 36% reported a patient interval ≥3 months. Risk factors for a very long patient interval were sarcoma of the skin or pelvis, liposarcoma, or rhabdomyosarcoma. Stage III disease was associated with a shorter patient interval. The diagnostic interval length was ≥1 month in 55% of patients and ≥3 months in 28% of patients. Risk factors for a very long diagnostic interval were female sex, age <70 years, or having a synovial sarcoma or chordoma. CONCLUSIONS: The patient and diagnostic interval lengths were prolonged in a substantial percentage of this sarcoma survivorship population. Factors found to be associated with the length of the patient interval or the diagnostic interval differed. Creating awareness among (especially young) patients to consult a physician and awareness among physicians to consider a sarcoma diagnosis will contribute to optimization of the total interval.

Systemic treatments in MDM2 positive intimal sarcoma: A multicentre experience with anthracycline, gemcitabine, and pazopanib within the World Sarcoma Network.

BACKGROUND: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS. METHODS: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method. RESULTS: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively. CONCLUSION: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.

Imatinib, sunitinib and pazopanib: From flat-fixed dosing towards a pharmacokinetically guided personalized dose.

Tyrosine kinase inhibitors (TKIs) are anti-cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure-treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.