RESUMO
BACKGROUND: Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. METHODS: This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18-75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0-3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1-14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting. FINDINGS: Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6-29·4) in the Debio 1143 group and 24·2 months (6·6-26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39-69) of 48 patients in the Debio 1143 group versus 16 (33%; 20-48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13-6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3-4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group. INTERPRETATION: To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. FUNDING: Debiopharm.
Assuntos
Cisplatino/administração & dosagem , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Adulto JovemRESUMO
BACKGROUND & AIMS: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC. METHODS: The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (nâ¯=â¯323) were randomly assigned to sorafenib-pravastatin combination (nâ¯=â¯162) or sorafenib alone (nâ¯=â¯161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life. RESULTS: After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35â¯months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7â¯months vs. 10.5â¯months; hazard ratioâ¯=â¯1.00; pâ¯=â¯0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported. CONCLUSION: Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC. LAY SUMMARY: Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pravastatina/uso terapêutico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/mortalidade , Diarreia/induzido quimicamente , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Pravastatina/efeitos adversos , Prognóstico , Intervalo Livre de Progressão , Qualidade de Vida , Sorafenibe/efeitos adversosRESUMO
BACKGROUND: The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. METHODS: This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. FINDINGS: Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). INTERPRETATION: Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. FUNDING: GERCOR and F Hoffmann-La Roche.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/secundário , Cloridrato de Erlotinib/administração & dosagem , Quimioterapia de Manutenção , Idoso , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: We report long-term efficacy and overall survival (OS) results from a randomised, double-blind, phase 2 study (NCT02022098) investigating xevinapant plus standard-of-care chemoradiotherapy (CRT) vs. placebo plus CRT in 96 patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). METHODS: Patients were randomised 1:1 to xevinapant 200 mg/day (days 1-14 of a 21-day cycle for 3 cycles), or matched placebo, plus CRT (cisplatin 100 mg/m2 every 3 weeks for 3 cycles plus conventional fractionated high-dose intensity-modulated radiotherapy [70 Gy/35 F, 2 Gy/F, 5 days/week for 7 weeks]). Locoregional control, progression-free survival, and duration of response after 3 years, long-term safety, and 5-year OS were assessed. RESULTS: The risk of locoregional failure was reduced by 54% for xevinapant plus CRT vs. placebo plus CRT but did not reach statistical significance (adjusted hazard ratio [HR] 0.46; 95% CI, 0.19-1.13; P = .0893). The risk of death or disease progression was reduced by 67% for xevinapant plus CRT (adjusted HR 0.33; 95% CI, 0.17-0.67; P = .0019). The risk of death was approximately halved in the xevinapant arm compared with placebo (adjusted HR 0.47; 95% CI, 0.27-0.84; P = .0101). OS was prolonged with xevinapant plus CRT vs. placebo plus CRT; median OS not reached (95% CI, 40.3-not evaluable) vs. 36.1 months (95% CI, 21.8-46.7). Incidence of late-onset grade ≥3 toxicities was similar across arms. CONCLUSIONS: In this randomised phase 2 study of 96 patients, xevinapant plus CRT demonstrated superior efficacy benefits, including markedly improved 5-year survival in patients with unresected LA SCCHN.
Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Seguimentos , Antineoplásicos/uso terapêutico , Cisplatino , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter study randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT. Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. The 9-year overall survival (OS) was similar in the HDT and conventional chemotherapy groups (76% and 80%, respectively). The 9-year progression-free survival (PFS) was higher in the ASCT than the chemotherapy group (64% vs 39%; P = .004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the per-formance status score, the number of nodal areas involved, and the treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary myelodysplastic syndrome/acute myeloid leukemia and 6 second solid tumor cancers vs 1 acute myeloid leukemia, P = .01). The occurrence of a PFS plateau suggests that a subgroup of patients might have their FL cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under identifier NCT00696735.
Assuntos
Purging da Medula Óssea , Linfoma Folicular/mortalidade , Linfoma Folicular/terapia , Segunda Neoplasia Primária/mortalidade , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Adolescente , Adulto , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Taxa de Sobrevida , Transplante Autólogo , Irradiação Corporal TotalRESUMO
PURPOSE: To develop a radiomic model predicting nonresponse to induction chemotherapy in laryngeal cancers, from multicenter pretherapeutic contrast-enhanced computed tomography (CE-CT) and evaluate the benefit of feature harmonization in such a context. METHODS: Patients (n = 104) eligible for laryngeal preservation chemotherapy were included in five centers. Primary tumor was manually delineated on the CE-CT images. The following radiomic features were extracted with an in-house software (MIRAS v1.1, LaTIM UMR 1101): intensity, shape, and textural features derived from Gray-Level Co-occurrence Matrix (GLCM), Neighborhood Gray Tone Difference Matrix (NGTDM), Gray-Level Run Length Matrix (GLRLM), and Gray-Level Size Zone Matrix (GLSZM). Harmonization was performed using ComBat after unsupervised hierarchical clustering, used to determine labels automatically, given the high heterogeneity of imaging characteristics across and within centers. Patients with similar feature distributions were grouped with unsupervised clustering into an optimal number of clusters (2) determined with "silhouette scoring." Statistical harmonization was then carried out with ComBat on these 2 identified clusters. The cohort was split into training/validation (n = 66) and testing (n = 32) sets. Area under the receiver operating characteristics curves (AUC) were used to evaluate the ability of radiomic features (before and after harmonization) to predict nonresponse to chemotherapy, and specificity (Sp) and sensitivity (Se) were used to quantify their performance in the testing set. RESULTS: Without harmonization, none of the features identified as predictive in the training set remained significant in the testing set. After ComBat, one textural feature identified in the training set keeps a predictive trend in the testing set-Zone Percentage, derived from the GLSZM, was predictive of nonresponse in the training set (AUC = 0.62, Se = 70%, Sp = 64%, P = 0.04) and obtained a satisfactory performance in the testing set (Se = 80%, Sp = 67%, P = 0.03), although significance was limited by the size of the testing set. These results are consistent with previously published findings in head and neck cancers. CONCLUSIONS: Radiomic features from CE-CT could help in the selection of patients for induction chemotherapy in laryngeal cancers, with relatively good sensitivity and specificity in predicting lack of response. Statistical harmonization with ComBat and unsupervised clustering seems to improve the predictive value of features extracted in such a heterogeneous multicenter setting.
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Neoplasias Laríngeas , Estudos de Coortes , Humanos , Quimioterapia de Indução , Neoplasias Laríngeas/diagnóstico por imagem , Neoplasias Laríngeas/tratamento farmacológico , Curva ROC , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND/AIMS: The Bretagne-Pays de la Loire cancer observatory, an oncology network created by the French Ministry of Health, is specifically dedicated to assess the use of new targeted anticancer therapies in routine practice. In line with the French National Cancer III program, our cancer network set up a real-life cohort, which is independent of the pharmaceutical industry, for patients with colorectal cancer to monitor patient safety and quality of care and promote pharmacovigilance. MATERIALS AND METHODS: Panitumumab monotherapy was assessed in 243 patients with wild-type Kirsten rat sarcoma who were treated for metastatic colorectal cancer (mCRC) between July 2008 and December 2010 after prior chemotherapy using oxaliplatine and irinotecan. This was a post-European medicine agency marketing (EMA-M) study Results: This study shed light on the best practices, strategic adaptations, clinical results (treatment objective responses, 13%; progression free survival, 2.99 months [2.73-3.15]; and overall survival, 6.8 months [5.49-8.38]) as well as expected or unexpected (grade 3 or 4: 11.5%) secondary effects in the phase IV panitumumab treatment of mCRC. CONCLUSION: Our results are similar to those by Amado whose phase III study led to obtaining EMA-M for panitumumab and tend to confirm the antitumor activity of this antiepidermal growth factor receptor antibody in the treatment of mCRC. In addition, our results opened avenues to further assessment of panitumumab use as monotherapy as well as its benefit-risk ratio while taking into account the patients' general and clinical characteristics. In 2012, the French National Authority for Health appended these data to the panitumumab transparency committee report.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Panitumumabe/uso terapêutico , Vigilância de Produtos Comercializados , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Feminino , França , Geriatria , Humanos , Masculino , Oncologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Resultado do TratamentoAssuntos
Recombinação Homóloga , Janus Quinase 2/genética , Processos Neoplásicos , Policitemia Vera/genética , Substituição de Aminoácidos , Cromossomos Humanos Par 9/genética , Cromossomos Humanos Par 9/metabolismo , Granulócitos/metabolismo , Humanos , Janus Quinase 2/metabolismo , Linfócitos/metabolismo , Modelos Genéticos , Mosaicismo , Mutação , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Policitemia Vera/sangue , Policitemia Vera/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Trissomia/genética , Dissomia Uniparental/genética , Regulação para CimaRESUMO
INTRODUCTION: Paclitaxel (Taxol) is a drug derived from the bark of the Pacific yew tree and is widely used in cancer treatment, especially for breast, ovarian, and lung cancers. It has not previously been reported to induce lupus. CASE: We report the case of a woman with ovarian cancer who developed paclitaxel-induced lupus on two occasions. Both times, the paclitaxel dramatically improved the ovarian cancer. DISCUSSION: The diagnosis of lupus was confirmed by the initial skin appearance, elevated levels of antinuclear antibodies, recurrence on reintroduction, and biopsy results. To our knowledge, it is the first case reported of paclitaxel-induced lupus.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Lúpus Eritematoso Cutâneo/induzido quimicamente , Paclitaxel/efeitos adversos , Idoso , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Anticorpos Antinucleares/análise , Antineoplásicos Fitogênicos/uso terapêutico , Betametasona/administração & dosagem , Betametasona/análogos & derivados , Betametasona/uso terapêutico , Biópsia , Quimioterapia Combinada , Eritropoetina/administração & dosagem , Eritropoetina/uso terapêutico , Feminino , Humanos , Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Cutâneo/patologia , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Recombinantes , Recidiva , Pele/patologia , Resultado do TratamentoRESUMO
INTRODUCTION: The identification of RAS status (KRAS and NRAS) has changed the management of metastatic colorectal cancer (mCRC). The impact of the RAS mutation on cytotoxic chemotherapy efficacy has not yet been determined. Nevertheless, several retrospective studies suggest a greater efficacy of oxaliplatin in mCRC with KRAS mutation. METHODS: We analyzed retrospectively the progression free survival (PFS) and overall survival (OS) in 216 patients with mCRC receiving first line treatment between 2008 and 2010 according to KRAS status and chemotherapy regimen used (oxaliplatin- or irinotecan-based, in association with fluoropyrimidine and bevacizumab). RESULTS: In KRAS mutated tumors, median OS was 23.4 months with oxaliplatin-based regimen, and 23.6 months with irinotecan-based regimen, with no significant difference (HR 1.30; 95 % CI 0.81-2.09; P=0.27). In KRAS wild-type tumors, median OS was 30.3 months with oxaliplatin-based regimen, and 25.4 months with irinotecan-based regimen, with no significant difference (HR 0.81; 95 % CI 0.52-1.24; P=0.33). Similarly, KRAS mutational status had no significant effect on efficacy of oxaliplatin or irinotecan regarding PFS. DISCUSSION: In this retrospective study, KRAS mutational status does not influence the efficacy of first line cytotoxic chemotherapy in association with bevacizumab.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes ras , Compostos Organoplatínicos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , França , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Estudos Retrospectivos , Análise de SobrevidaRESUMO
INTRODUCTION: There is no predictive factor of response to bevacizumab in metastatic colorectal cancer. Nevertheless, preclinical studies demonstrated an interaction between primary tumor and metastatic sites for the neoangiogenesis regulation. The primary objective of our study was to identify an effect of up-front primary tumor resection (UPTR) on bevacizumab efficacy. PATIENTS AND METHODS: Between 2008 and 2010, we retrospectively analyzed progression-free survival (PFS) and overall survival (OS) of 316 patients with synchronous and metachronous metastatic colorectal cancer according to bevacizumab addition to first-line chemotherapy and UPTR. RESULTS: Among 206 patients with UPTR, the addition of bevacizumab to chemotherapy significantly improved OS compared to chemotherapy alone (29.8 vs. 23.9 months respectively; hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.40-0.83; P = .003). This effect was confirmed in multivariate analysis. There was also a nonsignificant trend toward improved PFS (9.7 vs. 8.4 months respectively; HR 0.71; 95% CI, 0.50-1.02; P = .062). Conversely, among 110 patients without UPTR, the addition of bevacizumab to chemotherapy had no effect on OS compared to chemotherapy alone (18.2 vs. 19.3 months respectively; HR 0.96; 95% CI, 0.65-1.42; P = .853). Bevacizumab significantly improved PFS (8.1 vs. 5.7 months respectively; HR 0.66; 95% CI, 0.45-0.96; P = .032) without confirmation in multivariate analysis. CONCLUSION: In this retrospective study, bevacizumab seems to improve OS only in patients with UPTR, which could suggest a complementarity of both therapeutic modalities for antiangiogenic effect.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Colectomia , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Adulto JovemRESUMO
This study addresses the extent of the heterogeneity of KRAS status, present in a minority of metastatic colorectal carcinomas (mCRCs), on the basis of a thorough analysis of surgical resection specimens. Eighteen patients with mCRC were included. KRAS mutations (exon 2, codons 12 and 13) were determined using PCR and subsequent direct sequencing. This analysis included primary tumours (n=21), synchronous (n=10) and metachronous (n=18) matched metastases, and pelvic recurrence (n=1). Heterogeneity of KRAS status consisted in KRAS mutated in (i) the primary tumour but not in its synchronous metastasis, (ii) the metastasis but not in the primary tumour, (iii) the pelvic recurrence but not in the primary tumour, (iiii) some metastases and not in others from the same patient. Finally, the KRAS status varied among different areas of the same metastatic focus. This study defines the concept of KRAS mosaicism that affects a minority of mCRCs.
Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Mosaicismo , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Análise Mutacional de DNA , DNA de Neoplasias/análise , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas p21(ras)RESUMO
Doxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.