Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSIONS: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab - study protocol.

BACKGROUND: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. METHODS: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. DISCUSSION: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.

Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. DISCUSSION: The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. TRIAL REGISTRATION: Clinical Trials: NCT04927780. Registered June 16, 2021.

Health-state utilities in long-term advanced melanoma survivors comparable with the general population.

BACKGROUND: Checkpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies, assessing their health-state utilities is essential and can be used for the calculation of quality-adjusted life years and for cost-effectiveness analyses. Therefore, we evaluated the health-state utilities in long-term advanced melanoma survivors. METHODS: Health-state utilities were evaluated in a cohort of advanced melanoma survivors 24-36 months (N = 37) and 36-plus months (N = 47) post-ipilimumab monotherapy. In addition, the health-state utilities of the 24-36 months survivor group were assessed longitudinally, and utilities of the combined survival groups (N = 84) were compared with a matched control population (N = 168). The EQ-5D was used to generate health-state utility values, and quality-of-life questionnaires were used to establish correlations and influencing factors of utility scores. RESULTS: Health-state utility scores were similar between the 24-36 months'- and the 36-plus months' survival group (0.81 vs 0.86; p = .22). In survivors, lower utility scores were associated with symptoms of depression (ß = - .82, p = .022) and fatigue burden (ß = - .29, p = .007). Utility scores did not significantly change after 24-36 months of survival, and the utilities of survivors were comparable to the matched control population (0.84 vs 0.87; p = .07). DISCUSSION: Our results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores.

Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT).

BACKGROUND: The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. METHODS: This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. DISCUSSION: This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. PROTOCOL VERSION: Version 3 dd 11-4-2022.

Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial.

BACKGROUND: The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response. METHODS: The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs. DISCUSSION: From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients. TRIAL REGISTRATION: The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

The treatment and survival of elderly patients with locally advanced pancreatic cancer: A post-hoc analysis of a multicenter registry.

BACKGROUND: The treatment options for patients with locally advanced pancreatic cancer (LAPC) have improved in recent years and consequently survival has increased. It is unknown, however, if elderly patients benefit from these improvements in therapy. With the ongoing aging of the patient population and an increasing incidence of pancreatic cancer, this patient group becomes more relevant. This study aims to clarify the association between increasing age, treatment and overall survival in patients with LAPC. METHODS: Post-hoc analysis of a multicenter registry including consecutive patients with LAPC, who were registered in 14 centers of the Dutch Pancreatic Cancer Group (April 2015-December 2017). Patients were divided in three groups according to age (<65, 65-74 and ≥75 years). Primary outcome was overall survival stratified by primary treatment strategy. Multivariable regression analyses were performed to adjust for possible confounders. RESULTS: Overall, 422 patients with LAPC were included; 162 patients (38%) aged <65 years, 182 patients (43%) aged 65-74 and 78 patients (19%) aged ≥75 years. Chemotherapy was administered in 86%, 81% and 50% of the patients in the different age groups (p<0.01). Median overall survival was 12, 11 and 7 months for the different age groups (p<0.01).Patients treated with chemotherapy showed comparable median overall survival of 13, 14 and 10 months for the different age groups (p=0.11). When adjusted for confounders, age was not associated with overall survival. CONCLUSION: Elderly patients are less likely to be treated with chemotherapy, but when treated with chemotherapy, their survival is comparable to younger patients.

Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls.

BACKGROUND: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer. MATERIAL AND METHODS: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines. RESULTS: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7 vs. 89.8, difference (diff) = -5.80, p=.005), role (83.5 vs. 90, diff = -5.97, p=.02), cognitive (83.7 vs. 91.9, diff = -8.05, p=.001), and social functioning (86.5 vs. 95.1, diff = -8.49, p= <.001) and had a higher symptom burden of fatigue (23.0 vs. 15.5, diff = 7.48, p=.004), dyspnea (13.3 vs. 6.7, diff = 6.47 p=.02), diarrhea (7.9 vs. 4.0, diff = 3.78, p=.04), and financial impact (10.5 vs. 2.5, diff = 8.07, p=.001) than matched controls. Group differences were indicated as clinically relevant. DISCUSSION: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.

Prospective practice survey of management of cetuximab-related skin reactions.

PURPOSE: Evidence-based guidelines on how to prevent or treat cetuximab-related skin reactions are lacking and multiple care and management strategies are used. The main purpose of the present study is to gain information about the different skincare products being used against skin reactions in metastatic colorectal cancer (mCRC) and recurrent/metastatic (R/M) or locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) patients treated with cetuximab. METHODS: An open-label, prospective observational study conducted in the Netherlands. The occurrence of skin reactions and the care and management options taken were documented for 16 weeks, starting from the first administration of cetuximab. RESULTS: A total of 103 patients were included in 7 hospitals. 38 patients (37%) developed a grade ≥ 2 skin reaction. Eighty-six patients could be analysed for the primary endpoint (73.3% males, mean age 62.4 years, n = 44 LA SCCHN, n = 16 R/M SCCHN, n = 26 mCRC). The most frequently used skin products at some point during the observation period were moisturizing products (70%), systemic antibiotics (64%), topical antibiotics (58%), lipid-regenerating (28%) and other topical products (28%). The overall use of products gradually increased from baseline to week 6-10, reducing by week 16. Hospital protocols were the primary reason (> 50%) for choice of the skincare products and medications. CONCLUSION: A variety of skin care products and antibiotics were commonly used. Only few patients developed severe cutaneous reactions. For patients, the occurrence of skin reactions did not influence their willingness to continue cetuximab therapy.

Consequences of testing for mismatch repair deficiency of colorectal cancer in clinical practice.

INTRODUCTION: Mismatch repair deficiency (dMMR) can be found in Lynch syndrome (LS)-associated colorectal carcinoma and in 15% of sporadic colorectal cancer (CRC). Outcome of MMR-deficiency testing is important for surgical decisions as extended colectomy is recommended in young LS-patients with CRC. Moreover, the finding of a dMMR tumour has consequences for the choices of adjuvant chemotherapy as MMR-deficient CRC is resistant to 5-fluorouracil (5-FU) monotherapy. Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC. METHODS: We performed a multicentre, retrospective study, in a community hospital and a University Medical Centre. We included all CRC-patients between 2012 and 2016 who were tested for microsatellite instability. We collected clinical data such as gender, age, referral to clinical geneticist, surgical procedure and choice of chemotherapy. RESULTS: We analysed 225 CRCs. Twenty-four (10.7%) of 225 CRC were MMR-deficient. Of the 24 patients with dMMR CRC, 18 (75%) were referred to the clinical geneticist and in nine (37%) patients a MMR mutation was identified. In one (4%) of the 24 patients, a subtotal colectomy was performed. In seven (35%) out of 20 MMR deficient patients, the chemotherapy regimen was adjusted. CONCLUSIONS: The finding of a dMMR CRC had consequences for decisions on chemotherapy in a relative high proportion of patients. We recommend testing in all patients with CRC independent of age at diagnosis, as proper treatment decisions and genetic counselling are very important.

Translating the ABC-02 trial into daily practice: outcome of palliative treatment in patients with unresectable biliary tract cancer treated with gemcitabine and cisplatin.

BACKGROUND: Biliary tract cancer (BTC) is an uncommon cancer with an unfavorable prognosis. Since 2010, the standard of care for patients with unresectable BTC is palliative treatment with gemcitabine plus cisplatin, based on the landmark phase III ABC-02 trial. This current study aims to evaluate the efficacy and safety of gemcitabine and cisplatin in patients with unresectable cholangiocarcinoma and gallbladder cancer in daily practice that meet the criteria for the ABC-02 trial in comparison to patients who did not. METHODS: Patients diagnosed with unresectable BTC between 2010 and 2015 with an indication for gemcitabine and cisplatin were included. We divided these patients into three groups: (I) patients who received chemotherapy and met the criteria of the ABC-02 trial, (II) patients who received chemotherapy and did not meet these criteria and (III) patients who had an indication for chemotherapy, but received best supportive care without chemotherapy. Primary outcome was overall survival (OS) and secondary outcome was progression-free survival (PFS). RESULTS: We collected data of 208 patients, of which 138 (66.3%) patients received first line chemotherapy with gemcitabine and cisplatin. Median OS of 69 patients in group I, 63 patients in group II and 65 patients in group III was 9.6 months (95%CI = 6.7-12.5), 9.5 months (95%CI = 7.7-11.3) and 7.6 months (95%CI = 5.0-10.2), respectively. Median PFS was 6.0 months (95%CI = 4.4-7.6) in group I and 5.1 months (95%CI = 3.7-6.5) in group II. Toxicity and number of dose reductions (p = .974) were comparable between the two chemotherapy groups. CONCLUSION: First-line gemcitabine and cisplatin is an effective and safe treatment for patients with unresectable BTC who do not meet the eligibility criteria for the ABC-02 trial. Median OS, PFS and treatment side effects were comparable between the patients who received chemotherapy (group I vs. group II).

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Consequence of restaging after neoadjuvant treatment for locally advanced rectal cancer.

BACKGROUND: Locally advanced rectal cancer is customarily treated with neoadjuvant chemoradiotherapy (CRT) followed by a total mesorectal excision. During the course of CRT, previously non-detectable distant metastases can appear. Therefore, a restaging CT scan of the chest and abdomen was performed prior to surgery. The aim of this study was to determine the frequency of a change in treatment strategy after this restaging CT scan. METHODS: Patients treated with neoadjuvant CRT for locally advanced rectal cancer between January 2003 and July 2013 were included retrospectively. To determine the value of the restaging CT scan, the surgical treatment as planned before CRT was compared with the treatment ultimately received. RESULTS: A total of 153 patients (91 male) were eligible, and median age was 62 (32-82) years. The restaging CT scan revealed the presence of distant metastases in 19 patients (12.4, 95 % confidence interval [CI] 7.0-17.8). In 17 patients (11.1, 95 % CI 6.1-16.1), a change in treatment strategy occurred due to the detection of metastases with a restaging CT scan. CONCLUSION: A restaging CT scan after completion of neoadjuvant CRT may detect newly developed metastases and consequently alter the initial treatment strategy. This study demonstrated the added value of the restaging CT scan prior to surgery.

Tumor-infiltrating lymphocytes and immune-related adverse events in advanced melanoma.

Background: The predictive value of tumor-infiltrating lymphocytes (TILs) in immune-related adverse event (irAE) development remains unknown, although an association between tumor immunogenicity and irAEs has been suggested. We investigated the association between TIL abundance in pretreatment primary and metastasis specimens and the subsequent development of severe irAEs. Patients and methods: We retrospectively identified patients with advanced cutaneous melanoma who received first-line anti-programmed cell death protein 1 (PD-1) with or without anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) from 10 hospitals in the Netherlands. TILs were scored on representative hematoxylin and eosin (H&E) stains of the primary melanoma and pretreatment melanoma metastasis as 'absent', 'nonbrisk', or 'brisk'. A univariable logistic regression analysis was carried out to assess the association between the TIL scores and the development of severe irAEs. Fine and Gray subdistribution hazard models were used to estimate the cumulative incidence of severe irAEs. Results: Of the 1346 eligible patients, 536 patients had primary melanoma specimens available, and 613 patients had metastasis specimens available. Severe irAEs occurred in 15% of anti-PD-1-treated patients and 49% of anti-PD-1 + anti-CTLA-4-treated patients. The presence of TILs was not associated with the occurrence of grade ≥3 irAEs in primary melanoma specimens (P = 0.70) nor pretreatment metastasis specimens (P = 0.91). In the univariable analysis, patients with brisk TILs did not have a higher chance of developing severe irAEs compared with patients with absent TILs, for both primary specimen (odds ratio 1.15, 95% confidence interval 0.60-2.18) and metastasis specimen (odds ratio 0.77, 95% confidence interval 0.37-1.59). There was also no significant difference in the lifetime risk or timing of the development of severe irAEs in patients with TILs present compared with patients with TILs absent. Conclusion: There was no association between the TIL scores on H&E-stained slides from the primary melanoma or pretreatment metastasis and the development of grade 3 or higher irAEs. Additionally, no correlation was found between the presence of TILs and the timing of irAEs.

Seasonal variation of anti-PD-1 outcome in melanoma-Results from a Dutch patient cohort.

Despite the improved survival rates of patients with advanced stage melanoma since the introduction of ICIs, many patients do not have (long-term) benefit from these treatments. There is evidence that the exposome, an accumulation of host-extrinsic factors including environmental influences, could impact ICI response. Recently, a survival benefit was observed in patients with BRAF wild-type melanoma living in Denmark who initiated immunotherapy in summer as compared to winter. As the Netherlands lies in close geographical proximity to Denmark and has comparable seasonal differences, a Dutch validation cohort was established using data from our nationwide melanoma registry. In this study, we did not observe a similar seasonal difference in overall survival and are therefore unable to confirm the Danish findings. Validation of either the Dutch or Danish findings in (combined) patient cohorts from other countries would be necessary to determine whether this host-extrinsic factor influences the response to ICI-treatment.

Long-Term Survival in Patients With Advanced Melanoma.

IMPORTANCE: Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival. OBJECTIVE: To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials. DESIGN, SETTING, AND PARTICIPANTS: Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023. EXPOSURES: Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab. MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR). RESULTS: A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69). CONCLUSIONS AND RELEVANCE: This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

Adjuvant immunotherapy in older patients with stage III and resected stage IV melanoma: Toxicity and recurrence-free survival outcomes from the Dutch melanoma treatment registry.

BACKGROUND: Adjuvant anti-PD-1 therapy improves relapse free survival in stage III melanoma, but also leads to immune-related adverse events (irAEs). Older patients are of particular interest due to comorbidities and frailty, which may impact their ability to tolerate irAEs and benefit from anti-PD-1 therapy. This study aimed to explore associations between clinical parameters and the occurrence of grade ≥ 3 irAEs and recurrence-free survival (RFS) in older patients with radically resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy. METHODS: Patients aged ≥ 65 with resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy between 2018 and 2022 were selected using real-world data from the nationwide Dutch Melanoma Treatment Registry (DMTR). A univariate and multivariable logistic regression was used to compare determinants of grade ≥ 3 irAEs, and univariate and multivariable Cox-proportional hazard models were fitted to identify factors influencing RFS. RESULTS: The study included 885 patients, with 280 aged 75 and older. The incidence of grade ≥ 3 irAEs was 15.5 % in the 65-74 age group and 13.9 % in the ≥ 75 age group. No significant correlation was found between age and grade ≥ 3 irAEs. However, an increasing number of comorbidities was associated with a higher risk of grade ≥ 3 irAEs (multivariable analyses: OR 1.83, 95 % C.I. 0.99-3.40). The 1-year RFS rate of 80.0 % of this study was comparable to those reported in previous registration trials and real-world data. Having ≥ 3 comorbidities was significantly associated with a decrease in RFS (HR: 1.68, 95 % C.I. 1.15-2.44). CONCLUSION: Older patients had similar benefit of adjuvant immunotherapy compared to older subgroups in previous trials. However, patients with multiple comorbidities were at increased risk of grade ≥ 3 irAEs and had a lower RFS. This should be considered when deciding upon adjuvant treatment.

Trends in survival and costs in metastatic melanoma in the era of novel targeted and immunotherapeutic drugs.

BACKGROUND: The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs. MATERIALS AND METHODS: Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan-Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis. RESULTS: Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million. CONCLUSION: Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma.