Search

Background: Forty to fifty percent of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) relapse despite multimodal treatment. Circulating tumor DNA (ctDNA) has the potential to detect minimal residual disease (MRD) after curative-intent therapy and to identify earlier which patients will progress. We developed a tumor-agnostic plasma ctDNA assay to detect MRD in unselected LA SCCHN with the aim of predicting progression-free survival (PFS) and overall survival without the need for tumor sequencing., Patients and Methods: A 26-gene next-generation sequencing panel was constructed that included the most frequently mutated genes in SCCHN and two HPV-16 genes. MRD was assessed in each patient through an in-house informatic workflow informed by somatic mutations identified in the corresponding pre-treatment plasma sample. The presence of MRD was defined as the detection of ctDNA in one plasma sample collected within 1-12 weeks of the end of curative treatment. The primary endpoint was the PFS rate at 2 years. At least 32 patients were planned for inclusion with the hypothesis that PFS at 2 years was >80% in MRD-negative patients and <30% in MRD-positive patients (α = 0.05, β = 0.9)., Results: We sequenced DNA from 116 plasma samples derived from 53 LA SCCHN patients who underwent curative-intent treatment. ctDNA was detected in 41/53 (77%) patients in the pre-treatment samples. Out of these 41 patients, 17 (41%) were MRD positive after treatment. The 2-year PFS rate was 23.53% (9.9% to 55.4%) and 86.6% (73.4% to 100%) in MRD-positive and MRD-negative patients, respectively (P < 0.05). Median survival was 28.37 months (14.30 months-not estimable) for MRD-positive patients and was not reached for the MRD-negative cohort (P = 0.011)., Conclusions: Our ctDNA assay detects MRD in LA SCCHN and predicts disease progression and survival without the need for tumor sequencing, making this approach easily applicable in daily practice., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: In the phase 3 KEYNOTE-040 study, pembrolizumab prolonged OS versus chemotherapy in previously treated recurrent or metastatic (R/M) HNSCC. We present a post hoc subgroup analysis by disease recurrence pattern: recurrent-only, recurrent and metastatic (recurrent-metastatic), and metastatic-only HNSCC., Materials and Methods: Patients had HNSCC that progressed during or after platinum-containing treatment for R/M disease or had recurrence or progression within 3-6 months of previous platinum-containing definitive therapy for locally advanced disease. Patients were randomly assigned (1:1) to pembrolizumab 200 mg Q3W or investigator's choice of standards of care (SOC): methotrexate, docetaxel, or cetuximab. Outcomes included OS, PFS, ORR, and DOR. The data cutoff was May 15, 2017., Results: There were 125 patients (pembrolizumab, 53; SOC, 72) in the recurrent-only subgroup, 204 in the recurrent-metastatic subgroup (pembrolizumab, 108; SOC, 96), and 166 in the metastatic-only subgroup (pembrolizumab, 86; SOC, 80). The hazard ratio (95% CI) for death for pembrolizumab versus SOC was 0.83 (0.55-1.25) in the recurrent-only, 0.78 (0.58-1.06) in the recurrent-metastatic, and 0.74 (0.52-1.05) in the metastatic-only subgroups. PFS was similar between treatment arms in all subgroups. ORR was 22.6% for pembrolizumab versus 16.7% for SOC in the recurrent-only, 10.2% versus 6.3% in the recurrent-metastatic, and 15.1% versus 8.8% in the metastatic-only subgroups. DOR was numerically longer with pembrolizumab in all subgroups., Conclusion: Pembrolizumab provided numerically longer OS and durable responses in all subgroups compared with SOC, suggesting that patients with previously treated R/M HNSCC benefit from pembrolizumab regardless of recurrence pattern., Competing Interests: Declaration of Competing Interest KJH reports honoraria from BMS, Merck-Serono, MSD, and Replimune; advisory/consultancy roles with Arch Oncology, AstraZeneca, BMS, Boehringer-Ingelheim, Codiak, Eisai, Inzen, Merck-Serono, MSD, Oncolys, Pfizer, and Replimune; speaker bureau for BMS, Merck-Serono, MSD, and Replimune; and research grant/funding from AstraZeneca, Boehringer-Ingelheim, and Replimune. EEWC reports advisory/consultancy roles with Axelia, Cel Sci, Eisai, Hoopika, ImmunoSensor, Istari, Janssen, Kahr Medical, Mana Therapeutics, Merck, Mirati, MSD, Nectin Tx, Pangea Therapeutics, and Roche; is a member of the board of directors for Psiouxus Therapeutics, and NCCN; has stock/shares with Kinnate Biopharma and Primmune Therapeutics; and has a leadership role with Ayala, Kura, and Kinnate Biopharma DS reports advisory/consultancy roles with Merck and Adlai-Nortye and research grant/funding from Merck, GSK, Adlai-Nortye, and BMS. JD reports advisory/consultancy role with Roche, PharmaMar, BMS, Merck Serono, and MSD; is a principal investigator for studies from Roche, BI, and MSD; and travel expenses from PharmaMar. LL reports research funding from Astrazeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La Roche ltd, IRX Therapeutics, Medpace, Merck-Serono, MSD, Novartis, Pfizer, Roche, and Buran; and occasional fees for participation as a speaker at conferences/congresses or as a scientific consultant for advisory boards from Astrazeneca, Bayer, MSD, Merck-Serono, AccMed, and Neutron Therapeutics, Inc. MJA reports honoraria from AstraZeneca, Lilly, MSD, Merck, TAKEDA, ONO, Amgen, YUHAN, and Roche; advisory/consultancy roles with AstraZeneca, Lilly, MSD, Merck, TAKEDA, ONO, Amgen, YUHAN, Roche, and Alpha Pharmaceuticals; and research grant/funding from YUHAN. AS reports honoraria from MSD, Merck Serono, Novartis Pharma, Bristol Myers Squibb, Pierre Fabre, and Sanofi; and advisory/consultancy roles with MSD, Merck Serono, Novartis Pharma, Bristol Myers Squibb, Pierre Fabre, and Sanofi. JPM reports advisory/consultancy roles with Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boerhinger, BMS, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, NEKTAR, F-Star, Seagen, Genmab, Astellas, and Psioxius; leadership roles with the EORTC head and neck group (Chair); travel/accommodation/expenses from Amgen, BMS, Pfizer, MSD, and Gilead; and non-remunerated activities with MSD (Advisory board). NM reports being a co-founder and shareholder MaxiVAX, a personalized cancer immunotherapy biotech, with ongoing Phase IIa in patients with advanced Head & Neck cancer; and being the Chief Medical Officer at MaxiVAX. RM reports advisor/consultancy role for Janssen, AstraZeneca (uncompensated), Coherus and Rakuten Medical; and research funding from Merck. BB reports advisory/consultancy roles with Genentech, Glaxo Smith Kline, Nektar, Debio, Merck KgA, Astra Zeneca,Vaccinex, Exelexis, Cue BioPharma, Fusion, Arvinas, Coherus, ALX Oncology, Hookipa Kura, Astra Zeneca/Medimmune, Nektar, and Roche; and research grant/funding from Cue Biopharma, Merck, Gilead, Exelexis, and Vaccinex. RFS reports employment at the time of the study at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; current employment at Carisma Therapeutics. JL reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stock ownership in Merck & Co., Inc., Rahway, NJ, USA. JG reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stock ownership in Merck & Co., Inc., Rahway, NJ, USA. NL reports employment at Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stock ownership in Merck & Co., Inc., Rahway, NJ, USA. CLT reports honoraria from MSD, BMS, Merck Serono, Celgene, Astra Zeneca, Seattle Genetics, Maxivax, Seagen, and Roche; research grant/funding from MSD; and travel/accommodation/expenses from MSD, Merck Serono, Astra Zeneca, and BMS., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC., Patients and Methods: Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed., Results: Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively., Conclusions: In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC., Competing Interests: Disclosure AP has received research funding from Bristol Myers Squibb, DEMO, KURA Oncology, and Roche and consultant/advisory/honoraria fees from AstraZeneca, Bristol Myers Squibb, HPVtRNA, Merck Serono, MSD, Nanobiotics, and Pfizer companies. JF has served in a consulting or advisory role for Bristol Myers Squibb, Innate Pharma, Merck, Merck Sharp & Dohme, Rakuten, and Roche and has received non-financial support from Bristol Myers Squibb and Merck Sharp & Dohme. KH has received research funding from AstraZeneca, Boehringer Ingelheim, MSD, and Replimune, and consultant/advisory/honoraria fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Codiak, Inzen, Merck Serono, Mersana Therapeutics, MSD, Pfizer, and Replimune. MG has received research funding from Agenus, Bristol Myers Squibb, Cullinan Labs, Genentech, Genocea Biosciences Inc., Kura, LaRoche, NRG, and University of Cincinnati. She has received consulting fees from Amgen Inc., Aspyrian Therapeutics, AstraZeneca Pharmaceuticals, Bayer Healthcare Pharmaceutics, Bicara Therapeutics, Bicara, BioNtech AG, Bristol Myers Squibb, Celgene Corp, Coherus Biosciences, Debiopharm, Eisai Medical Research Inc., EMD Serono, Inc., Genocea Biosciences Inc., Gilead Sciences Inc., Ipsen Biopharmaceuticals Inc., Istari Oncology Inc., iTeos Therapeutics, Kura Oncology, LLX Solutions, LLC, Merck & Co, Mirati Therapeutics, Nektar Therapeutics, NewLink Genetics Corp., OncLive Intellisphere, Roche Diagnostics GmbH, Roche, Seagen, Sensei Biotherapeutics Inc., Shattuck Labs Inc., and TRM Oncology. She received honoraria from OncLive and Roche. She has received support for attending meetings and/or travel from AACR, ASCO, and SITC. She reports an issued patent for NGVL4a-Sig/E7(detox)/HSP70 plasmid DNA for a clinical protocol entitled ‘An open-label phase one study of the safety with stage III or IV HPV16-positive head and neck squamous cell carcinoma’ and pending patents for oral HPV infection detection for oral cancer screening and diagnosis, and for HPV mRNA detection on oral cytology specimens for diagnosis and screening for oral cancer. She reports participation on a data safety monitoring board or advisory board for BioMimetix, Kura, NRG, Seagen, Sensei Biotherapeutics Inc., and SQZBiotech. She reports stock options with Sensei. MJA has received honoraria from AstraZeneca, Bristol Myers Squibb, MSD, ONO, and Roche and is a consultant or advisor for AstraZeneca, Bristol Myers Squibb, Takeda, MSD, Novartis, Roche, and Alpha pharmaceutical. ST reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from Eisai, Novartis, Taiho, MSD, Chugai, Bayer, and Daiichi-Sankyo, outside the submitted work. JW has stock and other ownership interests in Achilles Therapeutics, Nektar Therapeutics, Vesselon, Nuvalent, En Fuego Therapeutics, and Lyell Immunopharma. He has a consulting or advisory role with AstraZeneca, EMD Serono, Genentech, G1 Therapeutics, Jounce Therapeutics, AbbVie, Nanobiotix, Azitra, Eli Lilly, Blueprint Medicines, Pfizer, Saatchi Wellness, Jazz Pharmaceuticals, Boehringer Ingelheim, Regeneron, Genmab, SDP Oncology, and BeiGene. He has received research funding from Mirati Therapeutics, Sumitomo Dainippon Pharma Oncology, Boehringer Ingelheim, and PDS Biotechnology. His institution has received research funding from Amgen, G1 Therapeutics, Immunicum, Inspirna, and Loxo/Lilly. He has had travel, accommodations, or expenses paid by Mirati Therapeutics. JPM is an advisory board member or speaker with honoraria (institution managed) for: Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, and Nektar Therapeutics. He has accepted travel expenses from: Amgen, Bristol Myers Squibb, Pfizer, and MSD. He is on the data safety monitoring board with honoraria for Psioxus. His institutional conflict of interest (funding to institution for research support) includes all companies. He has an uncompensated advisory role with MSD. SB reports owning stock in Roche Holding AG and is an employee of Verana Health. SCT reports receiving grant or research support from AstraZeneca and Eisai and consultant fees from AstraZeneca. RH is an employee of Dana-Farber Cancer Institute and has a leadership role with NCCN. He is a consultant or advisor for Achilles Therapeutics, AstraZeneca, Bayer, BioNTech AG, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus Biosciences, Eisai, EMD Serono, Genentech, Gilead Sciences, GSK, Immunomic Therapeutics, Loxo, Merck, MIRATI, Pfizer, and Vaccinex. His institution has received research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Kura, Merck, and Pfizer. He has other relationships with ISA Pharmaceuticals and Nanobiotix. SK received honoraria from Merck Serono, MSD, Novartis, Bristol Myers Squibb, Amgen, Roche, Sanofi-Aventis, Servier, Incyte, and Lilly; research funding from Merck Serono, Lilly, Bristol Myers Squibb, and Roche. PSM received advisory/lecture honoraria from BMS, KLS Martin Group, and Roche. He has accepted travel expenses from: AstraZeneca, BMS, GSK, KLS Martin Group, MSD, and Roche. VB is a freelance contractor for, and shareholder in, AstraZeneca. PH, BE, SW, RFO, AY, JFK, and NM are or were employees and shareholders of AstraZeneca. SW and NM report published patent WO2021228988A1. TYS has received grants/research funding from AstraZeneca, Bristol Myers Squibb, CUE biopharma, Kura, Merck/MSD, Nanobiotix, Regeneron, and Roche/Genentech, as well as honoraria from Bayer, BioNTech/Syneos, Coherur Biosciences, Cue Biopharma, Innate, KURA, Merck/MSD, Nanobiotix, Sanofi, Vir Biotechnology. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Funding No external funding has been received for the preparation of this guideline. Production costs have been covered by ESMO from central funds.

Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN)., Patients and Methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME)., Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME., Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients., Competing Interests: Disclosure EG: Sanofi, Roche/Genentech, F. Hoffman La Roche, Ellipses Pharma, Neomed Therapeutics, Boehringer Ingelheim, Janssen Global Services, SeaGen, TFS, Alkermes, Thermo Fisher, Bristol Myers Squibb, MabDisovery, Novartis, AstraZeneca, Taiho, BeiGene, Merck Sharp & Dohme, Menarini, Glycotope. SL: Bristol Myers Squibb, Merck Serono, Bayer, Roche, Amgen, Servier, AstraZeneca, Lilly, Incyte, Daiichi-Sankyo, MSD. BM: Sanofi, Roche, BMS, Merck Serono, MSD, Pfizer, Astellas, Novartis, Bayer, Servier, AstraZeneca, Amgen, Janssen, Eisai, Eli Lilly, Pierre Farbre. VM: BMS, Bayer, Janssen, Pieris. MLY: Abbott, BMS, Gilead, Merck, AbbVie, Ascletis, Roche, Ipsen. EC: Nanobiotix, Novartis, BMS, Roche/Genentech, Servier, OncoDNA, Alkermes, PharmaMar, Beigene, PsiOxus Therapeutics, HM Hospitals Group and START Program, INTHEOS. JPM: Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer Ingelheim, BMS, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, Amgen, Pfizer, MSD, Psioxus Debio, Nanobiotix. AGM: GSK/Tesaro, Roche, AstraZeneca, Clovis, Genmab, Immunogen, MSD, Amgen, Oncoinvent, Merck/Pfizer, Pharmamar, SOTIO, GSK/Tesaro. LPA: MSD, BMS, Roche, AstraZeneca, Lilly, Merck, Novartis, Amgen, Incyte, Takeda, Bluprint, Bayer. CCL: BeiGene, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, Roche. DAR: Acerta Pharmaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, Omniox, Tragara, AbbVie, Advantagene, Amgen, Bayer, Bristol Myers Squibb, DelMar, Genentech/Roche, Merck, Monteris, Novocure, Regeneron. AS: Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, Merck Sharp & Dohme, Arqule, Sanofi, Takeda, Roche, AbbVie, Amgen, Celgene, AstraZeneca, Lilly, Sandoz, Novartis. RM, GA, FM, HL, QL, CC, NT, and SZL are employed by Sanofi and may hold stock and/or stock options in the company. CM: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion. All other authors have declared no conflicts of interest. Data sharing Qualified researchers can request access to patient-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report forms, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data-sharing criteria, eligible studies, and process for requesting access are at: https://www.vivli.org., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia., Competing Interests: Disclosure BK declares grants or contracts from Merck Sharp & Dohme (MSD) Oncology, Ono Pharmaceutical and AstraZeneca, consulting fees from AstraZeneca, MSD Oncology, ABL Bio, Genexine, Cellid, Handok, Celid, Trial Informatics and CBS Bio, payment or honoraria from MSD Oncology and Merck. J-PM declares consulting fees/honoraria from Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer, Bristol Myers Squibb (BMS), Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, TheRNA and NEKTAR, support for attending meetings and/or travel from Amgen, Pfizer and MSD and participation at a Safety or Advisory Board for PsiOxus. LL declares institutional grants or contracts from AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis Inc, Debiopharm International SA, Hoffman-La Roche Ltd., IRX Therapeutics Inc., Medpace Inc., Merck-Serono, MSD, Novartis, Pfizer, Roche Spa and Buran and receipt of honoraria or fees (for public speaking/teaching in medical meetings and/or for providing expert opinion in Advisory Boards) for AstraZeneca, Bayer, BMS, Eisai, MSD, Merck-Serono, Boehringer Ingelheim, Hoffman La Roche Ltd., Novartis, Roche, Debiopharm International SA, Sobi, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics and GlaxoSmithKline (GSK). CB declares payment or honoraria from Merck KGaA, BMS and Roche. MT declares consulting fees from Ono Pharmaceuticals, MSD, BMS and Merck Biopharma, and honoraria from Eisai, Ono Pharmaceuticals, BMS and Merck Biopharma. MA declares consulting fees from MSD, AstraZeneca, Eli Lilly, DKSH, Eisai, Roche, Novartis and Merck, payment or honoraria from MSD, AstraZeneca, Eli Lilly, DKSH, Eisai, Roche, Novartis and Merck, support for attending meetings and/or travel from MSD, Roche, Elekta/Abex and AstraZeneca, and is the president of the Malaysian Oncological Society. MKA declares honoraria for presentations from Pfizer and Boehringer Ingelheim, sponsorship for meetings from AstraZeneca, Boehringer Ingelheim and DKSH. QSNg declares support for attending meetings and or travel from BMS, Boehringer Ingelheim, MSD and Astellas, and participation in Safety or Advisory Boards for MSD and Boehringer Ingelheim. WIWZ declares honoraria for lectures from Amgen Malaysia, DKSH Malaysia, Eisai Malaysia, Eli Lilly Malaysia, Ipsen Malaysia, MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono Malaysia, Pfizer Malaysia and Roche Malaysia, travel grants from Amgen Malaysia, Celgene Malaysia, Eisai Malaysia, Eli Lilly Malaysia, MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche Malaysia, participation on an Advisory Board for Celgene Malaysia, Roche Malaysia, Eli Lilly Malaysia, Eisai Malaysia and MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a member of ASCO AP Regional Council and Greater Petaling Cancer City Challenge UICC. NK declares institutional grants or contracts from Ono Pharmaceutical, BMS, AstraZeneca, Pfizer, Chugai Pharmaceutical, Rakuten Medical, Bayer and Adlai Nortye, payment or honoraria from Ono Pharmaceutical, BMS, Merck Biopharma, MSD, Eisai and Bayer, participation on a Data Safety Monitoring Board or Advisory Board for Bayer and Adlai Nortye. GC declares institutional grants from Merck, consulting fees from BMS, Pfizer, MSD, AstraZeneca, Daichii Sankyo, Lilly, Novartis and Seattle Genetics, payment or honoraria from AstraZeneca, Roche and Daichii Sankyo. SP declares fees for consultancy/advisory roles from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, PharmaMar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, speaker roles for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Illumina, Imedex, Medscape, MSD, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda and the receipt of grants/research support: (Sub) investigator in trials (institutional financial support for trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics, Roche/Genentech. TWK declares institutional grants or contracts from Roche, and sanofi-aventis. TY declares institutional grants or contracts from Taiho Pharmaceutical, Sumitomo Dainippon, Ono Pharmaceutical, Chugai Pharmaceutical, Amgen, Parexel International, MSD, Daiichi-Sankyo and Sanofi. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues ( n = 21), independent unmatched tissues ( n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide ( n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents., (©2021 American Association for Cancer Research.)

Intelligent packaging is an emerging technology, aiming to improve the standard communication function of packaging. Radio frequency identification (RFID) assisted smart packaging is of high interest, but the uptake is limited as the market needs cost-efficient and sustainable applications. The integration of screen printed antennas and RFID chips as smart labels in reusable cardboard packaging could offer a solution. Although paper is an interesting and recyclable material, printing on this substrate is challenging as the ink conductivity is highly influenced by the paper properties. In this study, the best paper/functional silver ink combinations were first selected out of 76 paper substrates based on the paper surface roughness, air permeance, sheet resistance and SEM characterization. Next, a flexible high frequency RFID chip (13.56 MHz) was connected on top of screen printed antennas with a conductive adhesive. Functional RFID labels were integrated in cardboard packaging and its potential application as reusable smart box for third party logistics was tested. In parallel, a web-based software application mimicking its functional abilities in the logistic cycle was developed. This multidisciplinary approach to developing an easy-scalable screen printed antenna and RFID-assisted smart packaging application is a good example for future implementation of hybrid electronics in sustainable smart packaging.

Background: The viral pandemic coronavirus disease 2019 (COVID-19) has disrupted cancer patient management around the world. Most reported data relate to incidence, risk factors, and outcome of severe COVID-19. The safety of systemic anti-cancer therapy in oncology patients with non-severe COVID-19 is an important matter in daily practice., Methods: ONCOSARS-1 was a single-center, academic observational study. Adult patients with solid tumors treated in the oncology day unit with systemic anti-cancer therapy during the initial phase of the COVID-19 pandemic in Belgium were prospectively included. All patients (n = 363) underwent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) serological testing after the first peak of the pandemic in Belgium. Additionally, 141 of these patients also had a SARS-CoV-2 RT-PCR test during the pandemic. The main objective was to retrospectively determine the safety of systemic cancer treatment, measured by the rate of adverse events according to the Common Terminology Criteria for Adverse Events, in SARS-CoV-2-positive patients compared with SARS-CoV-2-negative patients., Results: Twenty-two (6%) of the 363 eligible patients were positive for SARS-CoV-2 by RT-PCR and/or serology. Of these, three required transient oxygen supplementation, but none required admission to the intensive care unit. Hematotoxicity was the only adverse event more frequently observed in SARS-CoV-2 -positive patients than in SARS-CoV-2-negative patients: 73% vs 35% (P < 0.001). This association remained significant (odds ratio (OR) 4.1, P = 0.009) even after adjusting for performance status and type of systemic treatment. Hematological adverse events led to more treatment delays for the SARS-CoV-2-positive group: 55% vs 20% (P < 0.001). Median duration of treatment interruption was similar between the two groups: 14 and 11 days, respectively. Febrile neutropenia, infections unrelated to COVID-19, and bleeding events occurred at a low rate in the SARS-CoV-2-positive patients., Conclusion: Systemic anti-cancer therapy appeared safe in ambulatory oncology patients treated during the COVID-19 pandemic. There were, however, more treatment delays in the SARS-CoV-2-positive population, mainly due to a higher rate of hematological adverse events.

Competing Interests: Disclosure PB reports receipt of advisory board or conference honoraria from Merck, Sanofi, Merck Sharp & Dohme, Sun Pharma, Angelini, AstraZeneca, Bristol Myers Squibb, Helsinn, GlaxoSmithKline. ATC reports receipt of grants/research support from Pfizer, Eli Lilly, Novartis, Merck Serono, Merck Sharp & Dohme; receipt of honoraria for participation in an advisory board for Merck Sharp & Dohme; receipt of honoraria for the provision of consultancy services for Merck Serono, Merck Sharp & Dohme, Cullinan Management Inc. LL reports receipt of honoraria or consultancy fees (for public speaking/teaching in medical meetings and/or for expert opinion in advisory boards) from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Merck Serono, Boehringer Ingelheim, Novartis, Roche, Debiopharm International SA, Sobi, Ipsen, Incyte Biosciences Italy srl, Doxa Pharma, Amgen, Nanobiotics Sa and GlaxoSmithKline; receipt of grants/research support (funds received by the institution for clinical studies and research activities) from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene International, Debiopharm International SA, Eisai, Exelixis Inc., Hoffmann-La Roche Ltd, IRX Therapeutics Inc., Medpace Inc., Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer and Roche. EPH reports receipt of speaker's honoraria from Merck Sharp & Dohme and Merck Serono; participation in a scientific advisory board for Merck Sharp & Dohme. JHal reports receipt of research support to Masaryk Memorial Cancer Institute from the Ministry of Health of the Czech Republic, MZ ČR - RVO (MOÚ, 00209805) and CZECRIN LM2018128. BB reports receipt of honoraria for participation in scientific advisory boards for AstraZeneca, Merck Sharp & Dohme, Merck Serono. CvH reports receipt of grants/research support to their institution from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Ipsen, Novartis and Sanofi; receipt of honoraria for participation in a scientific advisory board from Bayer, Bristol Myers Squibb, Ipsen, Merck Sharp & Dohme and Regeneron. AC reports receipt of grants/research support to their institution from Merck; participation in a sponsored speakers' bureau for Merck, Bristol Myers Squibb and Merck Sharp & Dohme; receipt of honoraria for participation in a scientific advisory board from Merck, Bristol Myers Squibb and Merck Sharp & Dohme; lecture fees from Bristol Myers Squibb, Merck Sharp & Dohme and Merck. J-PM reports acting in an advisory role for Merck Serono and Merck Sharp & Dohme. AT, EO, SM, JHar and LS have declared no potential conflicts of interest.

The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. SIGNIFICANCE: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis., (©2021 American Association for Cancer Research.)

In March the CEO of Tesla, Elon Musk, posted a Tweet about the possible effects of chloroquine for COVID-19. Celebrities and mainstream media joined the discussion and promoted (hydroxy-)chloroquine to a true hype and the miracle cure for COVID-19. Police surveillance was needed to protect the producer of chloroquine in the Netherlands. Was (hydroxy-)chloroquine just a hype? The first European study had many methodological issues, a misleading conclusion and was published without the peer review process. It took several weeks before better designed studies showed that (hydroxy-)chloroquine was not effective for COVID-19, after which the use of this medicine was no longer recommended. It is understandable that in a pandemic there is a high need for an effective cure, but physicians should have waited until effectiveness was demonstrated. In our opinion, the use of (hydroxy-)chloroquine for COVID-19 was indeed a hype.

Competing Interests: Disclosure JPM reports acting in an advisory role for Merck Serono and MSD; CRL reports acting in an advisory role for Rakuten Medical and MSD. LL reports participation for public speaking/teaching in medical meetings and/or for providing expert opinion in advisory boards for AstraZeneca, Bayer, BMS, Eisai, MSD, Merck Serono, Boehringer Ingelheim, Novartis, Roche, Debiopharm International SA, Sobi, Ipsen, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics and GSK. All other authors have declared no potential conflicts of interest.

We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic., Competing Interests: Disclosures AA reports personal fees from BMS, AstraZeneca, MSD, Pfizer, Roche, Takeda and Boehringer outside the submitted work. LA reports other from BMS, MSD, Novartis, Amgen, Ipsen, Roche, Pfizer, Merck, AstraZeneca, Exelixis, Peloton Therapeutics and Corvus Pharmaceuticals outside the submitted work. PAA reports grants and personal fees from BMS, Roche Genentech and Array outside the submitted work; personal fees from MSD, Novartis, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, and Eisai outside the submitted work; advisory role with Boehringer Ingelheim outside the submitted work. SB reports grants and personal fees from AstraZeneca/MedImmune and GSK/Tesaro outside the submitted work; personal fees from Amgen, Clovis, Mersana, Seattle Genetics, Genmabs, Merck Serono, Roche and Immunogen outside the submitted work. FB reports personal fees from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda outside the submitted work. CCa is a member of AstraZeneca's IMED External Science Panel, a member of Illumina's Scientific Advisory Board and a recipient of research grants (administered by the University of Cambridge) from Genentech, Roche, AstraZeneca and Servier. FC reports personal fees from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GSK, MacroGenics, Medscape, MSD, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Samsung Bioepis, Sanofi, Seattle Genetics and Teva outside the submitted work. AC reports grants, personal fees and other from Merck Serono, Servier, Roche, Lilly, Novartis, Takeda, Astellas and Bayer outside the submitted work; personal fees and other from Pierre Fabre, Amgen and Foundation Medicine outside the submitted work; grants from Genentech, FibroGen, Amcure, Sierra Oncology, AstraZeneca, MedImmune, BMS, MSD, AbbVie, Theradex, Array, Tesaro and Johnson & Johnson outside the submitted work. TKC reports grants, personal fees, non-financial support and other from BMS, Exelixis, Pfizer, (during the conduct of the study), Merck, BMS, Exelixis, AstraZeneca, Lilly, Eisai, Novartis, GSK, Lilly, Pfizer and EMD Serono outside the submitted work; has a patent null pending and stock ownership in Pionyr and Tempest; has received travel, accommodations and expenses in relation to consulting, advisory roles and clinical trials; medical writing and editorial assistance support may have been provided by communications companies funded by pharmaceutical companies; the institution (Dana Farber Cancer Institute) may have received additional independent funding from drug companies and/or royalties potentially involved in research around the subject matter; is a member of the NCCN kidney panel. MLKC reports personal fees from Janssen, Astellas, MSD Oncology, Bayer and Illumina outside the submitted work; personal fees and non-financial support from AstraZeneca and Varian outside the submitted work; non-financial support from PV Med and Decipher Biosciences outside the submitted work. CC reports personal fees from Pfizer, Novartis, Eli Lilly and Roche outside the submitted work. GC reports grants from Roche and Pfizer outside the submitted work; personal fees from Daiichi Sankyo, MSD and AstraZeneca outside the submitted work. EdA reports personal fees from Roche/Genentech, Novartis, Seattle Genetics and Zodiac; other from Roche/Genentech and GSK/Novartis; grants from AstraZeneca, GSK/Novartis, Roche/Genentech and Servier outside the submitted work. DDR reports advisory boards and grants from BMS, AstraZeneca, Boehringer Ingelheim, Celgene, Seattle Genetics, Roche/Genentech and Merck/Pfizer outside the submitted work; other from Philips and Olink outside the submitted work. EDV reports institutional financial support for her advisory role from Daiichi Sankyo, Merck, NSABP, Pfizer, Sanofi and Synthon outside the submitted work; institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche and Synthon outside the submitted work. RDe reports personal fees from AstraZeneca, Roche, MSD, Eisai, Pfizer and Novartis outside the submitted work. RDz reports personal fees and non-financial support from Roche and AstraZeneca outside the submitted work; personal fees from Novartis, Pfizer, Takeda, Seattle Genetics, Foundation Medicine and MSD outside the submitted work. CF-F reports grants and other from AstraZeneca and Elekta outside the submitted work. EF reports personal fees from AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, MSD, Novartis, Pfizer, prIME Oncology, Roche, Samsung, Takeda, TouchIME, GSK and Bayer outside the submitted work; grants from Grant For Oncology Innovation (GOI) and Fundación Merck Salud outside the submitted work; is an independent board member of Grifols. MG reports grants and personal fees from Eli Lilly, Otsuka Pharma, AstraZeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Bayer, MSD, GSK, Spectrum Pharmaceuticals, Blueprint Medicine and Boehringer Ingelheim outside the submitted work; personal fees from Seattle Genetics, Daiichi Sankyo, Janssen, Inivata, Takeda and Sanofi Aventis outside the submitted work; grants from United Therapeutics Corporation, Merck KGaA, Turning Point, Ipsen, MedImmune, Exelisis, Tiziana Sciences, Clovis and Merck Serono outside the submitted work; non-financial support from MSD, Pfizer and Eli Lilly outside the submitted work. PG reports personal fees from Roche, from MSD, BMS, Boehringer Ingelheim, Pfizer, AbbVie, Novartis, Lilly, AstraZeneca, Janssen, Blueprint Medicines, Takeda, Gilead and ROVI outside the submitted work. JH reports grants and other from BMS, MSD, Novartis, BioNTech and Amgen outside the submitted work; other from Achilles Therapeutics, GSK, Immunocore, Ipsen, Merck Serono, Molecular Partners, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures and Vaximm outside the submitted work; personal fees from Neogene Therapeutics outside the submitted work. EH reports grants, non-financial support and other from Lilly, Roche/Genentech, Daiichi Sankyo, AstraZeneca, Eisai and Novartis outside the submitted work; grants and non-financial support from Tesaro, Radius Health, Clovis, Medivation and EMD Serono outside the submitted work; grants and other from Puma Biotechnology, Pfizer, Mersana, Boehringer Ingelheim, Cascadian Therapeutics, Silverback and Black Diamond outside the submitted work; grants from Hutchinson MediPharma, OncoMed, MedImmune, Stem CentRx, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Millenium, TapImmune, BerGenBio, H3 Biomedicine, Acerta Pharma, Takeda, MacroGenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, NuCana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Syros, Clovis, CytomX, InventisBio, Deciphera, ArQule, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Torque Therapeutics, Harpoon Therapeutics, Fochon Pharmaceuticals, Orinove, Molecular Templates, Unum Therapeutics, Aravive, Compugen, Dana Farber Cancer Institute, G1 Therapeutics, Karyopharm Therapeutics and Torque Therapeutics outside the submitted work; other from Nanostring; non-financial support from Amgen, Bayer, BMS, Genzyme, Helsinn Therapeutics, HERON, Lexicon, Merck, Roche, Sysmex, Guardant Heallth and Foundation Medicine outside the submitted work. PAJ reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo and Takeda Oncology outside the submitted work; personal fees from Pfizer, Roche/Genentech, Merrimack Pharmaceuticals, Chugai Pharmaceuticals, Araxes Pharma, Ignyta, Mirati Therapeutics, Novartis, Voronoi, SFJ Pharmaceuticals, Biocartis and LOXO Oncology outside the submitted work; grants from Puma and Astellas Pharmaceuticals outside the submitted work; receives post-marketing royalties from DFCI owned intellectual property on EGFR mutations licensed to Lab Corp. KJ reports personal fees from MSD, Merck (USA), Amgen, Helsinn, Riemser, Tesaro, Kreussler, Voluntis, Pfizer, Pomme-med, PharmaMar, ClinSol Research, Hexal, G1 Therapeutics, Shire, prIME Oncology, medupdate, art tempi and UpToDate outside the submitted work. RK reports grants and personal fees from MSD, Janssen, Astellas, Bayer and Pfizer outside the submitted work. SBK has received research funding from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc and DongKook Pharm Co.; has participated as a consultant in advisory boards for Novartis, AstraZeneca, Lilly, Enzychem, Dae Hwa Pharmaceutical Co. Ltd., ISU Abxis and Daiichi-Sankyo. FL reports personal fees from Amgen, Astellas, AstraZeneca, BioNTech, Eli Lilly, Elsevier, Excerpta Medica, Imedex, Infomedica, medupdate, Merck Serono, MSD, Corvus, proMedicis, Springer Nature, streamedup!, Zymeworks, Bayer and Roche outside the submitted work; grants and personal fees from Iomedico and BMS outside the submitted work. JPM reports personal fees from Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer Ingelheim, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology and Pfizer outside the submitted work; grants and personal fees from BMS outside the submitted work; other from Amgen, MSD, PsiOxus, Debio and Nanobiotix outside the submitted work. TSKM reports grants, personal fees and other from AstraZeneca outside the submitted work; grants and personal fees from Roche/Genentech, Pfizer, MSD, Novartis, SFJ Pharmaceutical and BMS outside the submitted work; grants from Clovis Oncology, XCovery and G1 Therapeutics Inc. outside the submitted work; non-financial support from GeneDecode outside the submitted work; personal fees from Boehringer Ingelheim, Lilly, Merck Serono, Vertex Pharmaceuticals, Oncogenex, Celgene, Ignyta, Cirina, Fishawack Facilitate, Takeda Oncology, Janssen, OrigiMed, Hengrui Therapeutics, Sanofi-Aventis R&D, Yuhan Corporation, PrIME Oncology, Amoy Diagnostics, Loxo-Oncology, ACEA Pharma, Alpha Biopharma Co. Ltd., CStone Pharmaceuticals, IQVIA, MoreHealth, InMed Medical Communication, Virtus Medical Group, Biolidics Ltd., Bayer, Daiichi Sankyo, Incyte Corporation, Lunit Inc., Mirati Therapeutics Inc. and Gritstone Oncology Inc. outside the submitted work; other from Hutchison ChiMed, Sanomics, ASCO and CSCO outside the submitted work. AP reports honoraria for consulting, advisory role or lectures from AstraZeneca, Agilent/Dako, BMS, Eli Lilly, MSD and Roche Genentech. GP reports grants, personal fees and non-financial support from Merck outside the submitted work; grants and non-financial support from AstraZeneca outside the submitted work; grants and personal fees from Roche, BMS, MSD and Novartis outside the submitted work; grants from Amgen and Lilly outside the submitted work. SP has received educational grants, provided consultation, attended advisory boards and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody, from whom she has received honoraria (all fees to institution). MR reports personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, GSK, Lilly, Merck, MSD, Novartis, Pfizer, Roche and Samsung Bioepis outside the submitted work. RSS reports attending advisory boards for VCN-BCN, Agendia, Guardant Health, Roche Diagnostics, Ferrer, Pfizer, Novartis, Ipsen, Amgen, Merck, Roche Pharma, Lilly and MSD; speaker's fees from Pfizer, Amgen, Novartis, Merck, MSD, AstraZeneca and Celgene; leadership role and stocks or ownership interest with Sace Medhealth. FS reports financial interests, honoraria for speaker, consultancy or advisory role, royalties and/or direct research funding from Tesaro, Helsinn, Vifor, MSD, Roche, Amgen, Pierre Fabre Oncology, Pfizer, Leo Pharma, Arrow BMS, Mylan and Mundi-Pharma outside of the submitted work. SS reports grants and personal fees from AstraZeneca outside the submitted work; grants from Varian Medical Systems and ViewRay Inc. outside the submitted work; personal fees from MSD and Celgene, outside the submitted work. ES reports personal fees from Astellas, AstraZeneca, BMS, Celgene, Five Prime Therapeutics, Gritstone Oncology, Merck, Servier and Zymeworks outside the submitted work. RS reports grants and personal fees from AstraZeneca and Boehringer Ingelheim outside the submitted work; personal fees from BMS, Eli Lilly, MSD, Novartis, Pfizer, Taiho Pharmaceutical, Takeda, Yuhan and Amgen outside the submitted work. JCS reports personal fees from Abbvie, AstraZeneca, Bayer, Blend Therapeutics, Boeringher Ingelheim, Cytomix, Daiichi Sankyo, Eli Lilly, Genmab, Guardiant Health, Inivata, Merck, Netcancer, Roche, Servier, PharmaMar and Tarveda outside the submitted work; was a full time employee of AstraZeneca from September 2017 to December 2019. FS reports unrestricted research grants from Celgene, Fresenius and Helsinn; participation in company-led clinical trials with Novartis; advisory boards for Helsinn, Mundipharma, Novartis, Fresenius and Kaiku Health. JT reports personal fees from Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd., Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics outside the submitted work. EVC reports grants from Amgen, Bayer, Boehringer Ingelheim, BMS, Celgene, Ipsen, Lilly, MSD, Merck KGaA, Novartis, Roche and Servier; advisory boards for Array, AstraZeneca, Bayer, Biocartis, BMS, Celgene, Daiichi, Halozyme, GSK, Pierre Fabre, Incyte, Ipsen, Lilly, MSD, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex and Taiho outside the submitted work. PEvS reports IASLC board member; treasurer BACTS; external expert for AstraZeneca, MSD and Institut National du Cancer, France (institutional fees). GV reports grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministry of Health and Istituto Nazionale Assicurazione Infortuni sul Lavoro outside the submitted work; honoraria from Ab Medica SpA, Medtronic and Verb Medical. JY reports personal fees from Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Pfizer, Novartis, BMS, Ono Pharmaceuticals, AstraZeneca, Merck Serono, Celgene, Yuhan Pharmaceuticals, Daiichi Sankyo, Hansoh Pharmaceuticals, Takeda Oncology, Blueprint Medicines and Amgen outside the submitted work. IFC, NIC, JYD, DDU, NG, RGJ, VG, UG, OAM, GM, RO, KP, CS, DSW, JS, DT and HvH have declared no significant conflict of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials.

Background: To investigate the activity and safety of afatinib in the preoperative treatment of squamous cell carcinoma of the head and neck (SCCHN)., Patients and Methods: This study was an open-label, randomized, multicenter, phase II window of opportunity trial. Treatment-naïve SCCHN patients selected for primary curative surgery were randomized (5 : 1 ratio) to receive afatinib during 14 days (day -15 until day -1) before surgery (day 0) or no treatment. Tumor biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and magnetic resonance imaging (MRI) were carried out at diagnosis and just before surgery. The primary end point was metabolic FDG-PET response (according to EORTC guidelines). Other end points included response assessment based on the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, dynamic contrast-enhanced (DCE)-MRI, diffusion weighted (DW)-MRI, safety, and translational research (TR)., Results: Thirty patients were randomized: 25 to afatinib and 5 to control arm. Of the 23 eligible patients randomized to afatinib, 16 (70%; 95% CI: 47% to 87%) patients had a partial metabolic FDG-PET response (PMR). Five patients (22%; 95% CI: 8% to 44%) showed a partial response by RECISTv1.1. Responses assessed via DCE-MRI and DWI-MRI did not show a strong association with PMR or RECIST. One patient discontinued afatinib after 11 days for grade 3 diarrhea with subsequent renal failure and 24 days delay in surgery. No grade 4 toxicities or surgical comorbidities related to afatinib were reported. TR results indicated that PMR was more frequent in the tumors with high Cluster3-hypoxia score expression and with TP53 wild type., Conclusion: Afatinib given for 2 weeks to newly diagnosed SCCHN patients induces a high rate of FDG-PET partial metabolic response and partial response according to RECISTv1.1. Afatinib can be safely administered before surgery. Although exploratory, the hypoxic gene signature needs further investigations as a predictive biomarker of afatinib activity., Clinical Trial Registration: ClinicalTrials.gov: NCT01538381.

Background: In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1., Patients and Methods: Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes., Results: Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35)., Conclusions: Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings., Clinical Trial Registration: NCT01345682., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years., Patients and Methods: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed., Results: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups., Conclusions: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients., Clinical Trial Registration: NCT01345682 (ClinicalTrials.gov)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Lung cancer is the leading cause of cancer death. Beyond first line treatment, few therapeutic options are available, particularly for squamous cell carcinoma (SCC). Here, we have explored the phospholipidomes of 30 human SCCs and found that they almost invariably (in 96.7% of cases) contain phospholipids with longer acyl chains compared to matched normal tissues. This trait was confirmed using in situ 2D-imaging MS on tissue sections and by phospholipidomics of tumor and normal lung tissue of the L-IkkαKA/KA mouse model of lung SCC. In both human and mouse, the increase in acyl chain length in cancer tissue was accompanied by significant changes in the expression of acyl chain elongases (ELOVLs). Functional screening of differentially expressed ELOVLs by selective gene knockdown in SCC cell lines followed by phospholipidomics revealed ELOVL6 as the main elongation enzyme responsible for acyl chain elongation in cancer cells. Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models. These findings identify acyl chain elongation as one of the most common traits of lung SCC discovered so far and pinpoint ELOVL6 as a novel potential target for cancer intervention.

Background: Cetuximab in combination with platinum and 5-fluorouracil is the standard of care in the first-line treatment of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab and taxane combinations have shown promising activity. This study evaluated the efficacy and safety of four cycles of docetaxel associated with cisplatin and cetuximab (TPEx), followed by maintenance with cetuximab every 2 weeks., Patients and Methods: Patients with a histologically confirmed HNSCC with metastasis or recurrence unsuitable for locoregional curative treatment received docetaxel and cisplatin (75 mg/m(2) both) at day 1 and weekly cetuximab 250 mg/m(2) (loading dose of 400 mg/m(2)), repeated every 21 days for four cycles, followed by maintenance cetuximab 500 mg/m(2) every 2 weeks until progression or unacceptable toxicity. Prophylactic administration of granulocyte colony-stimulating factor was done systematically after each chemotherapy cycle. Patients had a good general status (performance status ≤1) and were under 71 years. Prior total doses of cisplatin exceeding 300 mg/m(2) were not allowed. The primary end point was objective response rate (ORR) after four cycles., Results: Fifty-four patients were enrolled. The primary end point was met with an ORR of 44.4% (95% CI 30.9-58.6). Median overall and progression-free survivals were, respectively, 14 months (95% CI 11.3-17.3) and 6.2 months (95% CI 5.4-7.2). The most common grade 3/4 adverse events were skin rash (16.6%) and non-febrile neutropenia (20.4%). There were one pulmonary embolism and two infectious events leading to death., Conclusions: The TPEx regimen showed promising activity as first-line treatment in fit patients with recurrent/metastatic HNSCC. Further studies are needed to compare the TPEx versus EXTREME regimen in this population., Clinicaltrialgov: NCT01289522., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The purpose of the trial was to assess the efficacy and tolerability of Sym004, a novel 1:1 mixture of two chimeric monoclonal antibodies (992 and 1024) targeting non-overlapping epitopes of the anti-epidermal growth factor receptor (EGFR), in patients with squamous cell carcinoma of the head and neck (SCCHN)., Methods: Incurable, recurrent and/or metastatic SCCHN patients with acquired resistance to anti-EGFR monoclonal antibody-containing treatment received weekly infusions of 12 mg/kg Sym004 until disease progression or unacceptable toxicity., Results: Among the 26 patients treated with Sym004, the proportion of patients alive without disease progression at 6 months was 12 % (95 % CI 1-39 %). The median duration of progression-free survival was 82 days (95 % CI 41-140 days). Of 19 patients evaluable for response, eight showed a decrease in the sum of the largest diameter in their target lesions (median 11 %; range 7-27 %). The best overall response was stable disease in 13 patients (50 %). Paired biopsies showed a significant down-regulation of EGFR in both skin and tumors following exposure to Sym004. All patients had EGFR-related adverse events, including grade 3 skin toxicities and grade ≥3 hypomagnesemia reported in 13 (50 %) and 10 (38 %) of 26 patients, respectively. One event fulfilling the protocol-defined criteria for infusion-related reactions (grade 2) was reported. No anti-drug antibodies were detected., Conclusions: The marked EGFR down-regulation shown in target tissues supports the proposed mechanism of action of Sym004. This trial revealed modest anti-tumor activity of Sym004 in extensively pretreated advanced SCCHN patients.

Objectives: Renal cell carcinoma (RCC) accounts for 2·4% of all new cancers in Belgium. Over the past decade, the armamentarium for systemic therapy of metastatic RCC (mRCC) has undergone important changes with implementation of targeted therapies directed against pathways involved in the pathogenesis of RCC. We describe first-line treatment choice of a group of patients in 9 Belgian oncology centres between October 2009 and November 2012., Methods: A clinical report form was established to assess patient characteristics, Karnofsky performance score, Memorial Sloan-Kettering Cancer Center risk criteria (MSKCC) and first-line therapy of mRCC patients. Choice of therapy and starting dose was analyzed before and after reimbursement of pazopanib in Belgium., Results: Ninety-six patients were eligible for the study. Non-smokers accounted for 53% of the patients. Seventy-three per cent of the patients had 0 or 1 MSKCC criteria in the group of patients that started treatment more than 1 year after initial diagnosis. In the group of patients that started therapy less than 1 year after diagnosis, 85% had 2 or more MSKCC criteria. This difference was statistically significant (P<0·0001). Overall distribution of the first-line therapies consisted of 43% sunitinib, 33% pazopanib, 14% temsirolimus, 7% everolimus and 3% sorafenib. Seventeen (18%) out of 96 patients started at a reduced dose level., Conclusion: This report shows that the guidelines for the start of first-line treatment in mRCC in 9 centres in Belgium were applied most of the time: a tyrosine kinase inhibitor was the first treatment choice for most patients while temsirolimus was an option for poor prognosis patients. In the majority of patients standard dose levels were initiated, although in some patients adaptation of dosage/treatment schedule was recorded.

Background: An association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and better outcome after mastectomy and lung surgery for cancer has been recently suggested. In a retrospective analysis, we investigated the association between intraoperative NSAIDs use in conservative breast cancer surgery and breast cancer disease-free survival (DFS). Similarly, we also evaluated the association between breast cancer DFS and preoperative neutrophil:lymphocyte ratio (NLR)., Methods: A retrospective analysis of a single-centre cohort was performed in breast cancer patients (n=720) with uni- and multivariate analyses, using a Cox regression model., Results: In conservative breast cancer surgery, the intraoperative use of NSAIDs (ketorolac or diclofenac) was associated with an improved DFS {hazard ratio (HR)=0.57 [95% confidence interval (CI): 0.37-0.89], P=0.01} and an improved overall survival (OS) [HR=0.35 (95% CI: 0.17-0.70), P=0.03]. In these patients, an NLR >3.3 (identified by a receiver-operating characteristic curve) was associated with a shorter DFS [HR=1.99 (95% CI: 1.16-3.41), P=0.01] and OS [HR=2.35 (95% CI: 1.02-5.43), P=0.046]., Conclusions: Intraoperative NSAIDs and higher preoperative NLR are associated with improved outcome in conservative breast cancer surgery. Prospective, randomized trials to evaluate if these associations are causal are warranted., (© The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

About 3-5% of metastatic cancers originate from an unknown primary origin. Some have a signet-ring cell (SRC) component. We report the medical history of three patients with SRC carcinoma expressing both the oestrogen (ER) and progesterone receptors (PR). Although no primary breast cancer could be identified, we considered these three patients as having metastatic breast cancer. All of them were therefore treated with standard breast anti-hormonal therapies and all demonstrated benefit. The pitfalls of clinical presentation, diagnostic work-up, and treatment are discussed.

Background: Hypoxia can activate autophagy, a self-digest adaptive process that maintains cell turnover. Mammalian target of rapamycin (mTOR) inhibitors are used to treat cancer but also stimulate autophagy., Methods: Human mammary cancer cells and derived xenografts were used to examine whether hypoxia could exacerbate autophagy-mediated resistance to the mTOR inhibitor rapamycin., Results: Rapamycin exerted potent antitumour effects in MCF-7 and MDA-MB-231 mammary tumours through a marked inhibition of angiogenesis, but the autophagy inhibitor chloroquine (CQ) failed to further sensitise tumours to mTOR inhibition. Rapamycin treatment actually led to tumour reoxygenation, thereby preventing the development of autophagy. Chloroquine alone, however, blocked the growth of MCF-7 tumours and in vitro blunted the hypoxia-induced component of autophagy in these cells. Finally, when initiating CQ treatment in large, hypoxic tumours, a robust antitumour effect could be observed, which also further increased the antiproliferative effects of rapamycin., Conclusion: The mTOR inhibitor rapamycin significantly contributes to tumour growth inhibition and normalisation of the tumour vasculature through potent antiangiogenic effects. The resulting reduction in hypoxia accounts for a lack of sensitisation by the autophagy inhibitor CQ, except if the tumours are already at an advanced stage, and thus largely hypoxic at the initiation of the combination of rapamycin and CQ treatment.

Background: Preclinical studies have shown that PTEN loss enhances sensitivity to mammalian target of Rapamycin (mTOR) inhibitors because of facilitated PI3K (phosphatidylinositol-3 kinase)/Akt activation and consecutive stimulation of the mTOR pathway. In patients with advanced transitional cell carcinoma (TCC) treated with the mTOR inhibitor everolimus, PTEN loss was, however, associated with resistance to treatment., Methods: Transitional cell carcinoma specimens, human bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors., Results: Transitional cell carcinoma patients with a shorter progression-free survival under everolimus exhibited PTEN deficiency and increased Akt activation. Moreover, PTEN-deficient bladder cancer cells were less sensitive to rapamycin than cells expressing wild-type PTEN, and rapamycin strikingly induced Akt activation in the absence of functional PTEN. Inhibition of Akt activation by the PI3K inhibitor wortmannin interrupted this rapamycin-induced feedback loop, thereby enhancing the antiproliferative effects of the mTOR inhibitor both in vitro and in vivo., Conclusion: Facilitation of Akt activation upon PTEN loss can have a more prominent role in driving the feedback loop in response to mTOR inhibition than in promoting the mTOR pathway. These data support the use of both PI3K and mTOR inhibitors to treat urothelial carcinoma, in particular in the absence of functional PTEN.

Background: To investigate the safety and activity of cetuximab in the pre-operative treatment of squamous cell carcinoma of the head and neck (SCCHN)., Patients and Methods: Cetuximab was administered for 2 weeks before surgery to 33 treatment-naïve patients selected for primary surgical treatment. Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography ((18)FDG-PET) and imaging were carried out at baseline and before surgery. The primary aim of the study was safety and the secondary aims included metabolical, radiological and pathological tumour response. Five untreated patients were included as controls., Results: Cetuximab given 24 h before surgery was safe. Ninety percent of patients had (18)FDG-PET partial response (EORTC guideline) in the cetuximab group versus 0% in the control group. Delta maximal standardized uptake values (ΔSUVmax) were correlated with tumour cellularity on the surgical specimens (P < 0.0001). For patients with ΔSUVmax less than -25% or less than -50%, Ki67 was significantly decreased by cetuximab (P = 0.01 and 0.003). Cetuximab induced down-regulation of pEGFR (P = 0.0004) and pERK (P = 0.003)., Conclusions: Short-course pre-operative administration of cetuximab is safe and shows a high rate of (18)FDG-PET response. (18)FDG-PET response was correlated with residual tumour cellularity suggesting that (18)FDG-PET deserves further investigation as a potential early marker of cetuximab activity in SCCHN.

Background: Percutaneous endoscopic gastrostomy (PEG) is a relatively safe procedure and is an important supportive treatment for patients with advanced head and neck cancer. Although tumor seeding has been reported in various sites, seeding at the PEG exit site is a rare complication., Methods and Results: We describe a clinical case in which squamous cell carcinoma of the hypopharynx implanted at the site of PEG insertion and was successfully removed by surgery. PEG was previously placed by the "pull" technique. A review of the literature, discussion of the mechanism of spread, and recommendations to avoid this complication are discussed., Conclusions: To avoid this rare and poor prognostic complication, the "pull" technique should be avoided for PEG placement in any patient with head and neck squamous cell carcinoma. An alternative method such as the "push" technique should be preferred., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m(2)/paclitaxel (Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m(2) (regimen A) or cisplatin 75-100 mg/m(2)/5-fluorouracil 750-1000 mg/m(2) (regimen B) in patients with advanced solid tumors., Patients and Methods: The primary objective was to assess dose-limiting toxicities (DLTs) during cycle 1 for each regimen, from which the maximum tolerated dose (MTD) was determined. Patients received once daily oral afatinib 20, 30, 40 or 50 mg in 21-day cycles (3 + 3 design)., Results: The MTD for afatinib in regimens A (n = 26) and B (n = 21) was determined as 20 mg and 30 mg following DLTs in five and four patients in cycle 1, respectively. Most frequent adverse events (AEs, any grade) were diarrhea and nausea. Disease control was observed in 54% and 29% of patients in regimens A and B, respectively. Plasma sampling suggested no relevant pharmacokinetic interaction between afatinib and the chemotherapeutic agents., Conclusions: The MTD of afatinib was 20 mg with cisplatin-paclitaxel and 30 mg with cisplatin-5-fluorouracil. Pre-emptive management of side-effects is important to maintain adequate safety and tolerability. Both combinations showed antitumor activity across tumor types and lines of prior treatment.

Haemangiopericytoma is a rare tumor of vascular origin. We report the case of patient with severe refractory anaemia due to peripheral destruction of red blood cells by spleen metastases. Anaemia was successfully treated by splenectomy. Afterwards, our patient developed liver and lung metastases and was treated, in a clinical trial, with gefitinib that stabilised the disease during nine years. These interesting features are discussed.

Growth of tumors can accelerate during the peri-operative period. Accordingly, early relapse of cancer occurs in some patients during the first two postoperative years. Temporal and biologic analyses of cancer pathophysiology suggest a link between peri-operative pathophysiological changes and acceleration of tumor growth. Understanding the role of inflammation and its consequences (i.e., immune response, growth factors, dissemination of tumor cells) could lead to define a role of anesthesiologists in reducing cancer recurrence following surgery. We argue for peri-operative pharmacological interventions to reduce cancer relapse, with a focus on non-steroidal anti-inflammatory drugs.

Background: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy., Patients and Methods: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control., Results: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD., Conclusions: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.

Background: Preclinical studies suggest that insulin-like growth factor-1 receptor (IGF-1R) blockage could be a promising therapeutic target in squamous cell carcinoma of the head and neck (SCCHN). Therefore, we investigated the efficacy and toxicity of figitumumab, an anti-IGF-1R monoclonal antibody, in palliative SCCHN., Patients and Methods: Patients with palliative SCCHN progressing after platinum-based therapy were treated with figitumumab i.v. 20 mg/kg, every 3 weeks. The primary end point was the disease control rate at 6-8 weeks after treatment initiation. Tumor biopsies and plasma samples were collected before and after figitumumab administration to monitor the molecular response., Results: Seventeen patients were included. Only two patients achieved stable disease at 6-8 weeks. Median overall survival and progression-free survival were 63 and 52 days, respectively. The main grade 3-4 adverse event was hyperglycemia (41%). Translational research showed that figitumumab downregulated IGF-1R at the surface of tumor cells with activation of the epidermal growth factor receptor (EGFR) pathway, as shown by the upregulation of p-EGFR in tumor cells (P=0.016), and an increase in the plasma level of tumor growth factor-alpha (P=0.006)., Conclusion: Figitumumab monotherapy has no clinically significant activity in unselected palliative SCCHN.

We report the case of a woman with a metastatic breast cancer, who started a third-line treatment with dasatinib, a new oral tyrosine kinase inhibitor, and who developed, one week later, a progressive breathless sensation. Workup demonstrated pleuropericardial effusion that turned out to be a side effect of this new investigational drug. Although this dasatinib-induced side effect is well known, this case clearly illustrates the importance of an accurate diagnosis and adequate treatment of complications of new agents which are easy to use since most of them are orally taken, and the difficulty to clearly separate drug origin and cancer morbidities. The patient recovered completely one month after discontinuation of dasatinib. In this report, we will review the differential diagnosis and management of pleuropericardial effusion.

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3 weeks; days 1 and 8 every 3 weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250 mg/m(2)/DXR 40 mg/m(2) every 3 weeks for schedule 1 and VFL 120 mg/m(2)/DXR 25 mg/m(2) days 1 and 8 every 3 weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluation.

Background: Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines., Patients and Methods: In part I, we used a 3+3 dose-escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice daily (days 1-14) every 3 weeks. In part II, we evaluated the objective response rate (ORR) at the MTD., Results: Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20mg/m(2) plus capecitabine 1000 mg/m(2) was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3-4 toxicities were asthenia (n=5), hand-foot syndrome (n=5), neutropenia (n=21), neutropenic infection (n=1), and neutropenic colitis (n=1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2-47.2%). The median response duration was 3.1 months (95% CI: 2.1-8.4 months), with four of five lasting for more than 3 months. Median time to progression was 4.9 months., Conclusions: Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The majority of human epithelial cancers is frequently characterized by a functional activation of the epidermal growth factor receptor (EGFR)-driven-pathways. Today, two classes of EGFR inhibitors are routinely used in the clinic: anti-EGFR monoclonal antibodies such as cetuximab and panitumumab and small-molecule inhibitors of the EGFR tyrosine kinase activity such as erlotinib and gefitinib. Anti-EGFR therapies have been approved in several countries for the treatment of metastatic nonsmall-cell lung cancer, colorectal cancer, squamous-cell carcinoma of the head and neck, and pancreatic cancer. This article summarizes the clinical evidence of the anticancer activity of anti-EGFR treatment, and considers the current, and controversial, clinical issues with respect to their optimal use in the treatment of patients with cancer. Mechanisms of resistance to anti-EGFR treatment are also briefly discussed.

Background: half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed., Methods: primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006., Results: a total of 1218 patients were included. The prevalence of elevated SCR (> or =1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR<90 ml min(-1) per 1.73 m(2). In all, 78.6% of treated patients (n=1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment., Conclusions: the RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing., (2010 Cancer Resaerch UK.)

Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers., (©2010 AACR.)

Objectives: The primary objectives of this study were to analyse the outcome of patients diagnosed with head and neck soft tissue sarcomas (HNSTS) and to identify relevant prognostic factors. As well as this, we compared the prognostic value of two staging systems proposed by the American Joint Committee on Cancer (AJCC) and the Memorial Sloan-Kettering Cancer Center (MSKCC)., Methods: From 07/1988 to 01/2008, the charts of 42 adult patients were retrospectively reviewed. Potential prognostic factors were analysed according to overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS)., Results: At 5 years, OS was 57%, DFS 47% and DSS 72%. On univariate analysis, statistically significant prognostic factors were for OS, distant or lymph node metastasis at diagnosis (p=0.032), for DFS, margins after surgery (p=0.007), for DSS, regional or distant metastasis at diagnosis (p=0.002), initial AJCC and MSKCC stage (p=0.018 and p=0.048) and margins after surgery (p=0.042). On multivariate analysis, margins remained statistically significant for DFS (p=0.039) when there was a trend with the initial AJCC stage (p=0.054) for OS. The AJCC staging system was of more prognostic value than the MSKCC staging system., Conclusions: Achieving clear margins after surgery is vital for improved local control and the best chance of survival. Adjuvant chemotherapy and radiotherapy were not shown to provide additional benefit. To better identify prognostic factors, it seems essential to set up national and international databases allowing multicenter registration for those patients.

Background: Treatment options for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are limited with response rates to cytotoxic chemotherapy of approximately 30% and median survival of 6 months., Patients and Methods: In a multicentre phase II study, 32 patients with recurrent or metastatic HNSCC received 3-AP Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), an inhibitor of ribonucleotide reductase, 96 mg/m2, daily for 4 days every 14 days (one cycle). Eligibility criteria required Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to two with a life expectancy of >3 months; one prior chemotherapy regimen was allowed., Results: Thirty patients were assessable for response and toxicity. Median age was 57 years (range 36-79) and median ECOG PS was one (range 0-2). Thirteen patients had previously been treated with chemotherapy. A total of 130 cycles were administered with a median number of cycles of 3.5 (range 1-8). Mild anaemia (40%), nausea (22%) and fatigue (22%) were commonly reported with G3 and G4 neutropenia documented in 22% and 22%, respectively. Overall response rate was 5.9% (95% confidence interval 0.2% to 28.7%). One patient achieved a partial response, eight had stable disease and 21 progressive disease. Median time to disease progression was 3.9 months., Conclusions: 3-AP Triapine as a single agent, at this dose and schedule, is well tolerated but has only minor activity in the treatment of advanced HNSCC.

Trastuzumab (Herceptin, Roche) is a recombinant, humanized monoclonal antibody directed against the neu-HER2 protein, since May 2002 reimbursed in Belgium for the treatment of metastatic HER2+ breast cancer and since June 2007 also in adjuvant therapy of HER2+ early stage breast cancer. The purpose of this study was to estimate the cost-effectiveness from the Belgian health care payer perspective of reimbursing trastuzumab in the Latter indication. A Markov state transition model was designed to adequately capture the natural history and course of disease for early stage breast cancer patients, and to simulate cost and disease progression over a life time perspective. The model estimates differences in outcomes for patients treated with adjuvant trastuzumab during 1 year compared to current therapy, and captures cost consequences and health benefits of trastuzumab treatment. Health benefits were expressed in terms of quality-adjusted life years gained, and future benefits were discounted at 1.5%. Costs were calculated from the perspective of the Belgian authorities' health care budget, and future costs were discounted at 3%. Where relevant, the costs per Markov state were obtained from the IMS Hospital Disease database. Additionally, an expert opinion analysis on resource use during the follow-up of treated early breast cancer patients provided the cost estimates for states with minor or without hospital costs. The incremental cost-effectiveness ratio based on a life time simulation was estimated at Euro 10,315 per quality-adjusted life year gained. It can be concluded that trastuzumab treatment of HER2+ early stage breast cancer patients is cost-effective from the perspective of the Belgian health care authorities.

A 64-year-old woman was admitted with fever and cough. At admission, she had jaundice, hepatomegaly, and green-stained sputum. Computed tomography (CT) showed an intrahepatic abscess located near the dome, multiple hepatic metastases, biliary tract dilatation, and a right pleural effusion. Percutaneous transhepatic cholangiography demonstrated a communication between the intrahepatic biliary ducts and the bronchial tree. The patient was treated with antibiotic therapy, pleural and biliary drainages and a percutaneous drainage of the hepatic abscess.

A 64-year-olf woman has been treated by chemotherapy for a uterine cervical carcinoma with known pathological lymph nodes in the abdomen and in the thorax. She is admitted in our Intensive Care Unit for fever and cardiac tamponade attributed to a large pericardial effusion. No diagnostic could be concluded from the analysis of the liquid or the pericardial biopsy. Complementary investigations are performed and the differential diagnosis of pericardial effusion is discussed in the context of a neoplastic disease.