Assessing the clinical benefit of systemic anti-cancer treatments in the Netherlands: The impact of different thresholds for effectiveness.

BACKGROUND: In the Netherlands, the clinical benefit of systemic anti-cancer treatments (SACTs) is assessed by the Committee for the Evaluation of Oncological Agents (cieBOM). For non-curative SACTs, the assessment is based on the hazard ratio (HR) for progression-free survival and/or overall survival (OS), and the difference in median survival. We evaluated the impact of different thresholds for effectiveness by reassessing the clinical benefit of SACTs. METHODS: We reassessed SACTs that were initially assessed by cieBOM between 2015 and 2017. Four scenarios were formulated: replacing an "OR" approach (initial assessment) by an "AND" approach (used in all scenarios), changing the HR threshold from < 0.70 (initial assessment) to < 0.60, changing the threshold for the difference in median survival from > 12 weeks (initial assessment) to > 16 weeks, and including thresholds for OS rates. The outcomes of these scenarios were compared to the outcomes of the initial assessment. RESULTS: Reassessments were conducted for 41 treatments. Replacing the "OR" approach by an "AND" approach substantially decreased the number of positive assessments (from 33 to 22), predominantly affecting immunotherapies. This number further decreased (to 21 and 19, respectively) in case more restrictive thresholds for the HR and difference in median survival were used. Including thresholds for OS rates slightly mitigated the impact of applying an "AND" approach. CONCLUSIONS: The scenario-specific thresholds had a substantial impact; the number of negative assessments more than doubled. Since this was not limited to treatments with marginal survival benefits, understanding the potential challenges that may arise from applying more restrictive thresholds is essential.

Local treatment in metastatic GIST patients: A multicentre analysis from the Dutch GIST Registry.

BACKGROUND: The added value of local treatment in selected metastatic GIST patients is unclear. This study aims to provide insight into the usefulness of local treatment in metastatic GIST by use of a survey study and retrospective analyses in a clinical database. METHODS: A survey study was conducted among clinical specialists to select most relevant characteristics of metastatic GIST patients considered for local treatment, defined as elective surgery or ablation. Patients were selected from the Dutch GIST Registry. A multivariate Cox-regression model for overall survival since time of diagnosis of metastatic disease was estimated with local treatment as a time-dependent variable. An additional model was estimated to assess prognostic factors since local treatment. RESULTS: The survey's response rate was 14/16. Performance status, response to TKIs, location of active disease, number of lesions, mutation status, and time between primary diagnosis and metastases, were regarded the 6 most important characteristics. Of 457 included patients, 123 underwent local treatment, which was associated with better survival after diagnosis of metastases (HR = 0.558, 95%CI = 0.336-0.928). Progressive disease during systemic treatment (HR = 3.885, 95%CI = 1.195-12.627) and disease confined to the liver (HR = 0.269, 95%CI = 0.082-0.880) were associated with worse and better survival after local treatment, respectively. CONCLUSION: Local treatment is associated with better survival in selected patients with metastatic GIST. Locally treated patients with response to TKIs and disease confined to the liver have good clinical outcome. These results might be considered for tailoring treatment, but should be interpreted with care because only specific patients are provided with local treatment in this retrospective study.

Improved Efficacy of First-Line Imatinib in Advanced Gastrointestinal Stromal Tumors (GIST): The Dutch GIST Registry Data.

BACKGROUND: Patients with unresectable and metastasized gastrointestinal stromal tumor (GIST) experienced a remarkable improvement of progression-free survival (PFS) and overall survival (OS) after the introduction of imatinib. Our hypothesis is that the outcomes of treatment with imatinib are even better nowadays compared with the registration trials that were performed two decades ago. To study this, we used real-life data from a contemporary registry. METHODS: A multicenter, retrospective study was performed by exploring clinical data from a prospective real-life clinical database, the Dutch GIST Registry (DGR). Patients with advanced GIST treated with first-line imatinib were included and PFS (primary outcome) and OS (secondary outcome) were analyzed. Results of our study were compared with published results of the European Organisation for Research and Treatment of Cancer (EORTC) 62005 trial, which marked the first era of imatinib in the treatment of GIST. RESULTS: Overall, 420 of the 435 patients treated with imatinib in the DGR had recorded response evaluation and were included in the analysis. During a median follow-up of 35.0 months (range 2.0-136.0), progression of GIST was eventually observed in 217 patients (51.2%). The DGR cohort showed a longer median PFS (33.0 months, 95% confidence interval [CI] 28.4-37.6) compared with the EORTC 62005 trial (an estimated PFS of 19.5 months). Additionally, the median OS of 68.0 months (95% CI 56.1-80.0) was longer than the exposed median OS (46.8 months) published in the long-term follow-up results of the EORTC 62005 trial (median follow-up duration 10.9 years). CONCLUSION: This study provides an update on outcomes of imatinib in the treatment of advanced GIST patients and demonstrates improved clinical outcomes since the first randomized studies of imatinib 2 decades ago. Furthermore, these results represent outcomes in real-world clinical practice and can serve as a reference when evaluating effectiveness of imatinib in patients with advanced GIST.

[How long are medical oncology patients in The Netherlands willing to travel for their cancer care?] / Hoe lang zijn patiënten bereid te reizen voor medisch-oncologische zorg?

BACKGROUND: The number of people with cancer will increase in the Netherlands. Further concentration and network care is pursued. The aim of this study was to explore how long medical oncology patients are willing to travel for their cancer care. METHOD: A flashmob study into patients' willingness to travel for cancer care was conducted in 65 Dutch hospitals. Patients completed a questionnaire about willingness to travel and any experienced issues with traveling. RESULTS: A total of 4337 medical oncology patients completed the questionnaire. Of the patients, 20% were willing to travel more than 1 hour (one-way) for their current treatment, and more willing to travel for treatment in a hospital more experienced in their specific type of cancer (44% more than 1 hour). Willingness to travel longer was higher among patientsagedv40 years or younger, those with higher education, with better physical functioning and with a rare cancer. Willingness to travel longer was lowest among patients aged 75 or older. Approximately 30% of all patients experienced issues with traveling, especially those with comorbidities or with decreased physical functioning. CONCLUSION: In this flashmob study, 15% of patients were willing to travel up to 30 minutes (one-way) and 44% more than 1 hour for treatment and follow-up in a hospital more experienced in their specific type of cancer. Patients aged 75 years or older were less willing to travel longer. Thirty percent of patients experienced issues with travelling. It is important to take this into account in the future organization of cancer care.

Dutch Gastrointestinal Stromal Tumor (GIST) Registry Data Comparing Sunitinib with Imatinib Dose Escalation in Second-Line Advanced Non-KIT Exon 9 Mutated GIST Patients.

BACKGROUND: The prognosis of patients with advanced gastrointestinal stromal tumor (GIST) has improved greatly after the introduction of imatinib. However, primary or secondary resistance to imatinib occurs in the majority of patients. Sunitinib is the standard second line treatment in exon-9 mutated GIST. OBJECTIVE: We compared the clinical outcomes of sunitinib with imatinib dose escalation in patients with progressive advanced non-KIT exon 9 mutated GIST after failure of first line imatinib. PATIENTS AND METHODS: A retrospective study was performed, retrieving data from a real-life database (Dutch GIST Registry) including patients with GIST treated with sunitinib or imatinib dose escalation after failure on first line imatinib 400 mg daily. Primary outcome measures were progression free survival (PFS) and overall survival (OS). RESULTS: In total, 110 patients were included, 72 (65.5%) patients were treated with sunitinib (group A) and 38 (34.5%) received an imatinib dose escalation (group B). Important prognostic features at baseline, such as tumor size, stage at diagnosis, mitotic count and localization were equally distributed in both groups. No significant difference (p = 0.88) between median PFS in group A [8.7 months (95% CI 5.6-11.3)] and group B [5.6 months, (95% CI 2.6-8.7)] was observed. Moreover, the OS was similar between group A and group B; 63.2 months and 63.4 months, respectively. CONCLUSION: This study represents a proper sample size cohort containing detailed data on mutational status of patients with advanced GIST. We illustrated that imatinib dose escalation could serve as a good alternative for sunitinib as second-line treatment in patients with a non-KIT exon 9 mutation.

Early response evaluation using 18F-FDG-PET/CT does not influence management of patients with metastatic gastrointestinal stromal tumors (GIST) treated with palliative intent.

AIM: The aim of this study was to investigate the impact of 18F-FDG-PET/CT on treatment decision making in metastatic gastrointestinal stromal tumor (GIST) patients. METHODS: This study retrospectively evaluated 18F-FDG-PET/CT scans to monitor response of metastatic GIST patients treated with palliative intent. Data from the Dutch GIST Registry was used. Early scans (<10 weeks after start of treatment) and late scans (>10 weeks after start of treatment) were scored on the impact in change of treatment. RESULTS: Sixty-one PET/CT scans were performed for treatment evaluation in 39 patients with metastatic GIST of which 36 were early scans and 25 were late scans. Early PET/CT scans led to a change in management in 5.6% of patients and late PET/CT scans led to a change in management in 56% of patients. Change in management was more often seen after scans with lack of metabolic response (48% vs. 11% in scans with metabolic response, p=0.002). Neither metabolic response nor change in treatment were more often seen in patients with KIT mutations compared to patients with non-KIT mutations (metabolic response 65% KIT vs. 46% non-KIT, p=0.33, and change in management 28% KIT vs. 21% non-KIT, p=0.74). CONCLUSION: 18F-FDG-PET/CT is not recommended for early response evaluation in an unselected patient population with metastatic GIST, since it does not influence treatment decisions. 18F-FDG-PET/CT, however, can be useful for late response assessment, especially in case of indeterminate CT results.

Outcomes of ICU patients with and without perceptions of excessive care: a comparison between cancer and non-cancer patients.

BACKGROUND: Whether Intensive Care Unit (ICU) clinicians display unconscious bias towards cancer patients is unknown. The aim of this study was to compare the outcomes of critically ill patients with and without perceptions of excessive care (PECs) by ICU clinicians in patients with and without cancer. METHODS: This study is a sub-analysis of the large multicentre DISPROPRICUS study. Clinicians of 56 ICUs in Europe and the United States completed a daily questionnaire about the appropriateness of care during a 28-day period. We compared the cumulative incidence of patients with concordant PECs, treatment limitation decisions (TLDs) and death between patients with uncontrolled and controlled cancer, and patients without cancer. RESULTS: Of the 1641 patients, 117 (7.1%) had uncontrolled cancer and 270 (16.4%) had controlled cancer. The cumulative incidence of concordant PECs in patients with uncontrolled and controlled cancer versus patients without cancer was 20.5%, 8.1%, and 9.1% (p < 0.001 and p = 0.62, respectively). In patients with concordant PECs, we found no evidence for a difference in time from admission until death (HR 1.02, 95% CI 0.60-1.72 and HR 0.87, 95% CI 0.49-1.54) and TLDs (HR 0.81, 95% CI 0.33-1.99 and HR 0.70, 95% CI 0.27-1.81) across subgroups. In patients without concordant PECs, we found differences between the time from admission until death (HR 2.23, 95% CI 1.58-3.15 and 1.66, 95% CI 1.28-2.15), without a corresponding increase in time until TLDs (NA, p = 0.3 and 0.7) across subgroups. CONCLUSIONS: The absence of a difference in time from admission until TLDs and death in patients with concordant PECs makes bias by ICU clinicians towards cancer patients unlikely. However, the differences between the time from admission until death, without a corresponding increase in time until TLDs, suggest prognostic unawareness, uncertainty or optimism in ICU clinicians who did not provide PECs, more specifically in patients with uncontrolled cancer. This study highlights the need to improve intra- and interdisciplinary ethical reflection and subsequent decision-making at the ICU.

Perceptions of involvement in advance care planning and emotional functioning in patients with advanced cancer.

PURPOSE: Advance Care Planning (ACP) is positively associated with the quality of care, but its impact on emotional functioning is ambiguous. This study investigated the association between perceptions of ACP involvement and emotional functioning in patients with advanced cancer. METHODS: This study analyzed baseline data of 1,001 patients of the eQuiPe study, a prospective, longitudinal, multicenter, observational study on quality of care and quality of life in patients with advanced cancer in the Netherlands. Patients with metastatic solid cancer were asked to participate between November 2017 and January 2020. Patients' perceptions of ACP involvement were measured by three self-administered statements. Emotional functioning was measured by the EORTC-QLQ-C30. A linear multivariable regression analysis was performed while taking gender, age, migrant background, education, marital status, and symptom burden into account. RESULTS: The majority of patients (87%) reported that they were as much involved as they wanted to be in decisions about their future medical treatment and care. Most patients felt that their relatives (81%) and physicians (75%) were familiar with their preferences for future medical treatment and care. A positive association was found between patients' perceptions of ACP involvement and their emotional functioning (b=0.162, p<0.001, 95%CI[0.095;0.229]) while controlling for relevant confounders. CONCLUSIONS: Perceptions of involvement in ACP are positively associated with emotional functioning in patients with advanced cancer. Future studies are needed to further investigate the effect of ACP on emotional functioning. TRIAL REGISTRATION NUMBER: NTR6584 Date of registration: 30 June 2017 IMPLICATIONS FOR CANCER SURVIVORS: Patients' emotional functioning might improve from routine discussions regarding goals of future care. Therefore, integration of ACP into palliative might be promising.

Clinicopathological features and treatment outcome of oesophageal gastrointestinal stromal tumour (GIST): A large, retrospective multicenter European study.

BACKGROUND: Oesophageal gastrointestinal stromal tumours (GISTs) account for ≤1% of all GISTs. Consequently, evidence to guide clinical decision-making is limited. METHODS: Clinicopathological features and outcomes in patients with primary oesophageal GIST from seven European countries were collected retrospectively. RESULTS: Eighty-three patients were identified, and median follow up was 55.0 months. At diagnosis, 59.0% had localized disease, 25.3% locally advanced and 13.3% synchronous metastasis. A biopsy (Fine Needle aspiration n = 29, histological biopsy n = 31) was performed in 60 (72.3%) patients. The mitotic count was low (<5 mitoses/50 High Power Fields (HPF)) in 24 patients and high (≥5 mitoses/50 HPF) in 27 patients. Fifty-one (61.4%) patients underwent surgical or endoscopic resection. The most common reasons to not perform an immediate resection (n = 31) were; unresectable or metastasized GIST, performance status/comorbidity, patient refusal or ongoing neo-adjuvant therapy. The type of resections were enucleation (n = 11), segmental resection (n = 6) and oesophagectomy with gastric conduit reconstruction (n = 33), with median tumour size of 3.3 cm, 4.5 cm and 7.7 cm, respectively. In patients treated with enucleation 18.2% developed recurrent disease. The recurrence rate in patients treated with segmental resection was 16.7% and in patients undergoing oesophagectomy with gastric conduit reconstruction 36.4%. Larger tumours (≥4.0 cm) and high (>5/5hpf) mitotic count were associated with worse disease free survival. CONCLUSION: Based on the current study, enucleation can be recommended for oesophageal GIST smaller than 4 cm, while oesophagectomy should be preserved for larger tumours. Patients with larger tumours (>4 cm) and/or high mitotic count should be treated with adjuvant therapy.

Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma patients in the Netherlands: a retrospective cohort study.

BACKGROUND: Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands. METHODS: A retrospective cohort study that included all patients ≥18 years with histologically proven basal cell carcinoma that received ≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands. RESULTS: In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95% confidence interval (CI), 7.5-22.6) for laBCC, 11.7 (95% CI, 5.2-17.5) for mBCC and 19.1 (95% CI, 7.4-20.2) for BCNS. Larger laBCCs were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p = 0.02). Of all BCNS patients, 63% received ≥2 treatment sequences with vismodegib; all achieved partial responses. CONCLUSIONS: Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment.

Molecular testing in metastatic basal cell carcinoma.

BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor. OBJECTIVE: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC. METHODS: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter. RESULTS: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib. LIMITATIONS: In 2 patients there was insufficient qualitative DNA available for genetic analysis. CONCLUSIONS: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value.

Gastrointestinal Stromal Tumours (GIST) in Young Adult (18-40 Years) Patients: A Report from the Dutch GIST Registry.

Gastrointestinal stromal tumour (GIST) is a disease of older adults and is dominated by KIT/PDGFR mutations. In children, GIST is rare, predominantly occurs in girls, has a stomach location and generally lacks KIT/PDGFR mutations. For young adults (YA), aged 18 to 40 years, the typical phenotypic and genotypic patterns are unknown. We therefore aimed to describe the clinical, pathological and molecular characteristics of GIST in in YA. YA GIST patients registered in the Dutch GIST Registry (DGR) were included, and data were compared to those of older adults (OA). From 1010 patients in the DGR, 52 patients were YA (54% male). Main tumour locations were stomach (46%) and small intestine (46%). GIST genetic profiles were mutations in KIT (69%), PDGFRA (6%), SDH deficient (8%), NF1 associated (4%), ETV6-NTRK3 gene fusion (2%) or wildtype (10%). Statistically significant differences were found between the OA and YA patients (localisation, syndromic and mutational status). YA presented more often than OA in an emergency setting (18% vs. 9%). The overall five-year survival rate was 85%. In conclusion, YA GISTs are not similar to typical adult GISTs and also differ from paediatric GISTs, as described in the literature. In this series, we found a relatively high percentage of small intestine GIST, emergency presentation, 25% non-KIT/PDGFRA mutations and a relatively good survival.

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.

A phase 1/2 study combining gemcitabine, Pegintron and p53 SLP vaccine in patients with platinum-resistant ovarian cancer.

PURPOSE: Preclinical tumor models show that chemotherapy has immune modulatory properties which can be exploited in the context of immunotherapy. The purpose of this study was to determine the feasibility and immunogenicity of combinations of such an immunomodulatory chemotherapeutic agent with immunotherapy, p53 synthetic long peptide (SLP) vaccine and Pegintron (IFN-α) in patients with platinum-resistant p53-positive epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: This is a phase 1/2 trial in which patients sequential 6 cycles of gemcitabine (1000 mg/kg2 iv; n = 3), gemcitabine with Pegintron before and after the first gemcitabine cycle (Pegintron 1 µg/kg sc; n = 6), and gemcitabine and Pegintron combined with p53 SLP vaccine (0.3 mg/peptide, 9 peptides; n = 6). At baseline, 22 days after the 2nd and 6th cycle, blood was collected for immunomonitoring. Toxicity, CA-125, and radiologic response were evaluated after 3 and 6 cycles of chemotherapy. RESULTS: None of the patients enrolled experienced dose-limiting toxicity. Predominant grade 3/4 toxicities were nausea/vomiting and dyspnea. Grade 1/2 toxicities consisted of fatigue (78%) and Pegintron-related flu-like symptoms (72%). Gemcitabine reduced myeloid-derived suppressor cells (p = 0.0005) and increased immune-supportive M1 macrophages (p = 0.04). Combination of gemcitabine and Pegintron stimulated higher frequencies of circulating proliferating CD4+ and CD8+ T-cells but not regulatory T-cells. All vaccinated patients showed strong vaccine-induced p53-specific T-cell responses. CONCLUSION: Combination of gemcitabine, the immune modulator Pegintron and therapeutic peptide vaccination is a viable approach in the development of combined chemo-immunotherapeutic regimens to treat cancer.

[Vulvar basal cell carcinoma with destructive consequences]. / Vulvair basaalcelcarcinoom met destructieve gevolgen.

BACKGROUND: Basal cell carcinoma is the most common form of skin cancer. Generally, the prognosis is relatively good and curative surgical treatment is accomplished in the great majority of patients. CASE DESCRIPTION: Here we report a case that illustrates the natural course of a vulvar basal cell carcinoma. It concerns an 80-year-old woman who was diagnosed with a so-called 'giant' vulvar basal cell carcinoma causing severe destruction of the anogenital anatomy. At the time of diagnosis, haematogenous metastases were strongly suspected and curative therapy was not possible. CONCLUSION: This case description illustrates that a basal cell carcinoma can transform into a 'giant' basal cell carcinoma if it is left untreated for many years. 'Giant' basal cell carcinomas carry a significantly higher risk of metastases than basal cell tumours smaller than 5 cm. In addition, 'giant' basal cell carcinoma is associated with higher morbidity and mortality rates.

A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients.

PURPOSE: Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib. EXPERIMENTAL DESIGN: Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging. RESULTS: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P < 0.01). For every 100 cm(3) increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed. CONCLUSIONS: This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level - clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance.

Consensus-based evaluation of clinical significance and management of anticancer drug interactions.

BACKGROUND: Anticancer drug interactions can affect the efficacy and toxicity of anticancer treatment and that of the interacting drugs. However, information on the significance, prevention, and management of these interactions is currently lacking. OBJECTIVE: The purpose of this study was to assess the clinical significance of interaction among anticancer agents and comedications and to provide recommendations for the management of clinically significant interactions. METHODS: Members of a multidisciplinary expert group of hospital and community pharmacists, medical oncologists, internists, and clinical pharmacologists were selected by their professional organizations, which participated in this consensus project. Literature was extensively searched for any drug interactions with anticancer agents using registration files, reference books, handbooks, and electronic databases. Interactions between anticancer agents were not considered. Interactions were classified by level of best available evidence for the interaction and by severity of the clinical effect, according to a structured assessment procedure. This assessment distinguished 5 levels for the amount and quality of evidence available and 6 severity levels for classification of potential drug-to-drug interactions. RESULTS: A total of 88 drug interactions with anticancer agents were identified from 146 combinations of drugs with anticancer agents found in literature. For 58 combinations, there was insufficient evidence of an interaction. Of the identified interactions, 38 were classified as clinically significant, defined as necessitating an alert or intervention, such as dose adaptation, comedication, discontinuation of treatment, or additional monitoring of treatment. Recommendations were made for management of these interactions. CONCLUSION: Numerous interactions with anticancer agents are clinically significant and should be considered by pharmacists and doctors in daily oncology practice.

Efficacy of radiotherapy for painful bone metastases during the last 12 weeks of life: results from the Dutch Bone Metastasis Study.

BACKGROUND: Radiotherapy is an effective treatment for painful bone metastases. Whether this applies also in patients with limited survival remains to be investigated. This study analyzed the effect of radiotherapy for painful bone metastases in patients with a survival < or =12 weeks. METHODS: In the Dutch Bone Metastasis Study, 1157 patients with painful bone metastases were randomized to single fraction (1 x 8 grays [Gy]) or multiple fraction (6 x 4 Gy) radiotherapy. Patients who died within 12 weeks after randomization were included in this analysis. Patients were classified as responders or nonresponders, based on their pain response to radiotherapy. This response was calculated considering changes in pain intensity (measured with an 11-point numeric rating scale) and analgesic usage. Cox proportional hazards models were used to analyze pain response and survival. RESULTS: Two hundred seventy-4 patients were included in this analysis. At randomization, the mean pain intensity score (+/-standard deviation) was 7 (+/-2). The proportion showing a pain response did not differ between the single fraction and multiple fraction groups. Toward death, pain intensity score decreased to 5 (+/-3) in responders (45%), whereas in nonresponders (55%) no change was observed. Despite the benefit in responders, in 60% of all patients pain intensity remained 5 after randomization. CONCLUSIONS: Pain responded in about half of the patients who survived < or =12 weeks after randomization into the Dutch Bone Metastasis Study. When considering radiotherapy, single fraction should be preferred. Additional palliative measures remain essential for adequate pain control.

Listening to music does not reduce pain during sigmoidoscopy.

OBJECTIVE: Up to 40% of the sigmoidoscopies are considered painful by patients. Nonpharmacological intervention would be attractive, as sedation and analgesia carry the risk of side-effects and increase procedure-related costs. Music might have the potential of pain reduction, but its effect during sigmoidoscopy has not been established yet. To study whether listening to music reduces experienced pain during sigmoidoscopy. METHODS: Consecutive patients, above 18 years of age, undergoing sigmoidoscopy without sedation or analgesia and who gave their informed consent were included in this study. Patients in the music group listened to their preferred music (classical, jazz, English or Dutch Popular) during the sigmoidoscopy. The control group received care as usual. The outcome measures were pain intensity during sigmoidoscopy (measured with a 100-mm-long visual analogue scale) and the proportion of patients with at least moderate pain during sigmoidoscopy (pain intensity score of 50 mm or higher). RESULTS: The music groups consisted of 153 patients, the control group of 154 patients. The mean pain intensity + or - standard deviation was 36 + or - 27 mm in the music group and 40 + or - 29 in the control group (P=0.27) during sigmoidoscopy. The proportion of patients with at least moderate pain during sigmoidoscopy was 29 and 37% in the respective groups (P=0.12). CONCLUSION: Listening to music by patients did not reduce pain intensity during sigmoidoscopy. As a consequence, music during sigmoidoscopy is not recommended for this purpose.

Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity.

PURPOSE: To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities: thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome, and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2. PATIENTS AND METHODS: A multicenter pharmacogenetic association study was performed in 219 patients treated with single-agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several nongenetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. RESULTS: The risk for leukopenia was increased when the G allele in CYP1A1 2455A/G (odds ratio [OR], 6.24; P = .029) or the T allele in FLT3 738T/C (OR, 2.8; P = .008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR, 1.74; P = .041) was absent. Any toxicity higher than grade 2 prevalence was increased when the T allele of vascular endothelial growth factor receptor 2 1191C/T (OR, 2.39; P = .046) or a copy of TT in the ABCG2 (-15622C/T, 1143C/T) haplotype (OR, 2.63; P = .016) were present. The risk for mucosal inflammation was increased in the presence of the G allele in CYP1A1 2455A/G (OR, 4.03; P = .021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR, 2.56; P = .035) was present. CONCLUSION: This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters, and drug targets are associated with sunitinib-related toxicities. A better understanding of genetic and nongenetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients.