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Background: In non-small cell lung cancer (NSCLC), the immune checkpoint inhibitors (ICI) revolution is rapidly moving from metastatic to early-stage, however, the impact of clinicopathological variables and optimal treatment sequencing remain unclear., Methods: Randomized controlled trials (RCTs) in patients with early-stage NSCLC treated with ICI as single agent or in combination with platinum-based chemotherapy (PCT) were included. Primary outcomes were pathological complete response (pCR), event free survival (EFS) (neoadjuvant/perioperative), and disease-free survival (DFS) (adjuvant). Secondary outcomes were major pathological response (MPR), overall survival (OS), toxicity, surgical outcomes (neoadjuvant/perioperative); OS and toxicity (adjuvant). An additional secondary endpoint was to compare EFS and OS between neoadjuvant and perioperative strategies., Results: 8 RCTs (2 neoadjuvant, 4 perioperative, 2 adjuvant) (4661 participants) were included. Neoadjuvant/perioperative ICI+PCT significantly improved pCR, EFS, OS, MPR and R0 resection compared to PCT. Adjuvant ICI significantly improved DFS compared to placebo. There was a significant subgroup interaction by PD-L1 status (χ 2 = 10.72, P = 0.005), pCR (χ 2 = 17.80, P < 0.0001), and stage (χ 2 = 4.46, P = 0.003) for EFS. No difference according to PD-L1 status was found for pCR, with 14% of patients having PD-L1 negative tumors still experiencing a pCR. No interaction by PD-L1 status was found for DFS upon adjuvant ICI. Indirect comparison showed no difference in EFS and OS between neoadjuvant and perioperative ICI+PCT., Conclusions: PD-L1 status, pCR and stage impact on survival upon neoadjuvant/perioperative ICI. The restriction of neoadjuvant/perioperative ICI to PD-L1 + patients could preclude pCR and long-term benefit in the PD-L1- subgroup. Neoadjuvant and perioperative could be equivalent strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T.C. reports (over the past 36 months) speaker fees/honoraria from the Society for Immunotherapy of Cancer (SITC), Mark Foundation for Cancer Research, Bristol Myers Squibb, Roche, Medscape, IDEOlogy Health, Physicians' Education Resource® LLC (PER®), OncLive, PeerView and Clinical Care Options (CCO); advisory role/consulting fees from MedImmune/AstraZeneca, Bristol Myers Squibb, Merck & Co., Genentech, Arrowhead Pharmaceuticals, Pfizer Inc. and Regeneron; institutional research funding from MedImmune/AstraZeneca and Bristol Myers Squibb; and travel, food and/or beverage expenses from Physicians' Education Resource® LLC (PER®), Dava Oncology, SITC, International Association for the Study of Lung Cancer, Parker Institute for Cancer Immunotherapy, IDEOlogy Health, OncLive, AstraZeneca and Bristol Myers Squibb.M.C.G. reports AstraZeneca, Abion, MSD International GmbH, Bayer, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Blueprint, Jansenn, Sanofi, AbbVie, BeiGenius, Oncohost, Medscape G.V. is consultant for Ab Medica, Roche, AstraZeneca, MSD, outside the submitted work R.F. reports advisory board for MSD and advisory board for BeiGene M.R. declares grants or contracts from AstraZeneca and participation on a Data Safety Monitoring Board or Advisory Board for Eli Lilly, PANAVANCE, Celgene, AstraZeneca, Viatris, Merck Sharp & Dohme, Servier, SOTIO, and Baxter. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The early crossing of survival curves in randomised clinical trials (RCTs) with immune checkpoint blockers suggests an excess of mortality in the first months of treatment. However, the exact estimation of the early death (ED) rate, the comparison between ED upon immune checkpoint inhibitors (ICI) alone or in combination with other agents and the impact of tumour type, and PD-L1 expression on ED are unknown., Methods: RCTs comparing ICI alone (ICI-only group) or in combination with other non-ICI therapies (ICI-OT group) (experimental arms) versus non-ICI treatments (control arm) were included. ED was defined as death within the first 3 months of treatment. The primary outcome was the comparison of ED between experimental and control arms, and the secondary outcome was the comparison of ED risk between ICI-only and ICI-OT. ED rates estimated by risk ratio (RR) were pooled by random effect model., Results: A total of 56 RCTs (40,215 participants, 14 cancer types) were included. ED occurred in 14.2% and 6.7% of patients in ICI-only and ICI-OT groups, respectively. ED risk significantly increased with ICI-only (RR: 1.29, 95% CI 1.05-1.57) versus non-ICI therapies, while it was lower with ICI-OT versus non-ICI treatments (RR: 0.81, 95% CI 0.73-0.90). ED risk was significantly higher upon ICI-only compared to ICI-OT (RR: 1.57, 95% CI 1.26-1.95). Gastric and urothelial carcinoma were at higher risk of ED. PD-L1 expression and ICI drug classes were not associated with ED., Conclusions: ED upon first-line ICI is a clinically relevant phenomenon across solid malignancies, not predictable by PD-L1 expression but preventable through the addition of other treatments to ICI., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Matteo Lambertini: advisory role for Roche, Lilly, Novartis, Pfizer, Astrazeneca, MSD, Seagen, Gilead and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Ipsen, Libbs, Knight. Dr Raimondo Di Liello: consultant Janssen, educational Astellas. Dr Martina Imbimbo: independent safety board member for Immatics. Dr Carminia Maria Della Corte: advisory board for MSD and Astrazeneca. Prof Floriana Morgillo: BMS, MSD, Astrazeneca, Incyte (Consultory/Advisory relationship). Dr Giuseppe Lo Russo: personal fees from AstraZeneca, Italfarmaco, Lilly, Novartis, Pfizer, and Roche; support for attending meetings/travel from Bristol-Myers Squibb, Italfarmaco, Merck Sharp & Dohme, and Roche; and participation as a DSMB or advisory board member for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Sanofi. Dr Claudia Proto: personal fees from BMS and MSD. Dr Arsela Prelaj: personal fees from Roche, AstraZeneca and BMS. Dr Diego Signorelli: personal fees from Astrazeneca, BMS, MSD, Sanofi, Boehringer Ingelheim, Roche. Prof Fortunato Ciardiello: Merck, Roche, Amgen, Bayer, Servier, Symphogen, Pfizer (Consultant/Avisory relationship), Roche, Merck, Amgen, Bayer, Ipsen (Research funding). Dr Nathalie Chaput: sponsored research from AstraZeneca, GSK, Roche, Sanofi, Cytune Pharma, Gilead, Servier. Lectures and educational activities: Gilead and Servier. Dr Jordi Remon: advisory board: MSD, Boehringer Ingelheim, BMS, Astrazeneca, Roche; Bayer, Janssen. Speaker: Pfizer, Janssen; travel reimbursement: Ose immunotherapeutics, BMS, Astrazeneca, Roche. Prof Benjamin Besse: grants from AstraZeneca, Pfizer, Eli Lilly, Onxeo, Bristol Myers Squibb, Inivata, AbbVie, Amgen, Blueprint Medicines, Celgene, GlaxoSmithKline, Ignyta, Ipsen, Merck KGaA, MSD Oncology, Nektar, PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Therapeutics, Cristal Therapeutics, Daiichi Sankyo, Janssen Oncology, OSE Immunotherapeutics, BeiGene, Boehringer Ingelheim, Genentech, Servier, Tolero Pharmaceuticals. Prof Filippo De Braud: Consultant Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini. Speaker: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, ACCMED, Nadirex, MSD, Pfizer, Servier, Sanofi, Roche, AMGEN, Incyte, Dephaforum. Principal Investigator for Novartis, F. Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Incorporated, DAICHI SANKIO Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA. Prof Marina Chiara Garassino: personal financial interests with the following organisations: AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S. p.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda; institutional financial interests with the following organisations: Eli Lilly, MSD, Pfizer (MISP), AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S. p.A, Celgene, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine; funding from the following organisations: AIRC, AIFA, Italian Moh, TRANSCAN. All the other authors have no conflicts to declare. Dr Roberto Ferrara: advisory board for Beigene and MSD. All the other authors (Dr Giuseppe Viscardi, Dr Antonino Carmelo Tralongo, Dr Francesco Massari, Dr Veronica Mollica, Dr Alessandro Rizzo, Dr Francesca Comito, Dr Salvatore Alfieri, Dr Vittorio Simeon, Dr Alessandro De Toma, Dr Giulia Galli, Dr Valter Torri, Dr Michela Cinquini) have no conflicts to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing 68 gallium-labelled somatostatin analogue ([ 68 Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing 18 fluorine-fluoro-2-deoxyglucose ([ 18 F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[ 68 Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [ 68 Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [ 18 F]FDG and [ 68 Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies., Competing Interests: Conflict of interest statement VA reports personal fees from ESMIT and AAA outside the submitted work and is a member of ENETS advisory board, ESMO faculty staff for NET and the scientific board of ITANET; JK reports personal fees from Bayer, outside the submitted work; LB reports non-paid consultant for AAA-Novartis, Ipson, Clovis Oncology, and Curium, and a research grant from AAA-Novaris; JC reports grants and personal fees from Bayer, Eisai, Advanced Accelerator Applications, and Ipsen, and grants from Astrazeneca, Novartis, Pfizer, Merck, Sanofi, Amgen, and Exelixis outside the submitted work; WDH reports personal fees and grants from Ipsen, personal fees from Novartis, and personal fees and grants, from AAA; CD reports consultancy/advisor for Ipsen; MaF reports personal fees from AAA, Novartis, Ipsen, and Celgene outside the submitted work; MeF reports personal fees and research funding from Ipsen; SF reports personal fees from ANMI, Astellas, Bayer, BlueEarth Diagnostics, GE Healthcare, Jenssen, Novartis, Sofie Biosciences, non-financial support from AAA, Bayer, GE Healthcare, Curium, Tema Sinergie, Sanofi, Telix, outside the submitted work; RJH reports holding shares in Telix Pharmaceuticals on behalf of his institution and receiving research funding from Ispen and ITM; VL reports advisory board member of AAA and Ipsen; DOT reports personal fees from Novartis, IPSEN, AstraZeneca and grants from Wyeth Lederle and Ipsen outside the submitted work; MP reports personal fees from AAA, Pfizer, and Riemser and grants and personal fees from Novartis and IPSEN outside the submitted work; RS reports consultancy for AAA, Ipsen, Novartis, ITM and Keocyt and participation in the NETTER 1 and COMPETE Trials; JS reports consultant for Novartis and speaker's bureau for Ipsen and Lexicon outside the submitted work; DT reports personal fees from AAA/Novartis, IPSEN and Sanofi-Genzyme, outside the submitted work; DW reports personal fees from Ipsen and grants form Siemens Healthineers and Debiopharm International S.A; KH reports personal fees from Bayer, other from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymabs, outside the submitted work; JY reports financial activities with Advanced Accelerated Applications (AAA), Chiasma, Crinetics, Hutchison MediPharma, Ipsen, Merck, Novartis, and Tarvedin. EB, CB, SM, MiC, MC, LK, GK, KO, WO, ASc, ASu, and IV declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Premenopausal women with hormone receptor-positive early breast cancer are candidates for adjuvant endocrine therapy, as recommended by the major international guidelines. To date, adjuvant endocrine options for premenopausal women include tamoxifen with or without ovarian function suppression (OFS) or an aromatase inhibitor with OFS. Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed, and the results of randomised clinical trials have been reported over the last years. Despite this evidence, the optimal algorithm for endocrine therapy for premenopausal women with hormone receptor-positive early stage invasive breast cancer shows open questions regarding the role of OFS in addition to tamoxifen and the optimal use of hormonal agents. The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer applied the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology on three critical questions on the choice of the adjuvant hormonal therapy in premenopausal breast cancer patients to summarise available evidence and to create recommendations to help physicians in their clinical practice., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The development of premature ovarian failure and subsequent infertility are possible consequences of chemotherapy use in pre-menopausal women with early-stage breast cancer. Among the available strategies for fertility preservation, pharmacological protection of the ovaries using luteinising hormone-releasing hormone analogues (LHRHa) during chemotherapy has the potential to restore ovarian function and fertility after anticancer treatments; however, the possible efficacy and clinical application of this strategy has been highly debated in the last years. Following the availability of new data on this controversial topic, the Panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guideline on fertility preservation in cancer patients decided to apply the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology around the relevant and current question on the clinical utility of temporary ovarian suppression with LHRHa during chemotherapy as a strategy to preserve ovarian function and fertility in breast cancer patients. To answer this question, preservation of ovarian function and fertility were judged as critical outcomes for the decision-making. Three possible outcomes of harm were identified: LHRHa-associated toxicities, potential antagonism between concurrent LHRHa and chemotherapy, and lack of the prognostic impact of chemotherapy-induced premature ovarian failure. According to the GRADE evaluation conducted, the result was a strong positive recommendation in favour of using this option to preserve ovarian function and fertility in breast cancer patients. The present manuscript aims to update and summarise the evidence for the use of this strategy in light of the new data published up to January 2016, according to the GRADE process., (Copyright © 2016 Elsevier Ltd. All rights reserved.)