Search

Supplementary Figure from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose:Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.Experimental Design:In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).Results:Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.Conclusions:Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.

Supplementary Table from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.

Introduction The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival in patients with BRAF V600-mutated melanoma. BRAF mutations are also frequently detected driver mutations in other tumor types, including thyroid carcinoma. Since thyroid carcinoma is not a labeled indication for BRAF/MEKi, a cohort for patients with BRAF V600-mutated thyroid carcinoma was opened within the Drug Rediscovery Protocol (DRUP), a national ongoing pan-cancer multi-drug trial, in which patients receive off-label treatment with approved drugs based on their molecular tumor profile. Results Here, we present two patients with BRAF-mutated thyroid carcinoma, who were successfully treated with vemurafenib/cobimetinib administered via a feeding tube. Plasma concentrations of vemurafenib and cobimetinib were determined. A partial response was observed in both patients, but they experienced significant toxicity. Conclusion Our cases show that vemurafenib/cobimetinib treatment is effective in BRAF V600-mutated thyroid carcinoma, also when administered via a feeding tube. Although serious side effects occurred in both patients, we hypothesize that this was not attributable to the administration route. Therefore, administration of vemurafenib/cobimetinib by feeding tube is feasible and effective. Trial registration Clinical trial identification: NCT02925234.

Background and aim Gastric cancer surgery highly impacts postoperative quality of life. The Quality of Recovery-40 (QoR-40) is a validated 40-item patient questionnaire, designed to evaluate the quality of recovery after anesthesia. QoR-40 is subcategorized in five dimensions; physical comfort, physical independence, psychological support, emotional state and pain. The aim of this study was to evaluate the quality of recovery after subtotal gastrectomy using the QoR-40 questionnaire and to establish a reference standard for the QoR-40 after gastrectomy to be used in future studies. Methods This prospective observational study included all patients undergoing subtotal gastrectomy between January 2020 and December 2020 in the Amsterdam UMC. Primary endpoint was the quality of recovery on day three after surgery, using the Dutch QoR-40. Secondary endpoint was the occurrence of poor quality of recovery (PQR), defined as impairment in 2 or more dimensions, or impairment in the global QoR-40. Results 27 Patients were included in this study, the median total score of the QoR-40 questionnaire was 184 [IQR 176–192]. Eight patients had a PQR, of whom four patients (50.0%) developed postoperative complications. Furthermore, two patients without PQR developed complications (7.4%). Impairment occurred mainly in dimensions physical comfort, physical independence and emotional state. Conclusion This study presents a reference standard for quality of recovery based on the QoR-40 questionnaire in patients undergoing subtotal gastrectomy. PQR may be related to postoperative complications. Future studies should focus on enhancing physical comfort, physical independence and emotional state to improve patient reported quality of recovery.

Background and aim Transthoracic minimally invasive oesophagectomy (MIO) is increasingly performed as part of curative multimodality treatment. There is no robust evidence on the preferred location of the anastomosis after transthoracic MIO. The aim of this study was to compare an intrathoracic with a cervical anastomosis in a randomised controlled trial. Methods An open multicentre randomised controlled superiority trial was performed. Patients with mid to distal oesophageal or gastro-oesophageal junction cancer planned for curative resection were included. Patients were randomly assigned (1:1) to transthoracic MIO with intrathoracic or cervical anastomosis. The primary endpoint was anastomotic leakage requiring endoscopic, radiologic or surgical intervention. Secondary outcomes were overall anastomotic leak rate, other postoperative complications, length of stay, mortality and quality of life. The ICAN trial is registered in the Dutch trial register under number NTR4333. Results Two hundred and sixty-two patients were randomised and 245 were eligible for analysis. Anastomotic leakage necessitating re-intervention occurred in 15 of 122 (12.3%) patients with intrathoracic anastomosis and in 39 of 123 (31.7%) patients with cervical anastomosis (risk difference − 19.4%, 95% CI -29.5%—-9.3%). Overall anastomotic leak rate was 12.3% in the intrathoracic anastomosis group and 34.1% in the cervical anastomosis group (risk difference − 21.9%, 95% CI -32.1%—-11.6%). ICU length of stay, mortality rates and overall quality of life were comparable between groups, but intrathoracic anastomosis was associated with less severe complications, lower incidence of recurrent laryngeal nerve palsy and better quality of life in three subdomains. Conclusion Intrathoracic anastomosis is the preferred technique for patients treated with transthoracic MIO for mid to distal oesophageal or gastro-oesophageal junction cancer.

Background and aim Patients with a para-oesophageal hernia (POH) report a range of symptoms and quality of life (QOL) issues. Clinicians often utilise existing health-related quality of life tools to identify patients eligible for surgical management and to evaluate the benefit of surgical intervention. However, the most commonly used tools for this purpose are not disease specific. Therefore, crucial POH-specific symptoms which impact QOL may not be captured. To address this, a modified Delphi consensus study was undertaken to establish a HRQOL instrument specific to POH. Methods A two-round modified Delphi consensus study was conducted with a group of international experts. Participants were identified through their authorship in landmark POH studies and the professional networks of the study investigators. Before the Delphi process, a scoping survey was undertaken to generate a list of candidate items. Participants were asked to rate the items’ importance in assessing patients with POH using a 5-point Likert scale. The a priori threshold for inclusion was 80% for scores of 4 or 5. If consensus was not achieved, the item was carried through to the next round. Results The candidate list of items consisted of 64 symptoms, refined to 20 for inclusion within the first modified Delphi round. Four symptoms; ‘difficulty getting solid foods down’, ‘chest pain after meals’, ‘difficulty getting liquids down’ and ‘shortness of breath only after meals’, reached consensus threshold of 80% in the first round and additionally, ‘early feeling of fullness after eating’, reached consensus in the second. A total of 26 participants took part in the first and 24 in the second round. These five symptoms form the initial version of the Para-Oesophageal Hernia Symptom Tool (POST). Conclusion POST is the first tool that aims to capture POH-specific symptoms that impact HRQOL. Prior to clinical use, this tool will be presented in international patient workshops to assess its construct validity. Thereafter, we aim to assess the content validity of the tool through a longitudinal study in a cohort of patients with undergoing POH repair. This tool aims to serve as a decision-support tool for clinicians when evaluating the risk–benefit of surgical intervention in this cohort of patients.

Background and aim Curative treatment for patients with esophageal cancer consists of neoadjuvant treatment followed by an esophagectomy. Different neoadjuvant strategies exist; perioperative chemotherapy (pCT) and neoadjuvant chemoradiotherapy (nCRT). Both strategies improve the 5-year overall survival rate, however, whether differences exist in long-term health related Quality of Life (HR-QoL) has not been studied. The aim of this study is to compare HR-QoL between perioperative chemotherapy and neoadjuvant chemoradiotherapy in esophagectomy for cancer patients. Methods Disease-free patients following esophagectomy for cancer in one of the participating LASER study centers between 2010 and 2016, following neoadjuvant treatment with chemoradiotherapy or chemotherapy, were extracted for analysis from the LASER study database. Included patients completed the LASER, EORTC-QLQ-C30 and QLQ-OG25 questionnaires at least one year following surgery. Primary outcome was to assess long-term HR-QoL between patients treated with pCT or nCRT, using univariable and multivariable logistic regression analysis. Results Among the 565 included patients, 349 (61.8%) received neoadjuvant chemoradiotherapy, and 216 (38.2%) patient were perioperatively treated with chemotherapy. The mean age was 63.7 years (± SD 8.6) with a mean time since surgery of 4.3 (± 1.7) years. After multivariable analysis patients treated with pCT reported worse outcomes on the ‘Social Functioning’ domain (∆means 4.56 P-value Conclusion Some differences in favor of nCRT were observed in long-term HR-QoL domains for patients following esophagectomy for cancer. However, none of the observed differences was clinically relevant (∆means≠ ≥ 10 points). HR-QoL is unhelpful when deciding on neoadjuvant strategy.

Background and aim Accurate determination of lymph node status after esophagectomy requires complete lymphadenectomy. Extended surgery might also lead to more postoperative morbidity. This study analyzed lymph node yield over time and investigated the influence of lymph node yield on the number of positive lymph nodes, postoperative morbidity and disease-free survival. Methods Patients who underwent transthoracic esophagectomy for esophageal adenocarcinoma between 2010 and 2018, were included. Lymph node yield was both analyzed as continuous variable and as categorical variable ( Results A total of 469 patients were included with a median follow-up of 20 months. The majority of the included patients received neoadjuvant chemo(radio)therapy (93.1%). The median lymph node yield increased from 25.0 lymph nodes (IQR 20–34) in 2010 to 36.0 lymph nodes (IQR 30–45) in 2018. Higher lymph node yield was significantly associated with more positive lymph nodes both as continuous variable (IRR 1.020, 95%CI 1.006–1.034), and as categorical variable with a threshold of ≥30 nodes (IRR 1.549, 95%CI 1.069–2.244). Lymph node yield was not associated with morbidity. Lymph node yield was not associated with disease-free survival when analyzed as a continuous variable (HR 0.996, 95%CI 0.984–1.008). There was also no difference in disease-free survival between patients with a lymph node yield of Conclusion A higher lymph node yield after esophagectomy was associated with a higher number of positive lymph nodes; a higher number of resected lymph nodes therefore improves staging. A higher lymph node yield did not result in increased morbidity and no association between lymph node yield and disease-free survival could be demonstrated in patients undergoing esophagectomy after neoadjuvant chemo(radio)therapy.

Background Large-scale genetic tumor profiling can identify increasing numbers of potentially actionable molecular variants for which approved anti-cancer drugs are available. In daily practice, however, when patients with such variants are treated with drugs outside of their approved label, successes and failures are not systematically collected or shared. Methods We initiated the Drug Rediscovery Protocol (DRUP), an innovative and adaptive precision oncology trial aimed at identifying signals of activity in cohorts of patients with defined tumor types and molecular variants, treated with anti-cancer drugs outside their approved label. Eligible patients have exhausted (or declined) standard therapies and have malignancies with potentially actionable variants for which no approved anti-cancer drugs are available. Results Here, we show an overall clinical benefit rate (defined as complete or partial response, or stable disease ≥16 weeks) of 34% in the first 215 treated patients. This comprised 136 patients who received targeted therapies, and 79 patients who received immunotherapy. Overall median clinical benefit duration was nine months (95% CI 8 – 11 months), including 26 patients with ongoing clinical benefit at data cutoff. The potential of DRUP was illustrated by the identification of a successful cohort of patients with microsatellite instable tumors receiving nivolumab, and a cohort of colorectal cancer patients with relatively low mutational load with limited clinical benefit from immunotherapy. Conclusions The DRUP hereby facilitates defined use of approved drugs beyond their label in (rare) cancer subgroups, identifies early signals of activity in these subgroups, accelerates clinical translation of new insights, and creates a publicly available knowledge-base for future decision making. Legal entity responsible for the study Netherlands Cancer Institute. Funding Hartwig Medical Foundation, Dutch Cancer Society, Barcode for Life, Roche, Novartis, MSD, GSK, Pfizer, AstraZeneca, BMS. Disclosure E.E. Voest: Research grant / Funding (self), Legally responsible for all contracts: All pharma. C. van Herpen: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Ipsen; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): Sanofi. M. Chalabi: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Netherlands Cancer Institute. E.F. Smit: Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution): Bayer; Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Research grant / Funding (institution): MSD; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution): Novartis ; Honoraria (institution): Pfizer; Honoraria (institution): Takeda; Honoraria (institution): Regeneron; Honoraria (institution), Research grant / Funding (institution): Roche Genentech; Honoraria (institution): Seattle Genetics. N. Mehra: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Janssen-Cilag; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Research grant / Funding (institution): Sanofi. E. Cuppen: Honoraria (institution), Advisory / Consultancy: Illumina; Honoraria (self), Advisory / Consultancy: InteRNA Technologies; Full / Part-time employment, Officer / Board of Directors: Hartwig Medical Foundation. H.M.W. Verheul: Honoraria (institution), Advisory / Consultancy: Glycostem; Honoraria (institution), Advisory / Consultancy: Lava Therapeutics. H. Gelderblom: Research grant / Funding (institution): Five Prime; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Teva. All other authors have declared no conflicts of interest.

High-risk early esophageal adenocarcinoma (i.e. submucosal invasion500 nm, poor differentiation, and/or presence of lymphovascular invasion) is currently treated with esophagectomy with lymph node (LN) dissection given the high rates of LN metastases. However, esophagectomy is associated with substantial morbidity and mortality. Endoscopic radical resection followed by thoracolaparoscopic LN dissection without concomitant esophagectomy could be an alternative. The study aim was to evaluate the feasibility and safety of thoracolaparoscopic dissection of esophageal LNs in a preclinical setting. (i) In human cadavers, thoracolaparoscopic dissection of LNs involved in drainage of the esophagus was performed. Subsequently, esophagectomy was performed to be able to detect retained LNs. Outcome parameters included the number of dissected LNs, the number of retained LNs in the esophagectomy specimen (ES), and technical success. (ii) In swine, thoracolaparoscopic LN dissection was also performed. After the procedure, the swine survived for 28 days. Thereafter, the swine were sacrificed and esophagectomy was performed. Outcome parameters included the presence of ischemia and/or stenosis in the ES and other complications. (i) In five human cadavers, a median of 26 LNs (interquartile range 22-46) were dissected. In two ES, one retained LN was found: one high paraesophageal, one low paraesophageal. Technical success rate was 100%. (ii) None of the seven porcine ES showed signs of ischemia or stenosis. One swine died because of ventricular fibrillation during surgery; during follow up no complications were observed. Thoracolaparoscopic dissection of LNs involved in the drainage of the esophagus is feasible in human cadavers and swine. The porcine survival study suggests that the esophageal vascularity is not severely compromised by the procedure. As anatomy differs between swine and humans, safety of the procedure will have to be investigated thoroughly before applying this new technique as the treatment of choice.