A phase II study of thalidomide and temozolomide in patients with brain metastases from malignant melanoma. Lymphopenia correlates with response

BACKGROUND: Central nervous system (CNS) metastases develop in nearly half of patients with advanced melanoma and in 15–20% CNS is the first site of relapse. Median overall survival is short, ranging from two to four months, and one-year survival rate is only 10–15%. THA has been shown to have both anti-angiogenetic and immuno-modulating effects. TMZ is an oral alkylating agent with an excellent oral bioavailability and it is highly lipophillic with an ability to penetrate the blood–brain barrier. TMZ and THA in combination were tested in patients with brain metastases from malignant melanoma. METHODS: Between June 2004 and February 2007 patients with measurable metastatic melanoma in progression and PS ≤ 1 received TMZ in a dose of 150 mg/m(2) qd for seven days, followed by seven days off therapy and THA in 200 mg qd, both orally administered. Concomitant treatment with steroids was allowed. PBMCs were collected from the last 14 consecutive patients for evaluation of immune parameters. RESULTS: Forty screened patients were eligible and evaluable for response, and 39 were evaluable for toxicity. 25 patients had asymptomatic and 15 symptomatic brain metastases. The toxicity was primarily grade 1–2 with no grade 4 or treatment-related deaths. Four patients had thromboembolic events grade 3. One patient obtained a CR and five a PR in the CNS, while two had CR and four had PR outside CNS. Overall response rate was 17.5%. We found a significant positive correlation between lymphopenia and objective response. CONCLUSIONS: The combination treatment was well tolerated but with more frequent thromboembolic events compared to single drug TMZ or THA. The treatment demonstrated activity in CNS as well as outside CNS. The correlation between lymphopenia and objective response needs further investigation

The role of FDG-PET/CT in preoperative staging of sentinel lymph node biopsy-positive melanoma patients

BACKGROUND: On April 1, 2015, Odense University Hospital (OUH) began a new diagnostic strategy, wherein all malignant melanoma (MM) patients in the Region of Southern Denmark with a positive sentinel lymph node biopsy (SLNB) underwent FDG-PET/CT preoperatively prior to lymph node dissection (LND). The purpose of this study is to determine FDG-PET/CT's efficacy in finding distant metastasis in the first year after the implementation of this new strategy, and to what extent these findings influence subsequent diagnostic testing and treatment in this patient group. We conducted a retrospective multicenter cohort study which included all patients with MM from all hospitals in the Region of Southern Denmark from April 1, 2015 to April 1, 2016 found to be SLNB-positive who subsequently underwent FDG-PET/CT. Patient information was acquired from the Danish Melanoma Database and was cross-referenced with OUH's patient records. The data was analyzed for a number of parameters including FDG-PET/CT findings and treatment strategy. Median follow-up time was 7 months.RESULTS: A total of 47 patients were eligible from the first year of this new diagnostic strategy. One patient was excluded due to undergoing LND prior to FDG-PET/CT. Thus, 46 patients were included in this study. Ultimately, preoperative FDG-PET/CT neither uncovered any distant metastases nor led to any alterations in treatment strategy in this patient group.CONCLUSIONS: Surprisingly, this new diagnostic strategy did not find any MM metastases or uncover anything else of relevance. FDG-PET/CT did, however, provide false positive findings in 13 % (6/46) of these patients. These scans triggered additional, predominantly invasive, procedures, which did not ultimately have an impact on the therapeutic strategy. Thus, these findings indicate a need for re-evaluation of this new diagnostic strategy as well as the necessity for further clinical trials evaluating FDG-PET/CT's utility in this clinical setting.</p

Impact of patient-reported outcomes on symptom monitoring during treatment with checkpoint inhibitors:health-related quality of life among melanoma patients in a randomized controlled trial

Introduction: In a randomized controlled trial, we previously investigated if melanoma patients receiving checkpoint inhibitors had fewer severe immune-related adverse events (irAEs) when they reported symptoms using electronic patient-reported outcomes (ePRO) with triggered alerts as an add-on to standard care, compared to standard care alone. The aim of this study is to examine between-group differences in health-related quality of life (HRQoL) and associations between irAEs severity and HRQoL. Methods: The study population of 138 patients completed the EuroQol EQ-5D-5L Index and FACT-M questionnaires at baseline and weeks 24 and 48. We analyzed HRQoL from all patients who completed at least one questionnaire. Missing FACT-M items were imputed following existing guidelines. Results: There was no difference in HRQoL at baseline as measured EQ-5D-5L between the intervention and the control group. Between baseline and 48 weeks, mean EQ-5D-5L scores were unchanged among patients in the intervention group (p = 0.81) but decreased significantly among patients in the control group (p = 0.03). Consequently, patients in the intervention group had higher mean scores than those in the control group (p = 0.05) at 48 weeks. Mean FACT-M scores did not differ significantly between the two groups at any of the time points. There were observed no between-group differences in mean EQ-5D-5 and mean FACT-M scores between patients with severe irAEs and patients who had none. Conclusion: Melanoma patients receiving CPIs who self-reported irAEs using ePRO with triggered alerts as a supplement to standard care maintained their HRQoL compared to patients who received standard care alone. Patients in the intervention group had a significantly better HRQoL measured by EQ-5D-5L than controls 48 weeks after baseline. The results suggest that including ePRO in standard care increases melanoma patients´ well-being. Further and larger studies are needed to confirm this finding and examine the impact of severe irAEs on cancer patients’ HRQoL. Trial registration: Clinicaltrials.gov NCT03073031 Registered 8 March 2017, Retrospectively registeredhttps://clinicaltrials.gov/.</p

Health care and socioeconomic costs for long-term survivors after implementation of checkpoint-inhibitors and targeted agents for metastatic melanoma

Background: Real-life data on health care costs and loss of productivity after implementing new agents for metastatic melanoma are important to supplement model-based economic data. Materials and methods: All patients registered in the Danish Metastatic Melanoma Database (DAMMED) and the National Patient Registry in 2007–2011 were compared to 2012–2016 after the implementation of checkpoint inhibitors and targeted therapy. Health care costs, social transfer income (STI), and loss of productivity were calculated with a 2-step one model generalised linear regression (GLM) model. Medicine costs were calculated separately. Results: In 2007–2011, 70 (15%) out of 464 patients were long-term survivors compared to 347 (32%) out of 1089 patients in 2012–2016. Total health care costs per patient year were significantly lower in the first treatment year (€41.457 versus €60.547, relative change (RC) 0.72, 95% confidence interval (CI) 0.56–0.94, p = 0.015) and without significant difference the second year in 2012–2016 compared to 2007–2011. Medicine costs per patient year increased the first (€85.464 versus €26.339, RC 3.39, 95% CI 2.61–4.41, p &lt; 0.001) and the second (€26.464 versus €11.150, RC 2.59, 95% CI 1.98–3.40, p &lt; 0.001) year in 2012–2016 compared to 2007–2011. Productivity increased for long-term survivors in 2012–2016 in contrast to 2007–2011. Conclusion: Implementation of targeted therapy and checkpoint-inhibitors has increased medicine costs more than three-fold for long-term survivors. Total health care costs excluding medicine costs were significantly lower for long-term survivors the first and without change the second treatment year in 2012–2016 compared to 2007–2011. However, the number of treated patients increased which leads to an increase in overall total health care costs. Importantly, productivity increased for long-term survivors in 2012–2016.</p

Impact of assessment-to-treatment interval and metastatic biopsy site on the predictive value of PD-L1 expression at the 1 % cut-off level in melanoma

Background: Intratumoral PD-L1 expression at the 1 % cut-off predicts clinical outcomes and may guide first-line immune checkpoint inhibitor (ICI) selection for metastatic melanoma (MM). However, the impact of the interval between PD-L1 assessment and ICI initiation and the metastatic site used for PD-L1 evaluation, remains unclear. Methods: In this nationwide cohort study we used the Danish Metastatic Melanoma Database (DAMMED) and the Danish Pathology Registry to analyze patients with MM treated with anti-PD-1 or anti-PD-1 plus anti-CTLA-4 from January 2017 to February 2024. Progression-free survival (PFS) and overall survival (OS) were analyzed using Log-rank tests and Cox regression. Results: Data from 1137 patients were analyzed. Among patients with PD-L1 assessed within 90 days of treatment (n = 964; 55.2 % PD-L1 &lt;1 %, 44.8 % PD-L1 ≥1 %), combination therapy improved outcomes in PD-L1 &lt; 1 % (PFS adjusted (a)HR 0.62; 95 % CI 0.48–0.80; p &lt; 0.001, OS aHR 0.64; 95 % CI 0.48–0.85; p = 0.002), while outcomes were comparable for PD-L1 ≥ 1 % patients (PFS aHR 0.90; 95 % CI 0.62–1.30; p = 0.57, OS aHR 0.97; 95 % CI 0.60–1.57; p = 0.89). For PD-L1 assessed &gt; 90 days prior (n = 173), this pattern was less pronounced. Among 48 paired PD-L1 assessments from the same organ, discordance occurred in 25 %. Combination therapy improved PFS for patients with PD-L1 &lt; 1 % skin/subcutaneous (aHR 0.51; 95 % CI 0.34–0.76; p &lt; 0.001) and visceral metastases (aHR 0.65; 95 % CI 0.42–1.02; p = 0.060) while this association was not evident for lymph node metastases (aHR 0.79; 95 % CI 0.48–1.29; p = 0.35). Conclusions: PD-L1 seems a reliable predictive biomarker in MM, when assessed on tissue obtained within 90 days prior to ICI initiation. Non-nodal metastatic sites appear preferable.</p

Does patient sex affect the treatment outcome of immune checkpoint inhibitors? A Danish, observational melanoma study

AIM: The objective of this study was to evaluate whether patient biological sex influences treatment outcomes in patients with metastatic melanoma (MM) undergoing first-line immune checkpoint inhibitor (ICI) therapy.METHODS: The Danish Metastatic Melanoma Database (DAMMED) was employed to identify patients who underwent first-line ICI therapy for MM in Denmark from 2013 to 2021. Excluding adjuvant treatment, uveal and mucosal histological subtypes, the study conducted univariable and multivariable analyses to evaluate the influence of patient sex in survival analyses. Further, landmark survival of this real-world national cohort was described for progression free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS).RESULTS: The analysis encompassed a cohort of 1378 patients with MM. Compared to male sex, females had significantly improved OS (p = 0.003) when tested in univariable testing. Multivariable analyses, controlling for age, performance status, lactate dehydrogenase level, BRAF status, M-stage, and number of metastatic sites revealed significant favourable outcomes associated with female sex irrespective of the considered survival metrics (pPFS = 0.014, pOS = 0.002, and pMSS = 0.03). The observed five-year OS rates of the entire cohort were 47% and 38%, while melanoma-specific survival were 50% and 45% for female and male, respectively.CONCLUSION: In this nationwide cohort of patients with MM undergoing first-line ICI treatment females exhibited superior treatment outcomes compared to males. Sex was identified as an independent predictive variable for treatment outcomes, irrespective of the chosen outcome measures considered. Our analyses are not able to conclude whether the differences in outcome is attributable to differences in biology or to treatment strategy.</p

Long-term clinical outcome of patients with metastatic melanoma and initial stable disease during anti-PD-1 checkpoint inhibitor immunotherapy with pembrolizumab

Background: A substantial number of patients with metastatic melanoma (MM) treated with anti-PD-1 monotherapy have initial stable disease (SD), yet the real-world prognosis of these patients remains unclear. Methods: In this nationwide cohort study, we analysed real-world outcomes of patients with MM treated with pembrolizumab in Denmark. Focusing on patients with initial SD, we assessed best overall response (BOR), progression-free survival (PFS), and overall survival (OS) and identified predictors of survival in multivariable analyses. Results: Out of 1048 included patients, 233 (22.2%) had initial SD with a median PFS and OS of 14.7 and 50.1 months. Subsequent partial response (PR) or complete response (CR) was developed by 44 (18.9%) and 52 (22.3%) patients showing significantly improved PFS compared to patients with continued SD (PR: HR 0.52, 95% CI 0.34–0.81, p = 0.003; CR: HR 0.15, 95% CI 0.07–0.32, p &lt; 0.001) and survival rates comparable to patients with initial PR and CR, respectively. Furthermore, 49 (21.0%) patients showed continued disease control (median follow-up of 82.3 months). For 51.0% of these patients, the last dose of pembrolizumab was administered during SD with a median treatment duration of 12.4 months. Conclusions: Of patients with initial SD, 40% developed a subsequent objective response with improved long-term prognosis comparable to patients with initial response. More than 20% exhibited continued disease control.</p

Total Thyroidectomy for Thyroid Cancer Followed by Thyroid Storm due to Thyrotropin Receptor Antibody Stimulation of Metastatic Thyroid Tissue

BACKGROUND: Graves disease (GD) is an autoimmune condition characterized by the presence of antibodies against the thyrotropin receptor (TRAB), which stimulate the thyroid gland to produce excess thyroid hormone. Theoretically, TRAB could stimulate highly differentiated thyroid cancer tissue and/or metastases to produce thyroid hormone.CASE: A 68-year-old male, with weight loss and palpitations, was diagnosed with thyrotoxicosis. A later MRI, due to persistent shoulder pain, revealed multiple bone metastases. A biopsy was diagnostic for follicular variant of papillary thyroid carcinoma, and total thyroidectomy was performed. One week after thyroidectomy the patient was admitted with severe hyperthyroidism. TRAB was &gt;40 IU/mL (normal &lt;0.7 IU/mL). High-dose antithyroid drug treatment was followed by high-dose radioactive iodine-131 (RAI) and local radiotherapy covering the right shoulder. Antithyroid drug treatment continued until after the fourth RAI dose. Hypothyroidism did not occur until following the fifth RAI treatment.SUMMARY AND CONCLUSIONS: We present a patient initially diagnosed with thyrotoxicosis and subsequently with metastatic follicular variant of papillary thyroid cancer. It is suggested that TRAB stimulated the highly differentiated extrathyroidal metastatic thyroid tissue to produce excessive amounts of thyroid hormone, delayed diagnosis, and potential aggravation of the course of thyroid cancer.</p

Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer:Post Hoc Analysis From the ZETA Trial

PURPOSE We conducted a post hoc analysis of the vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of vandetanib in patients with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients. PATIENTS AND METHODS Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated. RESULTS Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64; P, .0001), OS (HR, 1.08; 95% CI, 0.72 to 1.61; P 5 .71), and TWP (HR, 0.67; 95% CI, 0.43 to 1.04; P 5 .07), and the observed adverse events were consistent with the known safety profile of vandetanib. In this subgroup, the ORR was 37% in the treatment arm versus 2% in the placebo arm. CONCLUSION Vandetanib demonstrated clinical benefit—specifically, increased PFS—in patients with symptomatic and progressive MTC.</p