Therapeutic Drug Monitoring of Oral Anticancer Drugs: The Dutch Pharmacology Oncology Group-Therapeutic Drug Monitoring Protocol for a Prospective Study.

BACKGROUND: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes. METHODS: In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (Cmin) will be calculated. In cases where Cmin falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase. DISCUSSION: Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs.

Predictive potential of tumour-stroma ratio on benefit from adjuvant bevacizumab in high-risk stage II and stage III colon cancer.

BACKGROUND: The tumour-stroma ratio (TSR) has proven to be an independent prognostic factor in colon cancer. METHODS: Haematoxylin eosin tissue slides of patients from the AVANT trial were microscopically scored for TSR and categorised as stroma -low or stroma -high. Scores were correlated to the primary and secondary endpoint disease-free survival (DFS) and overall survival (OS). RESULTS: Patients with stroma-high tumours (N = 339, 28%) had a significantly shorter DFS (p < 0.001) compared to stroma-low tumours (N = 824, 68%). In the bevacizumab-FOLFOX-4 arm, DFS was significantly shorter compared to FOLFOX-4 in stroma-low tumours, with a hazard ratio (HR) of 1.94 (95% CI 1.24-3.04; p = 0.004). In stroma-high tumours a trend for better DFS was seen in bevacizumab-FOLFOX-4 vs. FOLFOX-4 (HR 0.61 (95% CI 0.35-1.07; p = 0.08)). For bevacizumab-XELOX vs. FOLFOX-4, this was not seen (stroma-low HR 1.07 (95% CI 0.64-1.77; p = 0.80); stroma-high HR 0.78 (95% CI 0.47-1.30; p = 0.35)). OS showed the same pattern for bevacizumab-FOLFOX-4 vs. FOLFOX-4 with a HR of 2.53 (95% CI 1.36-4.71; p = 0.003) for stroma-low and HR 0.50 (95% CI 0.22-1.14; p = 0.10) for stroma-high tumours. For bevacizumab-XELOX vs. FOLFOX-4, HR 1.13 (95% CI 0.55-2.31; p = 0.74) for stroma-low tumours and HR 0.74 (95% CI 0.37-1.51; p = 0.41) for stroma-high tumours. CONCLUSIONS: This exploratory analysis suggests a significantly shorter DFS and OS in stroma-low tumours with addition of bevacizumab to intravenous oxaliplatin-based chemotherapy, contrary to stroma-high tumours, where a beneficial trend is observed.

Quality of Surgery and Outcome in Localized Gastrointestinal Stromal Tumors Treated Within an International Intergroup Randomized Clinical Trial of Adjuvant Imatinib.

Importance: The association between quality of surgery and overall survival in patients affected by localized gastrointestinal stromal tumors (GIST) is not completely understood. Objective: To assess the risk of death with and without imatinib according to microscopic margins status (R0/R1) using data from a randomized study on adjuvant imatinib. Design, Setting, and Participants: This is a post hoc observational study on patients included in the randomized, open-label, phase III trial, performed between December 2004 and October 2008. Median follow-up was 9.1 years (IQR, 8-10 years). The study was performed at 112 hospitals in 12 countries. Inclusion criteria were diagnosis of primary GIST, with intermediate or high risk of relapse; no evidence of residual disease after surgery; older than 18 years; and no prior malignancies or concurrent severe/uncontrolled medical conditions. Data were analyzed between July 17, 2017, and March 1, 2020. Interventions: Patients were randomized after surgery to either receive imatinib (400 mg/d) for 2 years or no adjuvant treatment. Randomization was stratified by center, risk category (high vs intermediate), tumor site (gastric vs other), and quality of surgery (R0 vs R1). Tumor rupture was included in the R1 category but also analyzed separately. Main Outcomes and Measures: Primary end point of this substudy was overall survival (OS), estimated using Kaplan-Meier method and compared between R0/R1 using Cox models adjusted for treatment and stratification factors. Results: A total of 908 patients were included; 51.4% were men (465) and 48.6% were women (440), and the median age was 59 years (range, 18-89 years). One hundred sixty-two (17.8%) had an R1 resection, and 97 of 162 (59.9%) had tumor rupture. There was a significant difference in OS for patients undergoing an R1 vs R0 resection, overall (hazard ratio [HR], 2.05; 95% CI, 1.45-2.89) and by treatment arm (HR, 2.65; 95% CI, 1.37-3.75 with adjuvant imatinib and HR, 1.86; 95% CI, 1.16-2.99 without adjuvant imatinib). When tumor rupture was excluded, this difference in OS between R1 and R0 resections disappeared (HR, 1.05; 95% CI, 0.54-2.01). Conclusions and Relevance: The difference in OS by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse OS. Trial Registration: ClinicalTrials.gov Identifier: NCT00103168.

Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG.

PURPOSE: The role of surgery for first relapse locally recurrent retroperitoneal sarcoma (RPS-LR1) is uncertain. We report outcomes of the largest RPS-LR1 series and propose a new prognostic nomogram. EXPERIMENTAL DESIGN: Patients with consecutive RPS-LR1 without distant metastases who underwent resection at 22 centers (2002-2011) were included. Endpoints were disease-free and overall survival (DFS, OS) and crude-cumulative-incidence (CCI) of local/distant recurrence from second surgery. Nomograms predicting DFS and OS from second surgery were developed and validated (calibration plots); discrimination was assessed (Harrell C index). RESULTS: Of 684 patients identified, full prognostic variable data were available for 602. Initial surgery for primary RPS was performed at our institutions in 188 patients (31%) and elsewhere in 414 (69%). At a median follow-up of 119 months [Interquartile range (IQR), 80-169] from initial surgery and 75 months (IQR 50-105) from second surgery, 6-year DFS and OS were 19.2% [95% confidence interval (CI), 16.0-23.0%] and 54.1% (95% CI, 49.8-58.8%), respectively. Recurrence patterns and survival probability were histology-specific, with liposarcoma subtypes having the highest 6-year CCI of second local recurrence (LR, 60.2%-70.9%) and leiomyosarcoma (LMS) having higher 6-year CCI of distant metastasis (DM, 36.3%). Nomograms included age at second surgery, multifocality, grade, completeness of second surgery, histology, chemotherapy/radiotherapy at first surgery, and number of organs resected at first surgery. OS and DFS nomograms showed good calibration and discriminative ability (C index 0.70 and 0.67, respectively). CONCLUSIONS: We developed nomograms to predict DFS and OS for patients undergoing RPS-LR1 resection. Nomograms provide individualized, disease-relevant estimations of survival for RPS-LR1 patients and assist in clinical decisions.

Elderly patients with gastrointestinal stromal tumour (GIST) receive less treatment irrespective of performance score or comorbidity - A retrospective multicentre study in a large cohort of GIST patients.

OBJECTIVE: Although gastrointestinal stromal tumours (GIST) predominantly occur in older patients, data on treatment patterns in elderly GIST patients are scarce. METHODS: Patients registered in the Dutch GIST Registry (DGR) from January 2009 until December 2016 were included. Differences in treatment patterns between elderly (≥75 years) and younger patients were compared. Multivariate analyses were conducted using logistic regression. RESULTS: Data of 145 elderly and 665 non-elderly patients were registered (median age 78 and 60 years respectively). In elderly patients, performance score (WHO-PS) and age-adjusted Charlson comorbidity index (ACCI) were significantly higher (p < 0.05; p < 0.001), and albumin level significantly lower (p = 0.04). Hundred-and-nine (75.2%) elderly and 503 (75.6%) non-elderly patients had only localised disease. Surgery was performed in 57% of elderly versus 84% of non-elderly patients (p = 0.003, OR: 0.26, 95% CI: 0.11-0.63). No differences in surgery outcome or complications were found. Thirty-eight percent of elderly with an indication for adjuvant treatment did receive imatinib versus 68% of non-elderly (p = 0.04, OR: 0.47, 95% CI: 0.23-0.95). Thirty-six elderly and 162 non-elderly patients had metastatic disease. Palliative imatinib was equally given (mean dose 400 mg) and adverse events were mostly minor (p = 0.71). In elderly, drug-related toxicity was in 32.7% reason to discontinue imatinib versus 5.1% in non-elderly (p = 0.001, OR 13.5, 95% CI: 2.8-65.0). Median progression-free survival (PFS) was 24 months in elderly and 33 months in non-elderly (p = 0.10). Median overall survival (OS) was 34 months and 59 months respectively (p = 0.01). CONCLUSIONS: Elderly GIST patients with localised disease receive less surgery and adjuvant treatment, irrespective of comorbidity and performance score. Drug-related toxicity results more often in treatment discontinuation. This possibly results in poor outcome.

Comprehensive analysis of published phase I/II clinical trials between 1990-2010 in osteosarcoma and Ewing sarcoma confirms limited outcomes and need for translational investment.

BACKGROUND: High grade primary bone sarcomas are rare cancers that affect mostly children and young adults. Osteosarcoma and Ewing sarcoma are the most common histological subtypes in this age group, with current multimodality treatment strategies achieving 55-70% overall survival. As there remains an urgent need to develop new therapeutic interventions, we have reviewed published phase I/II trials that have been reported for osteosarcoma and Ewing sarcoma in the last twenty years. RESULTS: We conducted a literature search for clinical trials between 1990 and 2010, either for trials enrolling bone sarcoma patients as part of a general sarcoma indication or trials specifically in osteosarcoma and Ewing sarcoma. We identified 42 clinical trials that fulfilled our search criteria for general sarcoma that enrolled these patient groups, and eight and twenty specific trials for Ewing and osteosarcoma patients, respectively. For the phase I trials which enrolled different tumour types our results were incomplete, because the sarcoma patients were not mentioned in the PubMed abstract. A total of 3,736 sarcoma patients were included in these trials over this period, 1,114 for osteosarcoma and 1,263 for Ewing sarcoma. As a proportion of the worldwide disease burden over this period, these numbers reflect a very small percentage of the potential patient recruitment, approximately 0.6% for Ewing sarcoma and 0.2% for osteosarcoma. However, these data show an increase in recent activity overall and suggest there is still much room for improvement in the current trial development structures. CONCLUSION: Lack of resources and commercial investment will inevitably limit opportunity to develop sufficiently rapid improvements in clinical outcomes. International collaboration exists in many well founded co-operative groups for phase III trials, but progress may be more effective if there were also more investment of molecular and translational research into disease focused phase I/II clinical trials. Examples of new models for early translational and early phase trial collaboration include the European based EuroBoNeT network, the Sarcoma Alliance for Research through Collaboration network (SARC) and the new European collaborative translational trial network, EuroSarc.