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Subsequent to a medical examination, a 61-year-old male was referred to our hospital with jaundice. He was diagnosed with intrahepatic cholangiocarcinoma involving the hepatic hilum and was referred to our department to undergo a left trisectionectomy of the liver, extrahepatic bile duct resection, and regional lymphadenectomy. He was discharged on postoperative day 39 without liver failure. Two months postoperatively, positron-emission tomography/computed tomography(PET/ CT)indicated recurrences in the bone, and paraaortic lymph node. Gemcitabine and cisplatin combination first-line therapy was administered. Disease progression occurred after 4 courses of therapy. Gene panel testing was performed and the patient was switched to pembrolizumab owing to high microsatellite instability. After 2 courses of pembrolizumab, notable shrinkage of the paraaortic lymph node recurrence was confirmed on computed tomography as well as a partial response. PET-CT revealed disappearance of abnormal accumulation in all lesions at 20 months postoperatively. This has been sustained for 24 months following surgery without remarkable immune-related side-effects.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias dos Ductos Biliares , Colangiocarcinoma , Recidiva , Humanos , Masculino , Colangiocarcinoma/cirurgia , Colangiocarcinoma/genética , Colangiocarcinoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , HepatectomiaRESUMO
Background: The efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by pancreatoduodenectomy (PD) in elderly patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. Methods: This retrospective analysis of prospectively collected data examined the effect of NACRT followed by PD in elderly patients with PDAC. A total of 112 patients with resectable (R-) and borderline resectable (BR-) PDAC, who were planned for PD and received NACRT between 2009 and 2022, were assessed. Changes induced by NACRT, surgical outcomes, nutritional status, renal and endocrine functions, and prognosis were compared between elderly (≥75 years, n = 43) and non-elderly (<75 years, n = 69) patients over two years following PD. Results: Completion and adverse event rates during NACRT, nutritional status, renal function, endocrine function over two years postoperatively, and prognosis did not significantly differ between the two groups. Low prognostic index after NACRT and the absence of postoperative adjuvant chemotherapy may be adverse prognostic indicators for elderly patients undergoing NACRT for R- and BR-PDAC. Conclusions: Despite a higher incidence of postoperative complications, NACRT followed by PD can be safely performed in elderly patients, resulting in a prognosis similar to that in non-elderly patients.
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BACKGROUND: /Objective: Preoperative treatment of resectable pancreatic ductal adenocarcinoma (PDAC) is gaining popularity worldwide. However, the characteristics of tumors located in the pancreatic head (Ph), or those in the body or tail (Pbt), after surgery following neoadjuvant chemoradiotherapy (NACRT) remain unclear. This study aimed to evaluate and compare the clinicopathological features, perioperative outcomes, and prognosis of patients with resectable PDAC who underwent NACRT followed by curative pancreatic resection, focusing on distinguishing between Ph and Pbt PDACs. METHODS: We included 107 patients with resectable PDAC who underwent curative resection following NACRT between 2009 and 2023. Clinicopathological features, perioperative and prognostic outcomes, recurrence patterns, and prognoses were compared between Ph and Pbt PDAC groups. RESULTS: Tumors were found in the Ph and Pbt in 64 and 43 patients, respectively. Albumin levels and lymphocyte-to-monocyte ratios after NACRT were significantly lower in the Ph group than in the Pbt group. The Pbt group showed significantly higher rates of positive peritoneal lavage cytology and serosal, arterial, and portal vein invasion than the Ph group did. Overall and recurrence-free survival were similar between the two groups. The most common site of initial postoperative recurrence was the lung only in both groups; however, the rate of peritoneal dissemination only was significantly higher in the Pbt group than in the Ph group. CONCLUSIONS: The prognoses based on tumor locations in the Ph and Pbt after surgery following NACRT are similar. Following the resection of resectable Pbt PDAC, the possibility of peritoneal dissemination recurrence should be considered.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Prognóstico , Terapia Neoadjuvante , Estudos Retrospectivos , Quimiorradioterapia , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Pancreatectomia , Adenocarcinoma/patologiaRESUMO
Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments.
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Carcinoma , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Carcinoma/patologia , Pâncreas/cirurgia , Pâncreas/patologiaRESUMO
BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.
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Carcinoma Ductal Pancreático , DNA Tumoral Circulante , Neoplasias Pancreáticas , Humanos , DNA Tumoral Circulante/genética , Relevância Clínica , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Mutação , Biomarcadores Tumorais/genéticaRESUMO
PURPOSE: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. METHODS: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. RESULTS: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. CONCLUSION: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer , Humanos , Japão , Mutação , Prognóstico , Transdução de Sinais/genéticaRESUMO
BACKGROUND/AIM: We aimed to evaluate pancreatic cancer (PC) with positive peritoneal lavage cytology (CY1) outcomes following a change in adjuvant therapy. PATIENTS AND METHODS: The clinicopathological data of patients with pancreatic adenocarcinoma with CY1 at 14 institutions, between 2007 and 2015, were collected and analyzed. RESULTS: Of the 124 eligible patients, 114 underwent macroscopically curative resection. Of the 114 patients, 80 (70%) did not have early recurrence and received postoperative chemotherapy that was S-1 in 43 (54%), gemcitabine in 31 (39%), and others in six (7%). The median overall survival was 21.0 months in S-1 and 19.2 in gemcitabine therapy (p=0.23), whereas the median relapse-free survival was 10.2 and 7.1 months (p=0.03), respectively. CONCLUSION: Following the change in adjuvant therapy, most PC patients with CY1 who underwent macroscopically curative resection received S-1; however, it was insufficient. Further development of postoperative chemotherapy is required.
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Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/uso terapêutico , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Lavagem Peritoneal , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Análise de Sobrevida , Tegafur/uso terapêutico , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Endoscopic duodenal stent placement is an alternative technique to gastrojejunostomy for gastric outlet obstruction due to pancreatic cancer. We compared the efficacy of endoscopic duodenal stent placement with that of gastrojejunostomy for treating patients with pancreatic cancer who are candidates for intensive combination chemotherapies as the first line of treatment. METHODS: This retrospective observational study included 100 patients from 18 institutions in Japan. Inclusion criteria were as follows: (1) cytologically or histologically confirmed adenocarcinoma of the pancreas, (2) good performance status, (3) gastric outlet obstruction scoring system score of 0-1 and (4) no history of treatment for pancreatic cancer. RESULTS: There was no significant difference in the background characteristics of patients in the endoscopic duodenal stent placement (n = 57) and gastrojejunostomy (n = 43) groups. The median overall survival in the endoscopic duodenal stent placement and gastrojejunostomy groups was 5.9 and 6.0 months, respectively. Clinical success was achieved in 93 cases; the median time to food intake resumption was significantly shorter in the endoscopic duodenal stent placement group (median: 3 days, n = 54) than in the gastrojejunostomy group (median: 5 days, n = 43). Chemotherapy was introduced in 63% of the patients in both groups after endoscopic duodenal stent placement or gastrojejunostomy. Chemotherapy was started earlier in the endoscopic duodenal stent placement group (median: 14 days) than in the gastrojejunostomy (median: 32 days) group. CONCLUSIONS: Endoscopic duodenal stent placement showed similar or better clinical outcomes than gastrojejunostomy. Thus, it might be a promising option in patients with good performance status.
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Derivação Gástrica , Neoplasias Pancreáticas , Obstrução Duodenal , Humanos , Atresia Intestinal , Cuidados Paliativos , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Estudos Retrospectivos , Stents , Resultado do TratamentoRESUMO
BACKGROUND: An infusion-related reaction (IRR) is a well-known adverse event related to monoclonal antibodies, and antihistamine premedication is recommended to prevent IRRs. Ramucirumab plus FOLFIRI therapy is the standard second-line treatment for metastatic colorectal cancer (CRC). Ramucirumab is a fully human antibody, suggesting that the incidence of IRRs is lower, however, the current recommendation for the proper use of ramucirumab is antihistamine premedication, but the incidence and severity of ramucirumab-induced IRR without antihistamine premedication have not been elucidated. METHODS: A retrospective study to evaluate the incidence of ramucirumab-induced IRRs in unresectable CRC patients treated by ramucirumab plus FOLFIRI therapy. If the incidence of IRR without antihistamine premedication was not higher than that of cetuximab in a previous report (5.7%), planning a prospective study was considered. RESULTS: A total of 147 patients with unresectable CRC who had been treated by ramucirumab plus FOLFIRI therapy were identified. Of them, 106 (72%) patients received intravenous antihistamine premedication. An IRR occurred in 2 patients (1.4%), 1 grade 2 and 1 grade 3. They received antihistamine and steroid premedication. On the other hand, IRRs were not observed in 41 patients without antihistamine premedication, and the incidence of IRRs was significantly lower compared with the previous report of cetuximab (p < 0.001). CONCLUSION: The incidence of ramucirumab-induced IRRs without antihistamine premedication is low. Not using antihistamine premedication can decrease medical costs. These findings warrant further investigation in large-scale cohorts to clarify the incidence and severity of ramucirumab-induced IRRs and further clarify the proper use of ramucirumab.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Humanos , Estudos Prospectivos , Estudos Retrospectivos , RamucirumabRESUMO
BACKGROUND: The pathologic assessments of tumor response after neoadjuvant chemoradiotherapy (NACRT) are critical to improving the prognostic stratification for patients with pancreatic ductal adenocarcinoma (PDAC). Here we clarified the utility of our new grading system based on the area of residual tumor (ART) as compared to existing systems, such as the College of American Pathologists (CAP) and MD Anderson (MDA) score. METHODS: Eight reviewers individually evaluated the tumor regression grade of 30 patients with PDAC based on three types of grading systems. The interobserver concordance and clinicopathological characteristics were compared between the three systems. RESULTS: The interobserver concordance (kappa value) of the ART, CAP, and MDA score were 0.61, 0.48, and 0.53, respectively. Discrepant cases, which were 27% of the cases, exhibited smaller tumor and tumor bed sizes than concordant cases. The reduction in tumor size evaluated by microscopy showed a correlation with the rate of change in carcinoembryonic antigen (CEA) level, CA19-9 level, and tumor size on computed tomography (CT). The ART score was correlated with the tumor size on CT before and after NACRT and disease-free survival. The CAP and MDA scores were not associated with prognosis. CONCLUSION: The ART grading system may be the most practical system to assess the tumor response in post-NACRT resections of PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/cirurgia , Humanos , Terapia Neoadjuvante , Neoplasia Residual , Neoplasias Pancreáticas/cirurgia , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Neoplasias PancreáticasRESUMO
INTRODUCTION: Patients with advanced pancreatic cancer have a poor prognosis. FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) have been established as first-line treatment, but they have not been confirmed as second-line treatment after FFX. The aim of this study was to evaluate the safety and efficacy of GnP as second-line therapy after FFX in patients with unresectable pancreatic cancer. METHODS: Twenty-five patients with unresectable pancreatic cancer were enrolled. The patients were treated with GnP after FFX between September 2015 and September 2019. Tumor response, progression-free survival (PFS), overall survival (OS), and incidence of adverse events were evaluated. RESULTS: The response rate, disease control rate, median PFS, and median OS were 12%, 96%, 5.3 months, and 15.6 months, respectively. The common grade 3 or 4 adverse events were neutropenia (76%) and anemia (16%). CONCLUSIONS: GnP after FOLFIRINOX is expected to be one of the second-line recommendations for patients with unresectable pancreatic cancer.
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Albuminas/uso terapêutico , Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Albuminas/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Primary tumor location (PTL) is an important prognostic and predictive factor in the first-line treatment of metastatic colorectal cancer (mCRC). Although regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been introduced recently, the clinical impact of PTL in these treatments is not well understood. MATERIALS AND METHODS: We retrospectively evaluated patients with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, angiogenesis inhibitors, anti-epidermal growth factor receptor therapy (if RAS wild-type), and no prior use of REG and FTD/TPI. The impact of PTL on overall survival (OS) was evaluated using Cox proportional hazard models based on baseline characteristics. RESULTS: A total of 550 patients (223 patients in the REG group and 327 patients in the FTD/TPI group) were included in this study, with 122 patients with right-sided tumors and 428 patients with left-sided tumors. Although the right-sided patients had significantly shorter OS compared with the left-sided patients by univariate analysis (p = 0.041), a multivariate analysis revealed that PTL was not an independent prognostic factor (hazard ratio, 0.95; p = 0.64). In a subgroup analysis, the OS was comparable between the REG and FTD/TPI groups regardless of PTL (p for interactions = 0.60). CONCLUSIONS: In the present study, PTL is not a prognostic and predictive factor in patients with mCRC under later-line REG or FTD/TPI therapy.
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BACKGROUND: Only few studies in literature have analyzed the clinical effects of peritoneal lavage status in biliary tract cancers. AIM: We aimed to assess the effect of cytology-positive peritoneal lavage on survival for patients with biliary tract cancer who underwent curative resection. METHODS: The KHBO1701 study was a multi-institutional retrospective study that assessed the clinical effects of peritoneal lavage cytology in biliary tract cancers. Using clinicopathological data from 11 Japanese institutions, we compared long-term outcomes between patients with cytology-positive and cytology-negative peritoneal lavage. RESULTS: Of 169 patients who underwent curative resection, 164 were cytology-negative, and five were cytology-positive. The incidence of portal invasion and preoperative carbohydrate antigen 19-9 levels were higher in the cytology-positive group than in the cytology-negative group. The incidence of peritoneal metastatic recurrence was also higher, and overall survival tended to be worse in the cytology-positive group. In contrast, recurrence-free survival was similar between the cytology-negative and cytology-positive groups. CONCLUSIONS: The positive status of peritoneal lavage cytology could moderately affect the survival of patients with biliary tract cancers. Given that surgical resection is the only curative treatment option, it may be acceptable to resect biliary tract cancers without other non-curative factors, regardless of peritoneal lavage cytology status.
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Neoplasias do Sistema Biliar/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Lavagem Peritoneal/estatística & dados numéricos , Neoplasias Peritoneais/epidemiologia , Peritônio/patologia , Idoso , Neoplasias do Sistema Biliar/sangue , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/cirurgia , Antígeno CA-19-9/sangue , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/diagnóstico , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/secundário , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Platinum-containing regimens are widely used as first-line chemotherapy for unresectable pancreatic neuroendocrine carcinoma (NEC), but second-line chemotherapies have yet to be established. OBJECTIVES: We evaluated the safety and efficacy of everolimus in patients with pancreatic NEC refractory or intolerant to platinum-containing chemotherapy. METHODS: This study was a prospective, multicenter, phase II trial in patients with pancreatic NEC after platinum-containing chemotherapy. Everolimus treatment was continued until disease progression or intolerable toxicity was observed. The primary endpoint was progression-free survival (PFS). RESULTS: Participants comprised 25 patients. Median age was 63 years, median PFS was 1.2 months (95% confidence interval [CI] 0.9-3.1 months), median overall survival was 7.5 months (95% CI 3.1-13.5 months), overall response rate was 0%, and disease control rate was 39.1%. Common grade 3/4 adverse events were hyperglycemia (20%), thrombocytopenia (16%), and anemia (16%). CONCLUSION: The efficacy of everolimus was limited in patients with unresectable pancreatic NEC.
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Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/tratamento farmacológico , Everolimo/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Platina/uso terapêutico , Intervalo Livre de Progressão , Estudos ProspectivosRESUMO
BACKGROUND: Regorafenib is a multiple tyrosine kinase inhibitor, and the use of this drug is approved for the treatment of cancers that are resistant to chemotherapy, which include advanced colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. However, the drug causes adverse events, including skin toxicities that require dose modification in approximately 75% of cases. At present, the blood concentration of regorafenib is not assessed in clinical settings; thus, we recently developed a method that can assess the blood concentration of the drug using high-performance liquid chromatography. METHODS: We measured the trough blood concentrations (Ctrough) of regorafenib and its metabolites (M2 and M5) in 14 and 4 patients with advanced colorectal cancer and gastrointestinal stromal tumor, respectively, using high-performance liquid chromatography. Then, the correlation between the Ctrough and therapeutic outcomes of regorafenib was analyzed. RESULTS: In patients who were receiving regorafenib 40-160 mg/day, the Ctrough values of regorafenib, M2, and M5 were 318-9467, 34-3594, and 38-3796 ng/mL, respectively. The difference in the values was significant. Although the specific factors influencing this difference were not elucidated, the Ctrough of regorafenib was extremely lower in some patients, even though the drug was administered at a standard dose, which may explain the lower response rate. Moreover, the Ctrough value of M5 was significantly correlated to the incidence of skin toxicities, which is the most frequent cause of dose modification. CONCLUSIONS: The use of regorafenib may not be suitable in patients with a low Ctrough value. To prevent skin toxicities, the Ctrough value of M5 should be monitored.
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Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Compostos de Fenilureia/efeitos adversos , Piridinas/efeitos adversos , Dermatopatias/induzido quimicamente , Pele/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/patologia , Citocromo P-450 CYP3A/genética , Monitoramento de Medicamentos/métodos , Feminino , Tumores do Estroma Gastrointestinal/patologia , Glucuronosiltransferase/genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Compostos de Fenilureia/sangue , Compostos de Fenilureia/metabolismo , Compostos de Fenilureia/uso terapêutico , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/sangue , Piridinas/metabolismo , Piridinas/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study. METHODS: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. DISCUSSION: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. TRIAL REGISTRATION: Registered at August 23, 2017. Registry number: UMIN000028801 .
Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Neoplasias Pancreáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Caquexia/epidemiologia , Caquexia/fisiopatologia , Caquexia/prevenção & controle , Caquexia/terapia , Carcinoma Pulmonar de Células não Pequenas/dietoterapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Protocolos Clínicos , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Terapia por Exercício , Humanos , Japão , Neoplasias Pulmonares/dietoterapia , Neoplasias Pulmonares/patologia , Neoplasias Pancreáticas/dietoterapia , Neoplasias Pancreáticas/patologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Assessment of patient factors is essential for selecting later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated. PATIENTS AND METHODS: A total of 550 patients with mCRC who were registered in the REGOTAS study (Regorafenib versus TAS-102 as Salvage-line in patients with colorectal cancer refractory to standard chemotherapies: a multicenter observational study, UMIN 000020416) and treated with trifluridine/tipiracil (TFTD) or regorafenib as a later-line therapy were retrospectively stratified according to the modified Glasgow Prognostic Score (mGPS), which divided patients into mGPS 0 to 2 by serum albumin and C-reactive protein, and compared. RESULTS: The median overall survival (OS) of patients with mGPS 0, 1, and 2 was 10.0 months (95% confidence interval [CI], 9.2-11.6 months), 6.5 months (95% CI, 5.3-7.1 months), and 3.9 months (95% CI, 3.3-4.9 months), respectively. The median progression-free survival (PFS) with mGPS 0, 1, and 2 was 2.5 months (95% CI, 2.1-3.0 months), 2.0 months (95% CI, 1.9-2.3 months), and 1.7 months (95% CI, 1.4-1.9 months), respectively. There were significant differences by mGPS in both OS and PFS (all P < .001). No significant differences in OS and PFS were observed between the patient groups treated with TFTD and regorafenib in each mGPS group. In patients aged ≥ 65 years with mGPS 2, the OS and PFS were worse with regorafenib than with TFTD (OS: hazard ratio, 1.45; 95% CI, 0.93-2.25; P = .097; PFS: hazard ratio, 1.57, 95% CI, 1.01-2.44; P = .047), but there were no consistent trends observed as mGPS increased. The frequency of grade 3 and more adverse events was generally similar in each mGPS group. The multivariate analyses showed that mGPS was the strongest predictive factor for OS. CONCLUSIONS: The mGPS before later-line chemotherapy is strongly correlated with survival in patients with mCRC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias Colorretais/mortalidade , Neoplasias Hepáticas/mortalidade , Idoso , Proteína C-Reativa/análise , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Compostos de Fenilureia/administração & dosagem , Prognóstico , Piridinas/administração & dosagem , Pirrolidinas , Estudos Retrospectivos , Albumina Sérica Humana/análise , Taxa de Sobrevida , Timina , Trifluridina/administração & dosagem , Uracila/análogos & derivadosRESUMO
OBJECTIVE: Advances in chemotherapy and chemoradiotherapy have enabled conversion of initially unresectable locally advanced (UR-LA) pancreatic adenocarcinoma (PDAC) to a resectable disease. However, definitive criteria for conversion surgery have not been established. We evaluated the potential of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to indicate conversion surgery in patients with primary UR-LA PDAC. METHODS: Twenty consecutive patients with UR-LA PDAC underwent chemoradiation or chemotherapy followed by assessment with FDG-PET. We defined PET responders (standardized uptake value <3.0) with marked reduction (>80%) of carbohydrate antigen 19-9 as potential candidates for conversion surgery. Outcomes were compared with those of the patients with resectable (R; n = 94) and borderline resectable (BR; n = 37) PDAC. RESULTS: Eight of the 20 patients (40%) were considered PET responders with marked reduction of CA19-9 and received conversion surgery (UR-LAR) 3-9 months (median, 5 months) after the initiation of therapy. Complete resection (R0) was achieved in 7 of 8 patients (87.5%) with UR-LAR. There was no significant difference in R0 rates, morbidity, or mortality among the UR-LAR, R and BR groups. The overall survival (OS) curve was better in the UR-LAR group than in the group that did not receive surgery. There was no significant difference in OS between the UR-LAR and the R or BR groups. CONCLUSIONS: FDG-PET could be a potential indicator for conversion surgery in patients with primary UR-LA PDAC and may help in selecting patients who qualify for complete surgical resection and have a promising prognosis.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Fluordesoxiglucose F18/uso terapêutico , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Feminino , Fluordesoxiglucose F18/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , PrognósticoRESUMO
BACKGROUND: This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment. MATERIALS AND METHODS: The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug-naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics. RESULTS: A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95% confidence interval [CI], 6.8-9.2) in the regorafenib group and 7.4 months (95% CI, 6.6-8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio [HR], 0.96; 95% CI, 0.78-1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged <65 years (HR, 1.29; 95% CI, 0.98-1.69), whereas TFTD was favored in patients aged ≥65 years (HR, 0.78; 95% CI, 0.59-1.03). CONCLUSION: No significant difference in OS between regorafenib and TFTD was observed in patients with mCRC. Although the choice of the drug by age might affect survival, a clearly predictive biomarker to distinguish the two drugs should be identified in further studies. IMPLICATIONS FOR PRACTICE: Previous studies of patients with metastatic colorectal cancer refractory to standard chemotherapy had demonstrated that both regorafenib and trifluridine/tipiracil could result in increased overall survival compared with placebo, but there are no head-to-head trials. This large, multicenter, observational study retrospectively compared the efficacy of regorafenib and trifluridine/tipiracil in 550 patients with metastatic colorectal cancer refractory to standard chemotherapy who had access to both drugs. Although no difference in overall survival was found between the two drugs in adjusted analysis using propensity score, regorafenib showed favorable survival in patients aged <65 years, whereas trifluridine/tipiracil was favored in patients aged ≥65 years in the subgroup analysis.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Terapia de Salvação , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Japão , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Prognóstico , Pontuação de Propensão , Piridinas/administração & dosagem , Pirrolidinas , Estudos Retrospectivos , Taxa de Sobrevida , Timina , Trifluridina/administração & dosagem , Uracila/análogos & derivadosRESUMO
OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of transarterial (chemo)embolization [TA(C)E] for the control of liver metastasis in patients with neuroendocrine tumors (NETs). METHODS: In this retrospective study, we enrolled 43 patients with metastatic NETs who had been treated with TA(C)E between December 1999 and June 2013 at the National Cancer Center Hospital, Tokyo or the National Cancer Center Hospital East, Kashiwa. We assessed tumor response, time to treatment failure (TTF), overall survival (OS), and frequency of adverse events in these patients, and attempted to identify predictors of TTF. RESULTS: The site of the primary tumor was the pancreas in 29 patients (67%), the gastrointestinal tract in 11 patients (26%), and unknown in 3 patients (7%). Response rate, disease control rate, median TTF, and median OS were 56%, 96%, 24.7 months, and 86.1 months, respectively. No significant predictors of TTF could be identified. While 3 patients developed serious adverse events (including liver abscess in 2 patients and acute renal failure in 1 patient), the adverse events were well tolerated in all other patients. CONCLUSION: TA(C)E appears to be effective and feasible for controlling the liver metastases in patients with NETs.