The efficacy of anti-programmed death-1 (PD-1) monotherapy for advanced melanoma has been established, but it is unknown to what extent patients benefit in the real world. In this observational... Show moreThe efficacy of anti-programmed death-1 (PD-1) monotherapy for advanced melanoma has been established, but it is unknown to what extent patients benefit in the real world. In this observational study with nationwide population-based data from the Dutch Melanoma Treatment Registry, we analyzed real-world outcomes of first-line anti-PD-1 monotherapy in advanced melanoma patients diagnosed in 2015 to 2016. Overall survival (OS) was estimated with the Kaplan-Meier method. Competing risks analysis was used to estimate probabilities for second-line treatment, with death as competing risk. With a Cox model, the association of factors with OS was estimated. Patients who received anti-PD-1 monotherapy (n=550) had a median age of 65 years and 502 (95%) patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, 383 (70%) had normal lactate dehydrogenase (LDH), 370 (67%) had stage IV-M1c disease, and in 441 (81%), brain metastases were absent. The median OS was 24 months [95% confidence interval (CI): 20-30 mo]. The median OS of patients normally eligible for phase III trial participation was 31 months (95% CI: 23-not estimable). The BRAF mutation was associated with superior OS. ECOG PS of >= 1, symptomatic brain metastases, and liver metastases were associated with inferior OS and, together with elevated LDH, with death before second-line treatment. Patients with a complete response had a 2-year OS probability from first reported complete response of 92% (95% CI: 86%-99%). Real-world advanced melanoma patients in the Netherlands have benefitted from anti-PD-1 monotherapy. ECOG PS >= 1, symptomatic brain metastasis, liver metastasis, and elevated LDH are important prognostic factors for survival. The additional information that this study provides could help to improve more effective use in the real world. Show less
Introduction: Definitions regarding resectability and hence indications for preoperative chemotherapy vary. Use of preoperative chemotherapy may influence postoperative outcomes. This study aimed... Show moreIntroduction: Definitions regarding resectability and hence indications for preoperative chemotherapy vary. Use of preoperative chemotherapy may influence postoperative outcomes. This study aimed to assess the variation in use of preoperative chemotherapy for CRLM and related postoperative outcomes in the Netherlands.Materials and methods: All patients who underwent liver resection for CRLM in the Netherlands between 2014 and 2018 were included from a national database. Case-mix factors contributing to the use of preoperative chemotherapy, hospital variation and postoperative outcomes were assessed using multivariable logistic regression. Postoperative outcomes were postoperative complicated course (PCC), 30day morbidity and 30-day mortality.Results: In total, 4469 patients were included of whom 1314 patients received preoperative chemotherapy and 3155 patients did not. Patients receiving chemotherapy were significantly younger (mean age (+SD) 66.3 (10.4) versus 63.2 (10.2) p < 0.001) and had less comorbidity (Charlson scores 2+ (24% versus 29%, p = 0.010). Unadjusted hospital variation concerning administration of preoperative chemotherapy ranged between 2% and 55%. After adjusting for case-mix factors, three hospitals administered significantly more preoperative chemotherapy than expected and six administered significantly less preoperative chemotherapy than expected. PCC was 12.1%, 30-day morbidity was 8.8% and 30-day mortality was 1.5%. No association between preoperative chemotherapy and PCC (OR 1.24, 0.98-1.55, p = 0.065), 30-day morbidity (OR 1.05, 0.81-1.39, p = 0.703) or with 30-day mortality (OR 1.22, 0.75-2.09, p = 0.467) was found.Conclusion: Significant hospital variation in the use of preoperative chemotherapy for CRLM was present in the Netherlands. No association between postoperative outcomes and use of preoperative chemotherapy was found. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
Background: Mucosal melanoma (MM) is rare and has a poor prognosis. Since 2011, new effective treatments are available for advanced melanoma. It is unclear whether patients with mucosal melanoma... Show moreBackground: Mucosal melanoma (MM) is rare and has a poor prognosis. Since 2011, new effective treatments are available for advanced melanoma. It is unclear whether patients with mucosal melanoma equally benefit from these new treatments compared with patients with cutaneous melanoma (CM).Methods: Patients with advanced MM and CM diagnosed between 2013 and 2017 were included from a nationwide population-based registry the Dutch Melanoma Treatment Registry. Overall survival (OS) was estimated with the Kaplan-Meier method (also for a propensity score-matched cohort). A Cox model was used to analyse the association of possible prognostic factors with OS.Results: In total, 120 patients with MM and 2960 patients with CM were included. Median OS was 8.7 months and 14.5 months, respectively. Patients with MM were older (median age 70 versus 65 years) and more often female (60% versus 41%), compared with CM. In total, 77% and 2% of the MM patients were treated with first-line immunotherapy and targeted therapy, respectively, compared with 49% and 33% of the CM patients. In contrast to CM, OS for MM did not improve for patients diagnosed in 2015-2017, compared with 2013-2014. ECOG performance score >= 1 (HR = 1.99 [1.26-3.15; p = 0.003]) and elevated LDH level (HR = 1.63 [0.96-2.76]; p = 0.069) in MM were associated with worse survival.Conclusions: Within the era of immune and targeted therapies, prognosis for patients with advanced MM has not improved as much as for CM. Collaboration is necessary to enlarge sample size for research to improve immunotherapeutic strategies and identify targetable mutations. (C) 2020 Elsevier Ltd. All rights reserved. Show less
Kooij, M.K. van der; Wetzels, M.J.A.L.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Blank, C.U.; Boers-Sonderen, M.J.; ... ; Kapiteijn, E. 2020
Cutaneous melanoma is a common type of cancer in Adolescents and Young Adults (AYAs, 15-39 years of age). However, AYAs are underrepresented in clinical trials investigating new therapies and the... Show moreCutaneous melanoma is a common type of cancer in Adolescents and Young Adults (AYAs, 15-39 years of age). However, AYAs are underrepresented in clinical trials investigating new therapies and the outcomes from these therapies for AYAs are therefore unclear. Using prospectively collected nation-wide data from the Dutch Melanoma Treatment Registry (DMTR), we compared baseline characteristics, mutational profiles, treatment strategies, grade 3-4 adverse events (AEs), responses and outcomes in AYAs (n= 210) and older adults (n= 3775) who were diagnosed with advanced melanoma between July 2013 and July 2018. Compared to older adults, AYAs were more frequently female (51% versus 40%,p= 0.001), and had a better Eastern Cooperative Oncology Group performance status (ECOG 0 in 54% versus 45%,p= 0.004). BRAF and NRAS mutations were age dependent, with more BRAF V600 mutations in AYAs (68% versus 46%) and more NRAS mutations in older adults (13% versus 21%),p< 0.001. This finding translated in distinct first-line treatment patterns, where AYAs received more initial targeted therapy. Overall, grade 3-4 AE percentages following first-line systemic treatment were similar for AYAs and older adults; anti-PD-1 (7% versus 14%,p= 0.25), anti-CTLA-4 (16% versus 33%,p= 0.12), anti-PD-1 + anti-CTLA-4 (67% versus 56%,p= 0.34) and BRAF/MEK-inhibition (14% versus 23%,p= 0.06). Following anti-CTLA-4 treatment, no AYAs experienced a grade 3-4 colitis, while 17% of the older adults did (p= 0.046). There was no difference in response to treatment between AYAs and older adults. The longer overall survival observed in AYAs (hazard ratio (HR) 0.7; 95% CI 0.6-0.8) was explained by the increased cumulative incidence of non-melanoma related deaths in older adults (sub-distribution HR 2.8; 95% CI 1.5-4.9), calculated by competing risk analysis. The results of our national cohort study show that baseline characteristics and mutational profiles differ between AYAs and older adults with advanced melanoma, leading to different treatment choices made in daily practice. Once treatment is initiated, AYAs and older adults show similar tumor responses and melanoma-specific survival. Show less
Zeijl, M.C.T. van; Ismail, R.K.; Wreede, L.C. de; Eertwegh, A.J.M. van den; Boer, A. de; Dartel, M. van; ... ; Wouters, M.W.J.M. 2020
The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced... Show moreThe aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune- or targeted therapy, who met >= 1 trial exclusion criteria. These criteria were derived from the KEYNOTE-006 and CHECKMATE-067/-066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan-Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population-based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) >= 2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of >= 2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long-term survival is possible. The prognosis of ineligible patients with advanced melanoma in real-world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM. Show less
Groningen, J.T. van; Ceyisakar, I.E.; Gietelink, L.; Henneman, D.; Harst, E. van der; Westerterp, M.; ... ; Dutch Surg Colorectal Audit Grp 2020
Background: Comparing outcomes across hospitals to learn from best performing hospitals can be valuable. However, reliably identifying best performance is challenging. This study assesses the... Show moreBackground: Comparing outcomes across hospitals to learn from best performing hospitals can be valuable. However, reliably identifying best performance is challenging. This study assesses the possibility to distinguish best performing hospitals on single outcomes and consistency of performance on different outcomes.Methods: Data were derived from the Dutch ColoRectal Audit 2013-2015. Outcomes considered were textbook outcome (colon), (circumferential) resection margins, (serious) complications, mortality, and 'failure to rescue'. To include uncertainty in rankings, random effect logistic regression models were used to calculate expected ranks (ERs), for each hospital and outcome. Rankability was calculated for each outcome, as a measure of reliability of ranking. Furthermore, correlation between ERs on different outcomes was assessed. Correlation was considered weak <0.40, moderate between 0.40 - 0.59 and strong >0.60.Results: The study included 32 143 patients; of whom 11 373 were treated in 2015 across 84 hospitals, 8181 colon and 3192 rectal cancer patients. In this one-year period 'Postoperative complications' had the highest rankability for colon (57%) and rectal (41%) surgery. No (group of) hospital(s) had the highest ER(s) on all outcomes. Correlation between ERs of outcomes was moderate in 2 (of 25) and strong in 4 (of 25) combinations. Rankability of colorectal mortality increased from 14% in 2015 to 35% when data over 2013-2015 were used.Conclusion: The highest reliability of identifying best performance based on an outcome was 57%. However, the balance between reliability and relevance of outcomes is vulnerable. No (group of) hospital(s) could be identified as best performer on all outcomes. Performance was not consistent on outcomes. (C) 2020 Published by Elsevier Ltd. Show less
Elfrink, A.K.E.; Pool, M.; Werf, L.R. van der; Marra, E.; Burgmans, M.C.; Meijerink, M.R.; ... ; Dutch Hepatobiliary Audit Grp 2020
Background In patients with colorectal liver metastases (CRLM) preoperative imaging may include contrast-enhanced (ce) MRI and [F-18]fluorodeoxyglucose (F-18-FDG) PET-CT. This study assessed trends... Show moreBackground In patients with colorectal liver metastases (CRLM) preoperative imaging may include contrast-enhanced (ce) MRI and [F-18]fluorodeoxyglucose (F-18-FDG) PET-CT. This study assessed trends and variation between hospitals and oncological networks in the use of preoperative imaging in the Netherlands.Methods Data for all patients who underwent liver resection for CRLM in the Netherlands between 2014 and 2018 were retrieved from a nationwide auditing database. Multivariable logistic regression analysis was used to assess use of ceMRI, F-18-FDG PET-CT and combined ceMRI and F-18-FDG PET-CT, and trends in preoperative imaging and hospital and oncological network variation.Results A total of 4510 patients were included, of whom 1562 had ceMRI, 872 had F-18-FDG PET-CT, and 1293 had combined ceMRI and F-18-FDG PET-CT. Use of ceMRI increased over time (from 9.6 to 26.2 per cent; P < 0.001), use of F-18-FDG PET-CT decreased (from 28.6 to 6.0 per cent; P < 0.001), and use of both ceMRI and F-18-FDG PET-CT 16.9 per cent) remained stable. Unadjusted variation in the use of ceMRI, F-18-FDG PET-CT, and combined ceMRI and F-18-FDG PET-CT ranged from 5.6 to 100 per cent between hospitals. After case-mix correction, hospital and oncological network variation was found for all imaging modalities.Discussion Significant variation exists concerning the use of preoperative imaging for CRLM between hospitals and oncological networks in the Netherlands. The use of MRI is increasing, whereas that of F-18-FDG PET-CT is decreasing. Show less
Blankenstein, S.A.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Boers-Sonderen, M.J.; Eertwegh, A.J.M. van den; Franken, M.G.; ... ; Akkooi, A.C.J. van 2020
Opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapeutics over the past decade. The aim of this study is to present... Show moreOpportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapeutics over the past decade. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage IIIC and IV melanoma, who have previously been treated with immunotherapy or targeted therapy. Data was extracted from the Dutch Melanoma Treatment Registry (DMTR) on 154 patients obtaining disease control to systemic therapy and undergoing subsequent surgery. Disease control was defined as a complete response (CR), which was seen in 3.2% of patients; a partial response (PR), seen in 46.1% of patients; or stable disease (SD), seen in 44.2% of patients. At a median follow-up of 10.0 months (interquartile range 4-22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression-free survival (PFS) was 9.0 months (95% CI 6.3-11.7). A CR or PR at first follow-up after surgery was associated with both a better OS and PFS compared to stable or progressive disease (p < 0.001). We conclude that selected patients can benefit from surgery after achieving disease control with systemic therapy. Show less
Verheijden, R.J.; May, A.M.; Blank, C.U.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Eertwegh, A.J.M. van den; ... ; Suijkerbuijk, K.P.M. 2020
Purpose: Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity... Show morePurpose: Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown.Experimental Design: Using data from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analyzed whether toxicity management affected survival in these patients.Results: A total of 1,250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab, and 85 combination therapy. A total of 312 patients (25%) developed severe (grade >= 3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared with 15 months for patients without severe toxicity [hazard ratio (HRadj) = 0.77; 95% confidence interval (CI), 0.63-0.93]. Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF +/- steroids for steroid-refractory toxicity compared with patients whoweremanaged with steroids only (HRadj = 1.61; 95% CI, 1.03-2.51), with a median OS of 17 and 27 months, respectively.Conclusions: Patients experiencing severe ICI toxicity have a prolonged OS. However, this survival advantage is abrogated when anti- TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy. Show less
Karthaus, E.G.; Vahl, A.; Werf, L.R. van der; Elsman, B.H.P.; Herwaarden, J.A. van; Wouters, M.W.J.M.; Hamming, J.F. 2020
Objective: To evaluate reasons to deviate from aneurysm diameter thresholds, and focus on the difference in how Dutch vascular surgical units (VSUs) perceive their deviation and their actual... Show moreObjective: To evaluate reasons to deviate from aneurysm diameter thresholds, and focus on the difference in how Dutch vascular surgical units (VSUs) perceive their deviation and their actual deviation. Background: Guidelines recommend surgical treatment for asymptomatic abdominal aortic aneurysms (AAAs) with a diameter of at least 55 mm for men and 50 mm for women. We evaluate reasons to deviate from these guidelines, and focus on the difference in how Dutch vascular surgical units (VSUs) perceive their deviation and their actual deviation. Methods: All patients undergoing elective AAA repair between 2013 and 2016 registered in the Dutch Surgical Aneurysm Audit (DSAA) were included. Surgery at diameters of <55 mm for men and <50 mm for women were considered guideline deviations. National deviation and hospital variation in deviation were evaluated over time. Questionnaires were distributed among all Dutch VSUs, inquiring for acceptable reasons for guideline deviation. VSUs were asked to estimate the guideline deviation percentage in their hospital which was then compared with their DSAA percentage. Results: In all, 9039 patients were included. In 15%, we found guideline deviation, varying from 2% to 40% between VSUs. Over time, 21 VSUs were identified with a lower percentage of deviation than the national mean each year and 8 VSUs with a higher percentage. 44/60 VSUs completed the questionnaire. Most commonly reported reasons to deviate were concomitant large iliac diameter (91%) and saccular aneurysm (82%). The majority of the VSUs (77%) estimated their guideline deviation to be <5%. Eleven VSUs (25%) estimated their deviation concordant with their DSAA percentage, but 75% of VSUs underestimated their deviation. Conclusions: Dutch VSUs regularly deviate from the guidelines regarding aneurysm diameter, with variation between VSUs. Consensus exists amongst VSUs on acceptable reasons for guideline deviations; however, the majority underestimates their actual deviation percentage. Show less
Immunotherapeutic and targeted drugs improved survival of patients with metastatic melanoma. There is, however, a lack of evidence regarding their healthcare costs in clinical practice. The aim of... Show moreImmunotherapeutic and targeted drugs improved survival of patients with metastatic melanoma. There is, however, a lack of evidence regarding their healthcare costs in clinical practice. The aim of our study was to provide insight into real-world healthcare costs of patients with metastatic cutaneous melanoma. Data were obtained from the Dutch Melanoma Treatment Registry for patients who were registered between July 2012 and December 2018. Mean total/monthly costs per patient were reported for all patients, patients who did not receive systemic therapy, and patients who received systemic therapy. Furthermore, mean episode/monthly costs per line of therapy and drug were reported for patients who received systemic therapy. Mean total/monthly costs were Euro 89,240/Euro 6809: Euro 7988/Euro 2483 for patients who did not receive systemic therapy (n = 784) and Euro 105,078/Euro 7652 for patients who received systemic therapy (n = 4022). Mean episode/monthly costs were the highest for nivolumab plus ipilimumab (Euro 79,675/Euro 16,976), ipilimumab monotherapy (Euro 79,110/Euro 17,252), and dabrafenib plus trametinib (Euro 77,053/Euro 12,015). Dacarbazine yielded the lowest mean episode/monthly costs (Euro 6564/Euro 2027). Our study showed that immunotherapeutic and targeted drugs had a large impact on real-world healthcare costs. As new drugs continue entering the treatment landscape for (metastatic) melanoma, it remains crucial to monitor whether the benefits of these drugs outweigh their costs. Show less
Introduction: The revised Dutch colorectal cancer guideline (2014), led to an overall decrease in preoperative radiotherapy (RT) use. This study evaluates hospital variation in RT use for... Show moreIntroduction: The revised Dutch colorectal cancer guideline (2014), led to an overall decrease in preoperative radiotherapy (RT) use. This study evaluates hospital variation in RT use for resectable rectal cancer and the influence of guideline revision, including the nationwide impact of changing RT application on short term outcomes.Methods: Data of surgically resected rectal cancer patients registered in the Dutch ColoRectal Audit were extracted between 2011 and 2017. Patients were divided into groups based on time of guideline revision (<2014 and >= 2014). Primary outcome was guideline adherence at hospital level regarding RT application, stratified for three stage groups. Secondary outcomes included positive circumferential resection (CRM+) and 30-day complicated postoperative course.Results: The groups consisted of 7364 and 12,057 patients, respectively. In total, 6772 patients did not receive RT (17.6% (<2014) vs. 45.7% (>= 2014), p < 0.001). The largest increase of surgery alone was observed for cT1-2N0 stage rectal cancer (35.1% vs. 91.8%, p < 0.001), with a substantial decrease in hospital variation (IQR 22.2-50.0% vs. IQR 87.6-98.0%). For cT1-3N1MRF-stage rectal cancer, a substantial amount of hospital variation in short course RT remained after guideline revision (IQR 26.8-54.1% vs. IQR 26.2-50.0%). A significant decrease in CRMthorn (5.8% vs. 4.2%, p < 0.001) and complicated course (22.5% vs. 18.5%, p < 0.001) was observed.Conclusions: Radiotherapy for early-stage rectal cancer was uniformly abandoned after guideline revision, while substantial hospital variation remained for intermediate risk resectable rectal cancer in the Netherlands. The substantial nationwide decrease in the use of RT for rectal cancer treatment did not negatively impact CRM involvement. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Show less
Beck, N.; Brakel, T.J. van; Smit, H.J.M.; Klaveren, D. van; Wouters, M.W.J.M.; Schreurs, W.H. 2020
Background Pneumonectomy in lung cancer treatment is associated with considerable morbidity and mortality. Its use is reserved only for patients in whom a complete oncological resection by (sleeve)... Show moreBackground Pneumonectomy in lung cancer treatment is associated with considerable morbidity and mortality. Its use is reserved only for patients in whom a complete oncological resection by (sleeve) lobectomy is not possible. It is unclear whether a patients' risk of receiving a pneumonectomy is equally distributed. This study examined between-hospital variation of pneumonectomy use for primary lung cancer in the Netherlands. Methods Data from the Dutch Lung Cancer Audit for Surgery from 2012 to 2016 were used to study the use of pneumonectomy for primary lung cancer in the Netherlands. Using multivariable logistic regression, factors associated with pneumonectomy use were identified and the expected number of pneumonectomies per hospital was determined. Subsequently, the observed/expected ratio (O/E ratio) per hospital was calculated to study between-hospital differences. Results Of the 8446 included patients, 659 (7.8%) underwent a pneumonectomy with a mean postoperative mortality of 7.1% (n = 47). Factors associated with receiving a pneumonectomy were age, gender, cardiac and pulmonary comorbidities, tumor side, size and histopathology. The pneumonectomy use in the Netherlands varied considerably between hospitals (IQR 5.5-10.1%). Three hospitals out of 51 performed significantly less pneumonectomies than expected (O/E ratio < 0.5) and three significantly more (O/E ratio > 1.7). In the latter group, severe complications were more frequent, taking other influencing factors into account (OR 1.51, 95% CI 1.05-2.19). Conclusions There is a considerable between-hospital variation in pneumonectomy use in lung cancer treatment. To further optimize surgical lung cancer care, we suggest center-specific feedback on pneumonectomy use and the development of a risk-adjusted pneumonectomy indicator. Show less
Verheijden, R.J.; May, A.M.; Blank, C.U.; Veldt, A.A.M. van der; Boers-Sonderen, M.J.; Aarts, M.J.B.; ... ; Suijkerbuijk, K.P.M. 2020
Background Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has... Show moreBackground Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now. Methods Risk ratios of severe (grade >= 3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry. Results 111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RRadj) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RRadj 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs. Conclusion In patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found. Show less
Berg, J.H. van den; Heemskerk, B.; Rooij, N. van; Gomez-Eerland, R.; Michels, S.; Zon, M. van; ... ; Haanen, J.B.A.G. 2020
Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50... Show moreTreatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses. Purpose Execute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial. Experimental Ten patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products. Results Five out of 10 patients, who were all anti-PD-1 naive at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion. Conclusion The clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial. Show less
The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The... Show moreThe prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI). Data from all patients with BRAF-mutant metastatic melanoma with a highly elevated serum LDH at baseline (>= 2x upper limit of normal) receiving first-line targeted therapy between 2012 and 2019 in the Netherlands were collected. Patients were stratified according to response status to targeted therapy and change in LDH at start of subsequent treatment with ICI. Differences in overall survival (OS) between the subgroups were compared using log-rank tests. After a median follow-up of 35.1 months, median OS of the total study population (n = 360) was 4.9 months (95% CI 4.4-5.4). Of all patients receiving subsequent treatment with ICI (n = 113), survival from start of subsequent treatment was significantly longer in patients who had normalized LDH and were still responding to targeted therapy compared to those with LDH that remained elevated (median OS 24.7 vs. 1.1 months). Our study suggests that introducing ICI upon response to targeted therapy with normalization of LDH could be an effective strategy in obtaining long-term survival in advanced melanoma patients with initial highly elevated serum LDH. Show less
Aim This study aimed to determine predictive factors for the circumferential resection margin (CRM) within two northern European countries with supposed similarity in providing rectal cancer care.... Show moreAim This study aimed to determine predictive factors for the circumferential resection margin (CRM) within two northern European countries with supposed similarity in providing rectal cancer care. Method Data for all patients undergoing rectal resection for clinical tumour node metastasis (TNM) stage I-III rectal cancer were extracted from the Swedish ColoRectal Cancer Registry and the Dutch ColoRectal Audit (2011-2015). Separate analyses were performed for cT1-3 and cT4 stage. Predictive factors for the CRM were determined using univariable and multivariable logistic regression analyses. Results A total of 6444 Swedish and 12 089 Dutch patients were analysed. Over time the number of hospitals treating rectal cancer decreased from 52 to 42 in Sweden, and 82 to 79 in the Netherlands. In the Swedish population, proportions of cT4 stage (17% vs 8%), multivisceral resection (14% vs 7%) and abdominoperineal excision (APR) (37% vs 31%) were higher. The overall proportion of patients with a positive CRM (CRM+) was 7.8% in Sweden and 5.4% in the Netherlands. In both populations with cT1-3 stage disease, common independent risk factors for CRM+ were cT3, APR and multivisceral resection. No common risk factors for CRM+ in cT4 stage disease were found. An independent impact of hospital volume on CRM+ could be demonstrated for the cT1-3 Dutch population. Conclusion Within two northern European countries with implemented clinical auditing, rectal cancer care might potentially be improved by further optimizing the treatment of distal and locally advanced rectal cancer. Show less
Objectives Hospital variation in risk-adjusted outcomes after colorectal cancer surgery has been shown. However, explanatory factors are not sufficiently clear. The objective of this study was to... Show moreObjectives Hospital variation in risk-adjusted outcomes after colorectal cancer surgery has been shown. However, explanatory factors are not sufficiently clear. The objective of this study was to identify factors perceived by gastrointestinal surgeons as important to achieve excellent casemix-adjusted outcomes after colorectal cancer surgery.Design Based on literature and experts' opinion, 86 factors associated with serious complications, failure to rescue and mortality were listed. These were presented to gastrointestinal surgeons through two web-based surveys and an expert meeting. Participants were asked to choose their top 10 of most important factors.Participants Dutch gastrointestinal surgeons (n=52) of different hospitals and different hospital types (general/teaching/academic).Results Of 31 invited experts for the first survey and meeting, 71% responded. Of 130 invited surgeons, 34 responded to the second survey. Factors deemed important were: procedural hospital volume (46% in top 10), specialised surgeons performing surgery, (elective 87%, emergency 60% and reoperations 62% in top 10), accessibility of, and daily ward rounds by specialised surgeons (41% and 38% in top 10), preoperative screening for malnutrition (57% in top 10), a protocol for recognition of anastomotic leakage and rapid reintervention (54% and 49% in top 10).Conclusion Procedural hospital volume, specialisation of surgeons, screening for malnutrition, early recognition of complications followed by rapid action were perceived as most important factors to achieve good outcomes by gastrointestinal surgeons. Show less
