GILBERTO DE CASTRO JUNIOR

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Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/24 - Laboratório de Oncologia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder

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  • article 32 Citação(ões) na Scopus
    Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial(aEuro)
    (2016) CLEMENT, P. M.; GAULER, T.; MACHIELS, J. P.; HADDAD, R. I.; FAYETTE, J.; LICITRA, L. F.; TAHARA, M.; COHEN, E. E. W.; CUPISSOL, D.; GRAU, J. J.; GUIGAY, J.; CAPONIGRO, F.; CASTRO JR., G. de; VIANA, L. de Souza; KEILHOLZ, U.; CAMPO, J. M. del; CONG, X. J.; EHRNROOTH, E.; VERMORKEN, J. B.
    In the LUX-Head & Neck 1 study, older age (a parts per thousand yen65 years) did not adversely affect the benefit in patient-reported outcomes and antitumor activity observed with afatinib over methotrexate, which was consistent with findings from the overall population. Safety in older patients was also consistent with the overall population, favoring afatinib in terms of fewer dose reductions and discontinuations.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 a parts per thousand yen65 and < 65 years. 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. Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged a parts per thousand yen65 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. Advancing age (a parts per thousand yen65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. NCT01345682 (ClinicalTrials.gov).
  • article 57 Citação(ões) na Scopus
    Responses to Crizotinib Can Occur in High-Level MET-Amplified Non-Small Cell Lung Cancer Independent of MET Exon 14 Alterations
    (2017) CAPARICA, Rafael; YEN, Cheng Tzu; COUDRY, Renata; IGNATIUS, Sai-Hong; VARELLA-GARCIA, Marileila; CAMIDGE, D. Ross; CASTRO JR., Gilberto de
    Activation of the MET proto-oncogene (MET) highly sensitive to MET inhibition has recently been described in NSCLC through two mechanisms: high-level amplification of the MNNG HOS Transforming gene (MET) (usually expressed relative to the chromosome 7 centromere [CEP7] when using fluorescence in situ hybridization) and exon 14 alterations. As partial overlap of these biomarkers occurs, whether one is purely a surrogate for the other or both can represent true oncogenic driver states continues to be explored. Cases of MET inhibitor-sensitive NSCLC harboring exon 14 alterations without coincident amplification have already been described. Here we report two cases of MET inhibitor-sensitive NSCLC harboring high-level MET amplification (MET/CEP7 ratio >= 5) without coincident exon 14 alterations, suggesting that these two methods of MET activation can produce independent MET-addicted states in NSCLC. Molecular profiling designed to capture all cases of potentially MET-addicted NSCLC should address both activation mechanisms.
  • article 5 Citação(ões) na Scopus
    The wolf in sheep's clothing: Microtomographic aspects of clinically incipient radiation-related caries
    (2016) MORAIS-FARIA, Karina; NEVES-SILVA, Rodrigo; LOPES, Marcio-Ajudarte; RIBEIRO, Ana-Carolina-Prado; CASTRO JR., Gilberto de; CONCEICAO-VASCONCELOS, Karina-Gondim-Moutinho da; BRANDAO, Thais-Bianca; SANTOS-SILVA, Alan-Roger
    Background: Radiation-related caries (RRC) can cause rapid progression, with a high potential for dental destruction affecting mainly cervical and incisal areas. Unlike the injuries that occur in the conventional caries, incipient RRC present in unusual surfaces have difficult diagnosis and classification stages of cavitation. Material and Methods: Evaluate the radiographic patterns of demineralization of RRC by using micro-CT. Ten teeth with incipient RRC and 10 teeth with incipient conventional caries (control group) matched by anatomic teeth group and caries affected surfaces were evaluated by X-ray microtomography (micro-CT) Skyscan 1174V2 (50Kv, 1.3 megapixel, Kontich, Belgium). Teeth were placed in a standard position for micro-CT (coronal, transaxial and sagittal sections) during images acquisition. Lesions were classified according to the depth of invasion and relationship with enamel, dentin and pulp. Results: RRC samples presented deeper lesions with higher involvement of enamel and dentin. Control group presented focal and superficial lesions with lower involvement of enamel and dentin. Conclusions: Incipient RRC present aggressive microtomographic patterns of demineralization when compared to conventional caries, as indicated by deep lesions, regardless of its clinically incipient aspects.
  • article 946 Citação(ões) na Scopus
    First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study
    (2017) SORIA, Jean-Charles; TAN, Daniel S. W.; CHIARI, Rita; WU, Yi-Long; PAZ-ARES, Luis; WOLF, Juergen; GEATER, Sarayut L.; ORLOV, Sergey; CORTINOVIS, Diego; YU, Chong-Jen; HOCHMAIR, Maximillian; CORTOT, Alexis B.; TSAI, Chun-Ming; MORO-SIBILOT, Denis; CAMPELO, Rosario G.; MCCULLOCH, Tracey; SEN, Paramita; DUGAN, Margaret; PANTANO, Serafino; BRANLE, Fabrice; MASSACESI, Cristian; CASTRO JR., Gilberto de
    Background The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. Methods This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m(2) or carboplatin AUC 5-6 plus pemetrexed 500 mg/m(2)] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1-2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099. Findings Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16.6 months (95% CI 12.6-27.2) in the ceritinib group and 8.1 months (5.8-11.1) in the chemotherapy group (hazard ratio 0.55 [95% CI 0.42-0.73]; p<0.00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group. Interpretation First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC.
  • article 7 Citação(ões) na Scopus
    Effectiveness and toxicity of adjuvant chemotherapy in patients with non-small cell lung cancer
    (2021) HARADA, Guilherme; NEFFA, Maria Fernanda Batistuzzo Vicentini; BONADIO, Renata Colombo; MENDOZA, Elizabeth Zambrano; CAPARICA, Rafael; LAURICELLA, Leticia Leone; TAKAGAKI, Teresa Yae; ROITBERG, Felipe Santa Rosa; TERRA, Ricardo Mingarini; JR, Gilberto De Castro
    Objective: Adjuvant chemotherapy (AC) improves survival of patients with resected non-small cell lung cancer (NSCLC). However, the cisplatin-vinorelbine regimen has been associated with a significant risk of clinically relevant toxicity. We sought to evaluate the effectiveness, safety, and feasibility of AC for NSCLC patients in a real-world setting. Methods: This was a single-center, retrospective cohort study of patients with stage I-III NSCLC undergoing surgery with curative intent between 2009 and 2018. AC was administered at the discretion of physicians. The patients were divided into two groups: AC group and no AC (control) group. Study outcomes included overall survival (OS) and recurrence-free survival (RFS), as well as the safety profile and feasibility of the cisplatin-vinorelbine regimen in a real-world setting. Results: The study involved 231 patients, 80 of whom received AC. Of those, 55 patients received the cisplatin- vinorelbine regimen. Survival analyses stratified by tumor stage showed that patients with stage II NSCLC in the AC group had better RFS (p = 0.036) and OS (p = 0.017) than did those in the no AC group. Among patients with stage III NSCLC in the AC group, RFS was better (p < 0.001) and there was a trend toward improved OS (p = 0.060) in comparison with controls. Of those who received the cisplatin- vinorelbine regimen, 29% had grade 3-4 febrile neutropenia, and 9% died of toxicity. Conclusions: These results support the benefit of AC for NSCLC patients in a real-world setting. However, because the cisplatin-vinorelbine regimen was associated with alarming rates of toxicity, more effective and less toxic alternatives should be investigated.
  • article 0 Citação(ões) na Scopus
    Time to Recurrence as a Prognostic Factor in Parathyroid Carcinoma
    (2023) MAGNABOSCO, Felipe Ferraz; BRESCIA, Marilia D'Elboux Guimaraes; NASCIMENTO JUNIOR, Climerio Pereira; MASSONI NETO, Ledo Mazzei; ARAP, Sergio Samir; CASTRO JUNIOR, Gilberto de; LEDESMA, Felipe Lourenco; ALVES, Venancio Avancini Ferreira; KOWALSKI, Luiz Paulo; MARTIN, Regina Matsunaga; MONTENEGRO, Fabio Luiz de Menezes
    Background Parathyroid carcinoma (PC) is a rare and challenging disease without clearly understood prognostic factors. Adequate management can improve outcomes. Characteristics of patients treated for PC over time and factors affecting prognosis were analyzed. Methods Retrospective cohort study including surgically treated patients for PC between 2000 and 2021. If malignancy was suspected, free-margin resection was performed. Demographic, clinical, laboratory, surgical, pathological, and follow-up characteristics were assessed. Results Seventeen patients were included. Mean tumor size was 32.5 mm, with 64.7% staged as pT1/pT2. None had lymph node involvement at admission, and 2 had distant metastases. Parathyroidectomy with ipsilateral thyroidectomy was performed in 82.2%. Mean postoperative calcium levels were different between patients who developed recurrence vs those who did not (P = .03). Six patients (40%) had no recurrence during follow-up, 2 (13.3%) only regional, 3 (20%) only distant, and 4 (26.6%) both regional and distant. At 5 and 10 years, 79% and 56% of patients were alive, respectively. Median disease-free survival was 70 months. Neither Tumor, Nodule, Metastasis system nor largest tumor dimension (P = .29 and P = .74, respectively) were predictive of death. En bloc resection was not superior to other surgical modalities (P = .97). Time between initial treatment and development of recurrence negatively impacted overall survival rate at 36 months (P = .01). Conclusion Patients with PC can survive for decades and have indolent disease course. Free margins seem to be the most important factor in initial surgery. Recurrence was common (60%), but patients with disease recurrence within 36 months of initial surgery had a lower survival rate.
  • article
    Repurposing NF kappa B and HDAC inhibitors to individually target cancer stem cells and non-cancer stem cells from mucoepidermoid carcinomas
    (2023) SILVA, Luan Cesar; BORGATO, Gabriell Bonifacio; WAGNER, Vivian Petersen; MARTINS, Manoela Domingues; SANTOS-SILVA, Alan Roger; JR, Gilberto de Castro; KOWALSKI, Luiz Paulo; SQUARIZE, Cristiane Helena; VARGAS, Pablo Agustin; CASTILHO, Rogerio Moraes
    Drug resistance remains a major obstacle in the treatment of mucoepidermoid carcinomas (MEC) lead-ing to tumor recurrence, disease progression, and metastasis. Emerging evidence suggests that drug resistance is mediated by the presence of a highly adaptative subpopulation of cancer cells known as cancer stem cells (CSC). We have previously reported that solid tumors use NFkB signaling as a chemotherapy-resistant mechanism. We have also shown that interfering with the epigenome of solid tumors is an effective strategy to control the popula-tion of CSC. Here, we sought to investigate the effects of the NFkB inhibitor emetine and the HDAC inhibitor SAHA on the biology of MEC CSC and assessed whether this combination therapy would favor the standard of care therapy comprised of the administration of Cisplatin (CDDP). Our findings suggested that the administration of low concen-trations of emetine and SAHA is more effective in disrupting CSC in MEC, while the administration of emetine in combination with CDDP constitutes an effective therapy to target non-CSC MEC tumor cells.
  • article 0 Citação(ões) na Scopus
    NEPTUNE China cohort: First-line durvalumab plus tremelimumab in Chinese patients with metastatic non-small-cell lung cancer
    (2023) CHENG, Ying; ZHOU, Qing; HAN, Baohui; FAN, Yun; SHAN, Li; CHANG, Jianhua; SUN, Si; FANG, Jian; CHEN, Yuan; SUN, Jianguo; WU, Gang; MANN, Helen; NAICKER, Kirsha; SHIRE, Norah; MOK, Tony; JR, Gilberto de Castro
    Objectives: The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China. Materials and methods: Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (>= 25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020). Results: 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32-1.11), with medians of 15.0 months (95 % CI, 10.5-27.4) and 11.7 months (95 % CI, 8.6-20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2-54.2) and 17.9 % (95 % CI, 6.5-33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48-1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59-2.14) and ITT (HR 0.95; 95 % CI, 0.66-1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs. Conclusions: In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals.
  • article 34 Citação(ões) na Scopus
    Sorafenib for the Treatment of Progressive Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis
    (2016) CASTRONEVES, Luciana Audi de; NEGRAO, Marcelo Vailati; FREITAS, Ricardo Miguel Costa de; PAPADIA, Carla; LIMA JR., Jose Viana; FUKUSHIMA, Julia T.; SIMAO, Eduardo Furquim; KULCSAR, Marco Aurelio Vamondes; TAVARES, Marcos Roberto; JORGE, Alexander Augusto de Lima; CASTRO, Gilberto de; HOFF, Paulo Marcelo; HOFF, Ana Oliveira
    Background: Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC. Methods: This is a retrospective longitudinal study of 13 patients with progressive metastatic MTC treated with sorafenib 400mg twice daily between December 2011 and January 2015. The primary endpoints were to evaluate response and progression-free survival (PFS) in patients treated with sorafenib outside a clinical trial. The secondary endpoint was an assessment of the toxicity profile. One patient was excluded because of a serious allergic skin rash one week after starting sorafenib. Results: The analysis included 12 patients with metastatic MTC (median age 48 years), 10 with sporadic and 2 with hereditary disease. The median duration of treatment was 11 months, and the median follow-up was 15.5 months. At data cutoff, 2/12 (16%) patients were still on treatment for 16 and 34 months. According to Response Evaluation Criteria in Solid Tumors analysis, 10 (83.3%) patients showed stable disease, and two (16.6%) had progression of disease; no partial response was observed. The median PFS was nine months. However, three patients with extensive and rapidly progressive disease died within three months of sorafenib treatment. The median PFS excluding these three patients was 12 months. Adverse events (AE) occurred in nine (75%) patients. The main AEs were skin toxicity, weight loss, and fatigue. Five (41.6%) patients needed dose reduction, and one patient discontinued treatment because of toxicity. Conclusions: Treatment with sorafenib in progressive metastatic MTC is well tolerated and resulted in disease control and durable clinical benefit in 75% of patients. Sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.
  • article 30 Citação(ões) na Scopus
    Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial
    (2019) BURTNESS, Barbara; HADDAD, Robert; DINIS, Jose; TRIGO, Jose; YOKOTA, Tomoya; VIANA, Luciano de Souza; ROMANOV, Ilya; VERMORKEN, Jan; BOURHIS, Jean; TAHARA, Makoto; SEGALLA, Jose Getulio Martins; ESCOBAR, Yolanda; SORIA, Ainara; CHAVES, Mauel; JOHANSSON, Gun Wickart; FRIESLAND, Signe; TELL, Roger; NYMAN, Jan; ROTHSCHILD, Sacha; ZIPPELIUS, Alfred; ASARAWALA, Nirav; KARAVASILIS, Vasilios; RAUCH, Daniel; USLUOGLU, Nurguel; GOGUNSKA, Inna; ZABOLOTNIY, Dmytro; VINNYK, Yuriy; BURIAN, Oleksandr; HARRINGTON, Kevin; SYKES, Andrew; PEEL, David; LESTER, James; FOUNTZILAS, Georgios; NICOLAU, Ulisses Ribaldo; ROBINSON, Martin; SRINIVASAN, Devraj; FRAGKANDREA-NIXON, Ioanna; JUNOR, Elizabeth; GOLLINS, Simon; EVANS, Mererid; NEWBOLD, Kate; HWANG, David; SCHIPANI, Stefano; PSYRRI, Diamanto; RIZWANULLAH, Mohammed; RAUCH, Daniel; ATIQ, Omar; ARNAOUTAKIS, Konstantinos; BAUMAN, Jessica; BURTNESS, Barbara; MEHRA, Ranee; KANG, Hyunseok; CHUNG, Christine; DAVIS, Thomas; LANG, Istvan; HADDAD, Robert; JIMENO, Antonio; EVEN, Caroline; KERESZTES, Roger; NANGIA, Chaitali; IGNATIUS, Sai-Hong; SU, Yungpo Bernard; OVERTON, Lindsay Carol; GARRISON, Mitchell A.; JEONG, Woondong; BOER, Andras; WEHBE, Ahmad; ARGIRIS, Athanassios; CHIANG, Anne; WANG, Bushi; MORGENSZTERN, Daniel; HAIGENTZ JR., Missak; MARTINCIC, Danko; POROSNICU, Mercedes; GIBSON, Neil; EHRNROOTH, Eva; KOCSIS, Judit; HARRINGTON, Kevin; COHEN, Ezra E. W.; GIGLIO, Raul Eduardo; BLAJMAN, Cesar Raul; FREUE, Jose Mario; PILNIK, Norma Graciela; PALAZZO, Felipe Salvador; MCGRATH, Margaret; FUREDER, Thorsten; KORNEK, Gabriela; PAJKOS, Gabor; PICHLER, Angelika; BAUERNHOFER, Thomas; TINCHON, Christoph; GREIL, Richard; BURIAN, Martin; KIENZER, Heinz; SPECENIER, Pol; SAUTOIS, Brieuc; DEBRUYNE, Philip; GRAAS, Marie-Pascale; TAMAS, Laszlo; MAES, Annelies; LONCHAY, Christophe; DAISNE, Jean-Francois; FONTAINE, Christel; CASTRO JUNIOR, Gilberto; OLIVEIRA, Frias de; PEREIRA, Rodrigo Perez; MARCHI, Pedro Rafael Martins De; VIANA, Luciano de Souza; SEGALLA, Jose Getulio Martins; ANAND, A. L.; NICOLAU, Ulisses Ribaldo; LAZARETTI, Nicolas Silva; KULKARNI, Swati; ALAM, Yasmin; HO, Cheryl; SHENOUDA, George; SOULIERES, Denis; SULTANEM, Khalil; SINGH, Simron; MELLA, Pablo Gonzalez; SHARMA, Ajay; CAMPOS, Jose Antonio Solis; HOLECKOVA, Petra; PRAUSOVA, Jana; OBERMANNOVA, Radka; FRIBORG, Jeppe; SPECHT, Lena; ELSAID, Amr Abdelaziz; MINN, Heikki; MARTIN, Laurent; ROLLAND, Frederic; PSYRRI, Amanda; CERUSE, Philippe; CALAIS, Gilles; EVEN, Caroline; GUIGAY, Joe; FERTE, Charles; PEYRADE, Frederic; DUFFAUD, Florence; CHAMPEAUX-ORANGE, Elise; COUTTE, Alexandre; CLATOT, Florian; Sharma; FOURNEL, Pierre; MOAL, Laurence Bozec Le; DIETZ, Andreas; GRUENWALD, Viktor; GAULER, Thomas; GUNTINAS-LICHIUS, Orlando; HILDEBRANDT, Guido; KUHNT, Thomas; SCHMIDT, Horst-Juergen; HENKE, Michael; VOONA, Murali; RUECKERT, Anja; BRUGGER, Wolfram; ROTTER, Nicole; MAHLBERG, Rolf; PANDY, Ananda Selvakumar; KUMAR, Kirushna; NATHAN, Raj Kumar Poovna; SRINIVASAN, Venkatesan; ZADE, Bhooshan; JAIN, Minish; SRINIVASA, B. J.; NAIK, Radheshyam; VASILEVSKAYA, Irina; MOHANTY, B. K.; ASARAWALA, Nirav; CHARAS, Tomer; BILLAN, Salem; POPOVTZER, Aron; LICITRA, Lisa; FERRARI, Daris; FAO, Paolo; MERLANO, Marco; ROCCA, Maria Cossu; NANGIA, Chaitali Singh; HOMMA, Akihiro; FUJII, Hirofumi; TAHARA, Makoto; MINAMI, Syujiro; FUJII, Masato; YOKOTA, Tomoya; KADOWAKI, Shigenori; MURO, Kei; KIYOTA, Naomi; OKAMI, Kenji; CHAVES-CONDE, Manuel; YAGI, Toshinari; YOSHINO, Kunitoshi; MATSUMOTO, Koji; TAKAHASHI, Shunji; MATSUURA, Kazuto; AVITIA, Miguel Angel Alvarez; RIESTRA, Hector Jorge Gonzalez; MEERTEN, E. van; BUTER, J.; GELDERBLOM, A. J.; KIYOTA, Naomi; KAWECKI, Andrzej; GOLUSINSKI, Wojciech; DINIS, Jose; DINIS, Rui; RIBEIRO, Leonor; SILVA, Regina; MANSINHO, Helder; SELEZNEVA, Irina; BIAKHOV, Mikhail; GALIULIN, Rinat; HOMMA, Akihiro; IZMAILOV, Adel; ROMANOV, Ilya; VLADIMIROV, Vladimir; VINOGRADOV, Valery; MUFAZALOV, Fagim; VASILEVSKAYA, Irina; BASTE, Neus; CAMPO, Josep Ma del; NIN, Ricard Mesia; POUSA, Antonio Lopez; HOLECKOVA, Petra; CASTRO, Juan Jose Grau de; REIG, Oscar; VERA, Ruth; TRIGO, JoseManuel; IGLESIAS, Lara; TRUFERO, Javier Martinez; VAZQUEZ, Sergio; RUBIO, Belen; ALES, Jose Enrique; VILLAR, Esther; CAMPO, Josep Maria Del; RUBIO, Jordi
    ImportanceLocoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC. ObjectiveTo assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC. Design, Setting, and ParticipantsThis multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population. InterventionsPatients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal. Main Outcomes and MeasuresThe primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life. ResultsA total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P=.48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group). Conclusions and RelevanceThis study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended. Trial RegistrationClinicalTrials.gov identifier: NCT01345669