RESUMO
Studies of germline polymorphisms as predictors of tumor response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody agents in metastatic colorectal cancer have reported inconsistent results. We performed a systematic review of studies from 1990 to September 2015, followed by random-effects meta-analyses for polymorphisms examined in at least three studies. Of 87 studies, 40 passed the criteria for systematic review and 23 for meta-analysis. The polymorphisms suitable for meta-analysis were CCND1 (rs17852153), COX2 (rs20417), EGF (rs4444903), EGFR (rs712829, rs11543848, 3'UTR CA repeat), FCGR2A (rs1801274), FCGR3A (rs396991), IL8 (rs4073), KRAS (rs61764370) and VEGFA (rs3025039). Meta-analysis yielded nominal significance (at α=0.05) for rs4444903 and rs11543848, but showed no significant results after multiple testing correction; this was unchanged by sensitivity analyses to address subgroups, funnel-plot asymmetries, and study quality. This highlights a tendency for lack of replication in the face of initial positive results, and possibly the unsuitability of relying on tumor response as a surrogate marker in this setting.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/antagonistas & inibidores , Polimorfismo Genético , Neoplasias Colorretais/mortalidade , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. METHODS: A multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1-14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. RESULTS: Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0-50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh). CONCLUSIONS: Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.
RESUMO
BACKGROUND: Tissue factor pathway inhibitor (TFPI) is an anticoagulant with antimetastatic properties. The homozygous CC polymorphism of TFPI (-33T â C) is associated with higher TFPI levels and lower venous thromboembolism risk. This study was the first to evaluate the impact of this polymorphism on disease-free survival (DFS) in cancer patients after curative resection. METHODS: A prospectively maintained tumor bank with clinical data was used to identify patients who underwent curative surgery for colorectal cancer between 1994 and 2006. Germline DNA was extracted from formalin-fixed, paraffin-embedded normal colonic mucosa. Single nucleotide polymorphisms for TFPI (-33T â C), factor V Leiden (G1691A), and prothrombin (G20210A) were determined by polymerase chain reaction. Survival analysis was described using the Kaplan-Meier method. Multivariable regression analysis was performed using the Cox proportional hazard model. RESULTS: Of the 127 patients identified, the CC genotype was found in 11 %. Venous thromboembolism incidence was 18 % in the TT/TC (wild type/heterozygous) genotypes and 7 % in the CC genotype (p = 0.46). The CC genotype was associated with superior DFS (hazard ratio 0.34, 95 % confidence interval 0.14-0.84; p = 0.02) with 5-year DFS of 63 vs. 24 % for CC vs. TT/TC, respectively. In multivariate analysis, CC polymorphism (hazard ratio 0.28, p = 0.008) was independently associated with improved DFS. The prevalence of factor V Leiden (0.8 %) and prothrombin (1.6 %) polymorphisms was too low to detect interaction with TFPI polymorphism or DFS. CONCLUSIONS: These findings indicate that the inherited anticoagulant homozygous -33T â C TFPI polymorphism may protect against colon cancer recurrence and suggests a mediating role for the coagulation system in cancer outcomes.
Assuntos
Neoplasias Colorretais/mortalidade , Lipoproteínas/genética , Recidiva Local de Neoplasia/mortalidade , Polimorfismo de Nucleotídeo Único , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: There is insufficient information regarding the prognostic significance of baseline and change in quality of life (QoL) scores on overall survival (OS) in advanced pancreatic cancer. METHODS: QoL was assessed prospectively using the EORTC QLQ-C30 as part of the PA.3 trial of gemcitabine + erlotinib (G + E) vs. gemcitabine + placebo (G + P). Relevant variables and QoL scores at baseline and change at 8 weeks were analyzed by Cox stepwise regression to determine predictors of OS. RESULTS: 222 of 285 patients (pts) treated with G + E and 220 of 284 pts treated with G + P completed baseline QoL assessments. In a multivariable Cox analysis combining all pts, better QoL physical functioning (PF) score independently predicted longer OS (HR 0.86; CI: 0.80-0.93), as did non-white race (HR 0.64; CI: 0.44-0.95), PS 0-1 (HR 0.65; CI: 0.50-0.85), locally advanced disease (HR 0.55; CI: 0.43-0.71) and G + E (HR 0.78; CI: 0.64-0.96). Improvement in physical function at week 8 also predicted for improved survival (HR 0.89; CI: 0.81-0.97 for 10 point increase in score, p = 0.02). CONCLUSION: In addition to clinical variables, patient reported QoL scores at baseline and change from baseline to week 8 added incremental predictive information regarding survival for advanced pancreatic cancer patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/psicologia , Neoplasias Pancreáticas/terapia , Qualidade de Vida , Resultado do Tratamento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/administração & dosagem , Feminino , Humanos , Lactente , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Grupos Raciais , Análise de Sobrevida , Adulto Jovem , GencitabinaRESUMO
The prognosis for locally advanced esophageal cancer is poor despite the use of trimodality therapy. In this phase II study, we report the feasibility, tolerability and efficacy of adjuvant sunitinib. Included were patients with stage IIa, IIB or III cancer of the thoracic esophagus or gastroesophageal junction. Neoadjuvant therapy involved Irinotecan (65 mg/m2 ) + Cisplatin (30 mg/m2 ) on weeks 1 and 2, 4 and 5, 7 and 8 with concurrent radiation (50Gy/25 fractions) on weeks 4-8. Sunitinib was commenced 4-13 weeks after surgery and continued for one year. Sixty-one patients were included in the final analysis, 36 patients commenced adjuvant sunitinib. Fourteen patients discontinued sunitinib due to disease recurrence (39%) within the 12-month period, 12 (33%) discontinued due to toxicity, and 3 (8%) requested cessation of therapy. In the overall population, median survival was 26 months with a 2 and 3-year survival rate of 52% and 35%, respectively. The median survival for the 36 patients treated with sunitinib was 35 months and 2-year survival probability of 68%. In a historical control, a prior phase II study with the same trimodality therapy (n = 43), median survival was 36 months, with a 2-year survival of 67%. Initiation of adjuvant sunitinib is feasible, but poorly tolerated, with no signal of additional benefit over trimodality therapy for locally advanced esophageal cancer.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Esofágicas/terapia , Indóis/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Quimiorradioterapia , Quimioterapia Adjuvante/mortalidade , Cisplatino/administração & dosagem , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Esofagectomia , Junção Esofagogástrica/patologia , Estudos de Viabilidade , Feminino , Humanos , Indóis/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Período Pós-Operatório , Pirróis/efeitos adversos , Sunitinibe , Taxa de Sobrevida , Suspensão de Tratamento/estatística & dados numéricosRESUMO
Background The folate receptor alpha is selectively over-expressed in a number of human cancers. BMS-753493 is a folate conjugate of the epothilone analog BMS-748285 that was designed to selectively target folate receptor expressing cancer cells. Methods BMS-753493 was investigated in two parallel multi-institutional first-in-human phase I/IIa studies in patients with advanced solid tumors. In Study 1, patients were treated on a schedule of once daily dosing of BMS-753493 administered on Days 1, 4, 8 and 11 every 21 days with a starting dose of 5 mg daily and in Study 2, patients were treated once daily on Days 1-4 every 21 days, with a starting dose of 2.5 mg daily. Results A total of 65 patients were treated across the two studies. The maximum tolerated dose (MTD) was 26 mg in Study 1 and 15 mg in Study 2. Fatigue, transaminitis, gastrointestinal toxicity, and mucositis were dose-limiting toxicities. One patient in Study 2 developed Stevens-Johnson syndrome attributed to BMS-753493. Plasma exposures of both the conjugated and free epothilone increased in a dose related fashion in both studies and the half-life of the conjugated epothilone was 0.2-0.6 h across dose levels. No objective tumor responses were seen in either study. Conclusions BMS-753493 was generally tolerable and toxicities known to be associated with epothilone class of anticancer agents were common, although peripheral neuropathy and neutropenia appear to have been less frequent and less severe as compared to epothilones. Antitumor activity was not demonstrated and further development of BMS-753493 has been discontinued.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Epotilonas/efeitos adversos , Epotilonas/farmacocinética , Ácido Fólico/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Epotilonas/administração & dosagem , Feminino , Ácido Fólico/administração & dosagem , Ácido Fólico/efeitos adversos , Ácido Fólico/farmacocinética , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. METHODS: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction. RESULTS: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group. CONCLUSION: In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Fator de Crescimento Epidérmico/biossíntese , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Cetuximab , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Fator de Crescimento Epidérmico/genética , Epirregulina , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC. PATIENTS AND METHODS: Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome. RESULTS: The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02). CONCLUSIONS: In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Magnésio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Cetuximab , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Receptores ErbB/metabolismo , Feminino , Humanos , Hipercalciúria/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nefrocalcinose/induzido quimicamente , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Erros Inatos do Transporte Tubular Renal/induzido quimicamente , Resultado do Tratamento , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
PURPOSE: AT9283 is a potent inhibitor of the mitotic regulators, Aurora-kinases A and B, and has shown anti-tumor activity in patients with solid and haematological malignancies. This phase I study assessed safety, tolerability, pharmacokinetic and pharmacodynamic properties of AT9283. PATIENTS AND METHODS: Patients with advanced, incurable solid tumors or non-Hodgkin's lymphoma received AT9283 as a continuous 24-hour infusion on days 1, 8 of a 21-day cycle. A 3 + 3 dose escalation design was used with a starting dose of 1.5 mg/m(2)/day. Pharmacokinetic samples were collected from all patients on cycle one, and pharmacodynamic samples were collected from 4 patients at the recommended phase II dose (RP2D). RESULTS: 35 patients were evaluable for toxicity and 32 were evaluable for response. AT9283 was well tolerated, with main toxicities being reversible dose-related fatigue, gastrointestinal disturbance, anemia, lymphocytopenia and neutropenia. The dose limiting toxicities were febrile neutropenia (two patients) and neutropenia with grade 3 infection (1 patient) at 47 mg/m(2)/day (established as the maximum tolerated dose). The RP2D was 40 mg/m(2)/day. Pharmacokinetic analyses showed AT9283 appeared to follow linear kinetics, with a mean elimination half-life of 8.2 h. Pharmacodynamic analyses showed no consistent or significant changes, but trends suggested evidence of AT9283 inhibition and anti-proliferative activity. One patient had partial response and four patients experienced RECIST stable disease (median 2.6 months). CONCLUSION: In this study, AT9283 was well tolerated. The RP2D is 40 mg/m(2)/day on days 1, 8 of a 21-day cycle. Ongoing AT9283 trials will assess efficacy and safety in solid and haematological cancers.
Assuntos
Antineoplásicos/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Ureia/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Esquema de Medicação , Feminino , Histonas/metabolismo , Humanos , Infusões Intravenosas , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pele/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/farmacocinéticaRESUMO
BACKGROUND: the interplay between comorbidity, age and performance status (PS) as predictors of outcome in advanced colorectal cancer (ACRC) is poorly understood. We examined these factors as predictors of treatment toxicity and outcome in cetuximab-treated patients with ACRC. PATIENTS AND METHODS: comorbidity was independently evaluated using the Charlson Comorbidity Index (CCI), a validated measure of comorbidity based on the presence of medical conditions weighted according to their effect on mortality. CCI score was correlated with clinical and outcome data. RESULTS: five hundred and seventy-two patients were included; 41% were ≥ 65 years and 25% had comorbidities at randomization. In multivariate analysis (MVA) of all covariates, only older age was associated with greater comorbidity (P = 0.008). Overall survival (OS) was significantly better for patients with greater comorbidity in univariate analysis (P = 0.047). Conversely, better PS was associated with better OS in MVA (hazard ratio 1.92 for PS = 2 versus PS = 0, P < 0.0001). Age was not associated with OS (P = 0.13). Elderly patients had significantly less grade ≥ 3 vomiting (P = 0.034) but more dyspnea (P = 0.005). Patients with greater comorbidity had significantly less grade ≥ 3 vomiting (P = 0.002) but more non-neutropenic fever (P = 0.005). CONCLUSION: better PS was associated with improved OS. For patients with good PS, restricting cetuximab use in the setting of significant comorbidity does not appear justified.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/terapia , Cuidados Paliativos/métodos , Fatores Etários , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Cetuximab , Comorbidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Análise Multivariada , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. CONCLUSION: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.
Assuntos
Alanina/análogos & derivados , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Triazinas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina/farmacologia , Alanina/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/mortalidade , Neovascularização Patológica , Triazinas/uso terapêuticoRESUMO
BACKGROUND: Anal cancer is uncommon. We reviewed the treatment and outcomes of anal cancer patients in a population referred to the Ottawa Hospital Cancer Centre (TOHCC) over a 12-year period. METHODS: A chart review was conducted with patient data collected from hospital records, including: demographic, treatment and outcome information. Outcomes of interest included: overall survival (OS), disease free survival (DFS), and colostomy free survival (CFS). RESULTS: 180 patients were included in the study population. 72% (n = 130) female and 28% (n = 50) male. 6.7% (n = 12 males) of patients were HIV positive - all were on anti-retroviral therapy. 60% (n = 108) of patients were ever-smokers, mean patient age was 62 [range 35-90] years. The most frequent presenting symptoms were blood per rectum and anal pain. Treatment intent was curative in 87%. Treatment included radiotherapy (94%), brachytherapy (26%), chemotherapy (73%). Among patients treated with curative-intent, 72% had a complete response, 31% had local/regional recurrence, 16% required salvage surgery and 21% had distant recurrence. The colostomy rate was 23%. 5 year overall survival (OS) was not significantly different for patients by HIV status. Survival was superior if MMC-FU was used first vs. CIS-FU; OS HR 0.47 (0.24-0.94), p < 0.033. CONCLUSIONS: The outcomes of patients in this large retrospective cohort study are similar to the outcomes of patients in highly selective clinical trials. Five year overall survival and colostomy free survival are encouraging. MMC-FU was found to be superior to CIS-FU.
Assuntos
Canal Anal/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Colostomia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/epidemiologia , Neoplasias do Ânus/mortalidade , Braquiterapia , Institutos de Câncer , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Quimiorradioterapia , Cisplatino/administração & dosagem , Estudos de Coortes , Comorbidade , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Ontário/epidemiologia , Infecções por Papillomavirus/epidemiologia , Radioterapia , Estudos Retrospectivos , Terapia de Salvação , Fumar/epidemiologiaRESUMO
BACKGROUND: Right- and left-sided colon cancers (RC, LC) differ with respect to biology, pathology and epidemiology. Previous data suggest a mortality difference between RC and LC. We examined if primary tumour side also predicts for outcome in chemotherapy refractory, metastatic colon cancer (MCC). We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor (EGFR) inhibition with cetuximab. METHODS: Reanalyzing NCIC CO.17 trial (cetuximab versus best supportive care [BSC]), we coded the primary tumour side as RC (caecum to transverse colon) or LC (splenic flexure to rectosigmoid). The association between tumour side and baseline characteristics was assessed. Cox regression models determined factors affecting overall survival (OS) and progression free survival (PFS). RESULTS: Patients with RC (150/399) had more poorly differentiated, mutant KRAS, mutated PIK3CA and wild-type BRAF tumours, fewer liver and lung metastases, and shorter interval between diagnosis and study entry. Among BSC patients, tumour side was not prognostic for PFS (hazard ratios (HR) 1.07 [0.79-1.44], p = 0.67) or OS (HR 0.96 [0.70-1.31], p = 0.78). Among wild-type KRAS patients, those with LC had significantly improved PFS when treated with cetuximab compared to BSC (median 5.4 versus 1.8 months, HR 0.28 [0.18-0.45], p < 0.0001), whereas those with RC did not (median 1.9 versus 1.9 months, HR 0.73 [0.42-1.27], p = 0.26), [interaction p = 0.002]. CONCLUSION: In refractory MCC, tumour location within the colon is not prognostic, but is strongly predictive of PFS benefit from cetuximab therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Cetuximab , Neoplasias Colorretais/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos/métodos , Prognóstico , Análise de Regressão , Taxa de SobrevidaRESUMO
BACKGROUND: The effect of comorbidity, age and performance status (PS) on treatment of advanced pancreatic cancer is poorly understood. We examined these factors as predictors of outcome in advanced pancreatic cancer patients treated with gemcitabine +/- erlotinib. PATIENTS AND METHODS: Comorbidity was evaluated by two physicians using the Charlson Comorbidity Index (CCI) and correlated with clinical outcome data from the NCIC Clinical Trials Group (NCIC CTG) PA.3 clinical trial. RESULTS: Five hundred and sixty-nine patients were included; 47% were aged ≥ 65 years old, 36% had comorbidity (CCI>0). In multivariate analysis, neither age (p=0.22) nor comorbidity (p=0.21) was associated with overall survival. The baseline presence of better PS and lower pain intensity scores was associated with better overall survival (p < 0.0001 and p=0.01, respectively). An improvement in survival with the addition of erlotinib therapy was seen in patients age < 65 (adjusted hazard ratio (HR) 0.73, p=0.01) or in the presence of comorbidity (adjusted HR 0.72, p=0.03). However, neither age nor CCI score was predictive of erlotinib benefit after test for interaction. Patients treated with gemcitabine plus erlotinib who were ≥ 65 years of age or those with comorbidity had a higher rate of infections ≥ grade 3. CONCLUSION: Low baseline pain intensity and better PS were associated with improved overall survival, while age and comorbidity were not independent prognostic factors for patients treated with gemcitabine-based therapy.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Comorbidade , Desoxicitidina/administração & dosagem , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Avaliação de Resultados em Cuidados de Saúde , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/epidemiologia , Placebos , Modelos de Riscos Proporcionais , Risco , GencitabinaRESUMO
PURPOSE: The primary objective of this phase I dose-escalation study was to identify the maximum tolerated dose (MTD) of sunitinib plus pemetrexed in patients with advanced cancer. METHODS: Using a 3 + 3 dose-escalation design, patients received oral sunitinib qd by continuous daily dosing (CDD schedule; 37.5 or 50 mg) or 2 weeks on/1 week off treatment schedule (Schedule 2/1; 50 mg). Pemetrexed (300-500 mg/m(2) IV) was administered q3w. At the proposed recommended phase 2 dose (RP2D), additional patients with non-small cell lung cancer (NSCLC) were enrolled. RESULTS: Thirty-five patients were enrolled on the CDD schedule and seven on Schedule 2/1. MTDs were sunitinib 37.5 mg/day (CDD/RP2D) or 50 mg/day (Schedule 2/1) with pemetrexed 500 mg/m(2). Dose-limiting toxicities included grade (G) 5 cerebral hemorrhage, G3 febrile neutropenia, and G3 anorexia. Common G3/4 drug-related non-hematologic adverse events (AEs) at the CDD MTD included fatigue, anorexia, and hand-foot syndrome. G3/4 hematologic AEs included lymphopenia, neutropenia, and thrombocytopenia. No significant drug-drug interactions were identified. Five (24%) NSCLC patients had partial responses. CONCLUSIONS: In patients with advanced solid malignancies, the MTD of sunitinib plus 500 mg/m(2) pemetrexed was 37.5 mg/day (CDD schedule) or 50 mg/day (Schedule 2/1). The CDD schedule MTD was tolerable and demonstrated promising clinical benefit in NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Glutamatos/uso terapêutico , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Guanina/farmacocinética , Guanina/uso terapêutico , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Indóis/uso terapêutico , Neoplasias Pulmonares/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pemetrexede , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/farmacocinética , Pirróis/uso terapêutico , Sunitinibe , Resultado do TratamentoRESUMO
AIMS: The standard adjuvant therapy for resected stage III colon cancer has been intravenous 5-fluorouracil. However, newer chemotherapy agents, such as capecitabine, oxaliplatin and irinotecan, have been investigated in clinical trials since the publication of the original guidelines. The Gastrointestinal Cancer Disease Site Group (DSG) conducted a systematic review of the evidence for the use of adjuvant systemic chemotherapy for patients with resected stage II and III colon cancer and developed an updated practice guideline based on that evidence and expert consensus. The following research questions were addressed: Should patients with stage II or III colon cancer receive adjuvant systemic chemotherapy? What are the preferred adjuvant systemic chemotherapy options for patients with completely resected stage II or III colon cancer? Outcomes of interest were disease-free survival, overall survival, adverse effects and quality of life. MATERIALS AND METHODS: A systematic search of published studies was conducted for the time period following the publication of the original guidelines to identify relevant randomised trials and syntheses of evidence in the form of meta-analyses. Recommendations were based on that evidence, evidence contained in the original guidelines and consensus of the Gastrointestinal Cancer DSG. The systematic review and practice guideline were externally reviewed through a mailed survey of practitioners in Ontario, Canada. RESULTS: Recommendations were drafted based on the available evidence and expert consensus. CONCLUSIONS: The routine use of adjuvant chemotherapy for all patients with stage II colon cancer is not recommended. However, a subset of patients with high-risk stage II disease should be considered for adjuvant therapy. Patients with completely resected stage III colon cancer should be offered adjuvant chemotherapy. Treatment should depend on factors such as patient suitability and preference, and patients and clinicians must work together to determine the optimal course of treatment.
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Neoplasias do Colo/tratamento farmacológico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Humanos , Estadiamento de Neoplasias , OntárioRESUMO
To estimate the magnitude of benefit of chemotherapy in prolonging survival for patients with metastatic colorectal cancer, a meta-analysis of randomized controlled trial was performed. A systematic search was performed to identify randomized trials comparing chemotherapy with observation or supportive care alone. Trials were assessed for quality of reporting, publication bias and heterogeneity. Relative risks for outcomes from published data were pooled using a random-effects model. Seven trials with 614 patients were included. All trials used fluoropyrimidine-based chemotherapy, through a variety of routes and schedules, including intravenous, intra-portal and hepatic arterial infusion. Compared with the 'no-chemotherapy' arm, chemotherapy significantly reduced 1-year mortality (risk ratio 0.69; 95% confidence interval (CI) 0.60-0.81, P < 0.00001). The mortality at 2 years was not significantly different (risk ratio 0.93; 95% CI 0.87-1.00, P = 0.053). Between-trial comparisons demonstrated benefit with a variety of routes and schedules. Chemotherapy significantly prolongs 1-year survival for patients with metastatic colorectal cancer, and should be offered to those with good performance status.
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Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Análise de Sobrevida , Antineoplásicos/efeitos adversos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/fisiopatologia , Humanos , Metástase Neoplásica , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: To test the feasibility and effectiveness of a high-frequency short-term group cognitive-behavioral therapy (CBT) for recurrent suicide attempters. METHOD: CBT consisting of eight weekly and two "booster" sessions was given to nine female out-patients who had attempted suicide at least twice, seven of whom had a personality disorder. RESULTS: Four patients dropped out during the treatment; either because they were "chronic repeaters" (i.e., had a history of more than 8 suicide attempts), or because the last suicide attempt was too long ago. Although the patients were generally positive about the content of the therapy, no effects on psychiatric symptomatology or repetition of suicidal behavior could be demonstrated. CONCLUSIONS: Based on this experience, and on the two controlled studies of CBT of recurrent suicide attempters published in the literature, it is tentatively concluded that it is difficult to organize a short-term high-frequency group treatment for recurrent suicide attempters with personality disorders, and that CBT may delay repetition of suicidal behavior, but that "major repeaters" (i.e., who made 4 or more suicide attempts) with a borderline personality disorder tend to stay major repeaters.