RESUMO
BACKGROUND: The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis. METHODS: Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated. RESULTS: A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06). CONCLUSION: In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Oxaliplatina/uso terapêutico , Fluoruracila/uso terapêutico , Quimioterapia Adjuvante/métodos , Neoplasias Hepáticas/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , HepatectomiaRESUMO
BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. METHODS: We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. RESULTS: Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW. CONCLUSIONS: Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Leucovorina/administração & dosagem , Tegafur/administração & dosagem , Uracila/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Neoplasias do Colo/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Japão , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Pontuação de Propensão , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2 of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS). RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%-62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05). CONCLUSION: As postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Colectomia , Neoplasias do Colo/terapia , Recidiva Local de Neoplasia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/métodos , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Japão/epidemiologia , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oxaliplatina/administração & dosagem , Ácido Oxônico/administração & dosagem , Tegafur/administração & dosagemRESUMO
BACKGROUND: This trial was designed to verify the superiority of 6 months of postoperative adjuvant chemotherapy with SOX (S-1 with oxaliplatin) with UFT (tegafur and uracil) with LV (leucovorin) in terms of disease-free survival in patients with high-risk stage III colon cancer. We report the results of a planned safety analysis. PATIENTS AND METHODS: Patients who underwent curative resection for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries) were randomly assigned to receive either UFT/LV (300-600 mg/d UFT with 75 mg/d LV on days 1-28, every 35 days, for 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 with 80-120 mg/d S-1 on days 1-14, every 21 days, for 8 cycles). Treatment status and safety were evaluated. RESULTS: A total of 966 patients were enrolled, and 932 patients were included in safety analyses. The planned 6-month protocol treatment was received by 76.9% of the patients in the UFT/LV group and 65.8% of those in the SOX group. The overall incidence of any Grade adverse events (AEs) were 91.3% in the UFT/LV group and 98.7% in the SOX group, and those of Grade ≥ 3 AEs were 16.1% and 36.1%, respectively. As for Grade ≥ 3 AEs, leukopenia, neutropenia, thrombocytopenia, and sensory neuropathy were more common in the SOX group. The incidence of Grade ≥ 3 sensory peripheral neuropathy was 4.6% in the SOX group. CONCLUSION: The completion rate of adjuvant SOX and its incidence of AEs were acceptable in patients with colon cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Uracila/administração & dosagem , Uracila/efeitos adversosRESUMO
BACKGROUND: The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date. PATIENTS AND METHODS: This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m(2)/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/terapia , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/patologia , Humanos , Leucovorina/administração & dosagem , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Prospectivos , Fatores de Risco , Viés de Seleção , Tegafur/administração & dosagem , Uracila/administração & dosagemRESUMO
BACKGROUND: Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer. METHODS: We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2)l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699. FINDINGS: Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7-13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7-12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86-1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab). INTERPRETATION: SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations. FUNDING: Taiho.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Esquema de Medicação , Combinação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Japão , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Ácido Oxônico/administração & dosagem , Tegafur/administração & dosagem , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate comparative outcome between adjuvant postoperative chemoradiotherapy (postoperative CRT) and lateral pelvic lymph node dissection (LPLD) following total mesorectal excision (TME) in rectal cancer patients. BACKGROUND: Although TME results in lower rate of locoregional recurrence compared with conventional surgery, these 2 treatment modalities following TME have not adequately been appraised until the present trend of preoperative chemoradiotherapy. PATIENTS AND METHODS: Between 1995 and 2000, patients with stage II and III rectal cancer underwent TME plus postoperative CRT (n = 309) or LPLD (n = 176). Patients in the postoperative CRT group received 8 cycles of 5-fluorouracil plus leucovorin and 45 Gy pelvic radiotherapy. Patients in the LPLD group underwent lateral lymph node dissection outside the pelvic plexus. RESULTS: The 5-year overall and disease-free survival rates were 78.3% and 67.3% in the postoperative CRT group, respectively, and 73.9% and 68.6% in the LPLD group, respectively, without significant differences between these groups. Patients in the LPLD group with stage III lower rectal cancer had a locoregional recurrence rate 2.2-fold greater than those in the postoperative CRT group (16.7% vs. 7.5%, P = 0.044). Multivariate analysis showed that APR and advanced T-category (T4) were significantly associated with locoregional recurrence, whereas lymph node metastases, high preoperative serum carcinoembryonic antigen, and APR were significantly associated with shortening of disease-free survival. CONCLUSIONS: Postoperative-CRT and LPLD following TME resulted in comparable survival rates, but the locoregional recurrence rate was higher in the LPLD group. These findings suggest that initial surgery is appropriate for rectal cancer patients who are candidates for low anterior resection without extensive local disease (T1-T3), regardless of lymph node status.
Assuntos
Adenocarcinoma/terapia , Excisão de Linfonodo , Terapia Neoadjuvante/métodos , Neoplasias Retais/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Procedimentos Cirúrgicos do Sistema Digestório , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Pelve , Dosagem Radioterapêutica , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Resultado do Tratamento , Complexo Vitamínico B/administração & dosagemRESUMO
Thymidine phosphorylase (TP) is a unique enzyme involved not only in angiogenesis, but in 5-fluorouracil (5-FU) metabolism as well. TP is produced by both tumor and stromal cells. The aim of this study was to reveal the clinical implication of TP localization in tumor tissues. Advanced colorectal cancer specimens (n=97) were prepared for immunohistochemical staining using monoclonal antibodies against TP, p53, vascular endothelial growth factor (VEGF), factor VIII, CD68 and thymidylate synthase (TS). Clinicopathological factors and the clinical prognosis were examined for each indicator. High tumor TP expression and high stromal TP expression were observed in 38% (36/95 cases) and 49% (47/95 cases) of the cases, respectively. High tumor TP expression tended to correlate with microvessel density (MVD) (p=0.0511). Among patients who underwent curative resection, those with high stromal TP expression had a favorable prognosis (p=0.0127). High stromal TP status was also a strong prognostic factor in the group receiving adjuvant 5-FU derivatives (p=0.0222). TP produced by tumor cells has a stimulatory effect on tumor angiogenesis, while that produced by stromal cells plays an entirely different role. The latter may enhance the anticancer effect of 5-FU via its catalyzed function.
Assuntos
Carcinoma/genética , Carcinoma/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Timidina Fosforilase/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Antimetabólitos Antineoplásicos , Carcinoma/cirurgia , Neoplasias Colorretais/cirurgia , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica , Prognóstico , Estudos Prospectivos , Células Estromais , Análise de Sobrevida , Timidina Fosforilase/análiseRESUMO
The patient is a 66-year-old male who underwent gastrojejunostomy at another hospital with the diagnosis of type 3 unresectable gastric cancer. He was admitted to our hospital for adjuvant chemotherapy. A CT scan revealed both peritoneal dissemination and a large tumor directly invading the pancreas and liver. After 7 courses of combined chemotherapy with 5-FU, Leucovorin, cis-platinum and methotrexate, an effective response, tumor reduction and the disappearance of peritoneal dissemination, was verified by CT scan. Pancreatoduodenectomy with transverse colectomy was carried out and the pathological diagnosis was also curative (pT3, pN1, pP0, HO: stage III A). Although he unfortunately died from peritoneal recurrence after 9 months, he maintained good quality of life after re-operation. We think this case shows the possibility of NAC for patients with far advanced gastric cancer with peritoneal dissemination to improve their prognosis or QOL.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrectomia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Cisplatino/administração & dosagem , Esquema de Medicação , Fluoruracila/administração & dosagem , Humanos , Jejunostomia , Leucovorina/administração & dosagem , Neoplasias Hepáticas/patologia , Metástase Linfática , Masculino , Metotrexato/administração & dosagem , Terapia Neoadjuvante , Invasividade Neoplásica , Neoplasias Pancreáticas/patologia , Neoplasias Peritoneais/patologia , Qualidade de Vida , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgiaRESUMO
A pretherapeutic staging system to design operative or neoadjuvant treatments in gastric cancer is needed. In this study, a simple staging system based on diagnostic laparoscopic findings under local anesthesia to define a treatment was developed. This study was conducted with 68 patients with advanced gastric cancer. All the patients had been diagnosed as more than T3, or were suspected to have peritoneal seeding. Preoperative diagnostic laparoscopy under local anesthesia was performed in the operation room. After insertion of the trocars, the abdominal cavity was inspected, and biopsy and/or abdominal lavage sampling was performed. Patients were allocated into three stages based on laparoscopic and histopathologic findings. Twenty-eight out of 68 patients were diagnosed as P1, 34 patients as P0CY0 and 6 as P0CY1. Based on these results, 57 patients underwent operation. The accuracy rate of diagnosis was 95% in the P category, and 93% in the CY category. Lavage telomerase activity was examined on 10 patients with P0CY0 gastric cancer. Two out of 10 were positive for this activity, and both of them had died due to peritoneal recurrence within a year after operation. In conclusion, the proposed diagnostic laparoscopic staging system is a simple and reproducible method for selection of a suitable therapy. It is considered that diagnostic laparoscopy under local anesthesia is a useful preoperative examination in cases of advanced gastric cancer. Moreover lavage telomerase activity may be a more sensitive predictor of peritoneal recurrence than lavage cytology.