18F-fluorodeoxyglucose positron emission tomography/computed tomography and magnetic resonance imaging in patients with liver metastases from uveal melanoma: results from a pilot study.

PURPOSE: F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and MRI are used for detecting liver metastases from uveal melanoma. The introduction of new treatment options in clinical trials might benefit from early response assessment. Here, we determine the value of FDG-PET/CT with respect to MRI at diagnosis and its potential for monitoring therapy. MATERIAL AND METHODS: Ten patients with biopsy-proven liver metastases of uveal melanoma enrolled in a randomized phase III trial (NCT00110123) underwent both FDG-PET coupled with unenhanced CT and gadolinium-diethylene triamine pentaacetic acid-enhanced liver MRI within 4 weeks. FDG-PET and MRI were evaluated blindly and then compared using the ratio of lesion to normal liver parenchyma PET-derived standardized uptake value (SUV). The influence of lesion size and response to chemotherapy were studied. RESULTS: Overall, 108 liver lesions were seen: 34 (31%) on both modalities (1-18 lesions/patient), four (4%) by PET/CT only, and 70 (65%) by MRI only. SUV correlated with MRI lesion size (r=0.81, P<0.0001). PET/CT detected 26 of 33 (79%) MRI lesions of more than or equal to 1.2 cm, whereas it detected only eight of 71 (11%) lesions of less than 1.2 cm (P<0.0001). MRI lesions without PET correspondence were small (0.6±0.2 vs. 2.1±1.1 cm, P<0.0001). During follow-up (six patients, 30 lesions), the ratio lesion-to-normal-liver SUV diminished in size-stable lesions (1.90±0.64-1.46±0.50, P<0.0001), whereas it increased in enlarging lesions (1.56±0.40-1.99±0.56, P=0.032). CONCLUSION: MRI outweighs PET/CT for detecting small liver metastases. However, PET/CT detected at least one liver metastasis per patient and changes in FDG uptake not related to size change, suggesting a role in assessing early therapy response

FDG PET and MR imaging in patients with liver metastases from uveal melanoma : results from a pilot study

Le présent travail a eu comme but la comparaison de la performance de deux méthodes d'imagerie diagnostique pour la détection de métastases hépatiques du mélanome uvéal : la tomographie d'émission par positons au F-18-fluorodésoxyglucose (TEP FDG) couplée à la tomodensitométrie (TDM) et l'imagerie par résonance magnétique (IRM). Dans cette étude rétrospective, nous avons analysé les données radiologiques de patients inclus dans une étude multicentrique randomisée de phase III de l'Uveal Melanoma Group of the European Organization for Research and Treatment of Cancer (EORTC). L'IRM s'est révélée nettement plus sensible que le FDG-PET/CT pour mettre en évidence les métastases hépatiques notamment de taille infra-centimétrique. Néanmoins, l'analyse des changements de l'accumulation du traceur métabolique par les métastases hépatiques au cours du traitement suggère la possibilité d'évaluer, de manière précoce, la réponse des métastases hépatiques à la chimiothérapie. Le nombre de cas étudiés est trop faible pour déterminer la précision et la valeur clinique d'une telle évaluation mais les résultats obtenus dans cette étude pilote justifient une étude plus étendue

Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor.

PURPOSE: Positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) was used to evaluate treatment response in patients with gastrointestinal stromal tumors (GIST) after administration of sunitinib, a multitargeted tyrosine kinase inhibitor, after imatinib failure. PATIENTS AND METHODS: Tumor metabolism was assessed with FDG-PET before and after the first 4 weeks of sunitinib therapy in 23 patients who received one to 12 cycles of sunitinib therapy (4 weeks of 50 mg/d, 2 weeks off). Treatment response was expressed as the percent change in maximal standardized uptake values (SUV). The primary end point of time to tumor progression was compared with early PET results on the basis of traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Progression-free survival (PFS) was correlated with early FDG-PET metabolic response (P < .0001). Using -25% and +25% thresholds for SUV variations from baseline, early FDG-PET response was stratified in metabolic partial response, metabolically stable disease, or metabolically progressive disease; median PFS rates were 29, 16, and 4 weeks, respectively. Similarly, when a single FDG-PET positive/negative was considered after 4 weeks of sunitinib, the median PFS was 29 weeks for SUVs less than 8 g/mL versus 4 weeks for SUVs of 8 g/mL or greater (P < .0001). None of the patients with metabolically progressive disease subsequently responded according to RECIST criteria. Multivariate analysis showed shorter PFS in patients who had higher residual SUVs (P < .0001), primary resistance to imatinib (P = .024), or nongastric GIST (P = .002), regardless of the mutational status of the KIT and PDGFRA genes. CONCLUSION: Week 4 FDG-PET is useful for early assessment of treatment response and for the prediction of clinical outcome. Thus, it offers opportunities to individualize and optimize patient therapy

Guillain-Barré syndrome after adoptive cell therapy with tumor-infiltrating lymphocytes.

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a promising experimental immunotherapy that has shown high objective responses in patients with melanoma. Current protocols use a lymphodepletive chemotherapy before infusion of ex vivo expanded TILs, followed by high-dose interleukin-2 (IL-2). Treatment-related toxicities are mainly attributable to the chemotherapy regimen and to the high-dose IL-2 and are generally reversible. Neurological side effects have rarely been described. Nevertheless, due to improvements in cell production techniques and due to combinations with other immunomodulating molecules, side effects not previously described may be encountered. We report the case of a 53-year-old heavily pretreated patient with melanoma who developed Guillain-Barré syndrome (GBS) 19 days after ACT using autologous TILs, given in the context of a phase I trial. He presented with dorsal back pain, unsteady gait and numbness in hands and feet. Lumbar puncture showed albuminocytological dissociation, and nerve conduction studies revealed prolonged distal motor latencies in median, ulnar, tibial and peroneal nerves, compatible with a GBS. The patient was treated with intravenous immunoglobulins and intensive neurological rehabilitation, with progressive and full recovery at 21 months post-TIL-ACT. Concomitant to the onset of GBS, a cytomegalovirus reactivation on immunosuppression was detected and considered as the most plausible cause of this neurological side effect. We describe for the first time a case of GBS occurring shortly after TIL-ACT for melanoma, even though we could not identify with certainty the triggering agent. The report of such rare cases is of extreme importance to build on the knowledge of immune cellular therapies and their specific spectrum of toxicities

Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: A systematic review and meta-analysis

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis to assess its efficacy on previously treated advanced metastatic cutaneous melanoma. The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant interleukin-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary end point. Secondary end points were complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was carried out separately for high dose (HD) and low dose (LD) IL-2. Sensitivity analyses were carried out. Among 1211 records screened, 13 studies (published 1988 - 2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% [95% confidence interval (CI) 35% to 48%], and the overall CRR was 12% (95% CI 7% to 16%). For the HD-IL-2 group, the ORR was 43% (95% CI 36% to 50%), while for the LD-IL-2 it was 35% (95% CI 25% to 45%). Corresponding pooled estimates for CRR were 14% (95% CI 7% to 20%) and 7% (95% CI 1% to 12%). The majority of HD-IL-2 complete responders (27/28) remained in remission during the extent of follow-up after CR (median 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably with the nivolumab/ipilimumab combination following anti-PD-1 failure. TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach. © 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved

Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis.

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis to assess its efficacy on previously treated advanced metastatic cutaneous melanoma. The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant interleukin-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary end point. Secondary end points were complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was carried out separately for high dose (HD) and low dose (LD) IL-2. Sensitivity analyses were carried out. Among 1211 records screened, 13 studies (published 1988 - 2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% [95% confidence interval (CI) 35% to 48%], and the overall CRR was 12% (95% CI 7% to 16%). For the HD-IL-2 group, the ORR was 43% (95% CI 36% to 50%), while for the LD-IL-2 it was 35% (95% CI 25% to 45%). Corresponding pooled estimates for CRR were 14% (95% CI 7% to 20%) and 7% (95% CI 1% to 12%). The majority of HD-IL-2 complete responders (27/28) remained in remission during the extent of follow-up after CR (median 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably with the nivolumab/ipilimumab combination following anti-PD-1 failure. TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach

Oncologie [2021 Oncology update]

Despite COVID-19 pandemic, which is still deeply affecting world economy and global health, medical oncology specialists keep pursuing their effort for the identification of new therapeutic options to improve patients' life expectancy and quality of life. 2021 confirms the immunotherapy efficacy, alone or in combination with other modalities, across several indications. This year, we are summarizing the new approaches in the following sectors: lung, breast, melanoma, gynecological, digestive, urological and ENT areas

Optimizing Oral Targeted Anticancer Therapies Study for Patients With Solid Cancer: Protocol for a Randomized Controlled Medication Adherence Program Along With Systematic Collection and Modeling of Pharmacokinetic and Pharmacodynamic Data.

The strengthening or substitution of intravenous cytotoxic chemotherapy cycles by oral targeted anticancer therapies, such as protein kinase inhibitors (PKIs), has provided impressive clinical benefits and autonomy as well as a better quality of life for patients with cancer. Despite these advances, adverse event management at home and medication adherence remain challenging. In addition, PKI plasma concentrations vary significantly among patients with cancer receiving the same dosage, which could explain part of the observed variability in the therapeutic response. The aim of this optimizing oral targeted anticancer therapies (OpTAT) study is to optimize and individualize targeted anticancer treatments to improve patient care and self-monitoring through an interprofessional medication adherence program (IMAP) combined with measurement PKI plasma concentrations. The OpTAT study has two parts: (1) a 1:1 randomized medication adherence program, in which the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKIs in electronic monitors, and (2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. On the basis of the electronic monitor data, medication adherence will be compared between groups following the three operational definitions: implementation of treatment during the persistent period, persistence with treatment and longitudinal adherence. The implementation will be described using generalized estimating equation models. The persistence of PKI use will be represented using a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. PKI pharmacokinetics will be studied using a population approach. The relationship between drug exposure and efficacy outcomes will be explored using Cox regression analysis of progression-free survival. The relationship between drug exposure and toxicity will be analyzed using a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic analyses will be applied to evaluate the best exposure threshold associated with clinical benefits. The first patient was included in May 2015. As of June 2021, 262 patients had participated in at least one part of the study: 250 patients gave at least one blood sample, and 130 participated in the adherence study. Data collection is in process, and the final data analysis is planned to be performed in 2022. The OpTAT study will inform us about the effectiveness of the IMAP program in patients with solid cancers treated with PKIs. It will also shed light on PKI pharmacokinetic and pharmacodynamic properties, with the aim of learning how to adapt the PKI dosage at the individual patient level to increase PKI clinical suitability. The IMAP program will enable interprofessional teams to learn about patients' needs and to consider their concerns about their PKI self-management, considering the patient as an active partner. ClinicalTrials.gov NCT04484064; https://clinicaltrials.gov/ct2/show/NCT04484064. DERR1-10.2196/30090