RESUMO
Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%-37.8%) and 44.8% (30/67, 95% CI 32.6%-57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035-2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.
RESUMO
BACKGROUND: PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. METHODS: We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. FINDINGS: Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. INTERPRETATION: Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Terapia Neoadjuvante , Piridinas , Humanos , Pessoa de Meia-Idade , Feminino , Masculino , Terapia Neoadjuvante/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Idoso , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto Jovem , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , AdolescenteRESUMO
BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.
RESUMO
BACKGROUND: The current standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by radical surgery, but this approach can lead to multiple complications. We aimed to investigate the clinical activity and safety of neoadjuvant therapy with sintilimab, a single-agent PD-1 antibody, in patients with mismatch-repair deficient locally advanced rectal cancer. METHODS: This open-label, single-arm, phase 2 study was done at the Sun Yat-sen University Cancer Center, Guangzhou, China. Patients aged 18-75 years with mismatch-repair deficient or microsatellite instability-high locally advanced rectal cancer were enrolled and received neoadjuvant sintilimab monotherapy (200 mg by intravenous infusion) every 21 days. After an initial four cycles of treatment, patients and clinicians could choose one of the following options: total mesorectal excision surgery, followed by four cycles of adjuvant sintilimab with or without CapeOX chemotherapy (capecitabine 1000 mg/m2, orally administered twice daily on days 1-14; oxaliplatin 130 mg/m2, intravenously administered on day 1 every 3 weeks), determined by clinicians; or another four cycles of sintilimab followed by radical surgery or observation (only for patients with a clinical complete response; also known as the watch and wait strategy). The primary endpoint was the complete response rate, which included both a pathological complete response after surgery and a clinical complete response after completion of sintilimab treatment. Clinical response was evaluated by digital rectal examination, MRI, and endoscopy. Response was assessed in all patients who received treatment at least until the first tumour response assessment, after the first two cycles of sintilimab. Safety was analysed in all patients who received at least one dose of treatment. This trial is closed to enrolment and is registered with ClinicalTrials.gov (NCT04304209). FINDINGS: Between Oct 19, 2019, and June 18, 2022, 17 patients were enrolled and received at least one dose of sintilimab. The median age was 50 years (IQR 35-59) and 11 (65%) of 17 patients were male. One patient was excluded from efficacy analyses because they were lost to follow-up after the first sintilimab cycle. Of the remaining 16 patients, six underwent surgery, of whom three had a pathological complete response. Nine other patients had a clinical complete response and chose the watch and wait strategy. One patient had a serious adverse event and discontinued treatment; this patient did not have a complete clinical response and refused to undergo surgery. A complete response was thus noted for 12 (75%; 95% CI 47-92) of 16 patients. One of the three patients who underwent surgery but did not have a pathological complete response showed an increase in tumour volume after the initial four cycles of sintilimab (at which point they underwent surgery); this patient was deemed to have primary resistance to immune checkpoint inhibitors. After a median follow-up of 17·2 (IQR 8·2-28·5) months, all patients were alive and none had disease recurrence. Only one (6%) patient had a grade 3-4 adverse event, which was deemed a serious adverse event (grade 3 encephalitis). INTERPRETATION: The preliminary results of this study suggest that anti-PD-1 monotherapy is effective and tolerable for patients with mismatch-repair deficient locally advanced rectal cancer and could potentially spare some patients from radical surgery. Longer treatment courses might be needed to achieve maximum effects in some patients. Longer follow-up is also needed to observe the duration of response. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, Science and Technology Program of Guangzhou, and Innovent Biologics.
Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Retais/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.
Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Humanos , Terapia Neoadjuvante/métodos , Resultado do Tratamento , Capecitabina/uso terapêutico , Neoplasias Retais/patologia , Quimiorradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de NeoplasiasRESUMO
Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting metabolic enzymes remains an attractive approach for treating tumors. However, the influence and regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme in iron-sulfur (Fe-S) cluster biogenesis, in colorectal cancer (CRC) remain elusive. Here, using an in vivo metabolic enzyme gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss of NFS1 significantly enhanced the sensitivity of CRC cells to oxaliplatin. In vitro and in vivo results showed that NFS1 deficiency synergizing with oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, and ferroptosis) by increasing the intracellular levels of reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress enhanced the phosphorylation level of serine residues of NFS1, which prevented PANoptosis in an S293 phosphorylation-dependent manner during oxaliplatin treatment. In addition, high expression of NFS1, transcriptionally regulated by MYC, was found in tumor tissues and was associated with poor survival and hyposensitivity to chemotherapy in patients with CRC. Overall, the findings of this study provided insights into the underlying mechanisms of NFS1 in oxaliplatin sensitivity and identified NFS1 inhibition as a promising strategy for improving the outcome of platinum-based chemotherapy in the treatment of CRC.
Assuntos
Neoplasias Colorretais , Proteínas Ferro-Enxofre , Apoptose/genética , Liases de Carbono-Enxofre/metabolismo , Liases de Carbono-Enxofre/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Proteínas Ferro-Enxofre/química , Proteínas Ferro-Enxofre/metabolismo , Proteínas Ferro-Enxofre/uso terapêutico , Oxaliplatina/farmacologia , FosforilaçãoRESUMO
Fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) demethylase, participates in tumor progression and metastasis in many malignancies, but its role in colorectal cancer (CRC) is still unclear. Here, we found that FTO protein levels, but not RNA levels, were downregulated in CRC tissues. Reduced FTO protein expression was correlated with a high recurrence rate and poor prognosis in resectable CRC patients. Moreover, we demonstrated that hypoxia restrained FTO protein expression, mainly due to an increase in ubiquitin-mediated protein degradation. The serine/threonine kinase receptor associated protein (STRAP) might served as the E3 ligase and K216 was the major ubiquitination site responsible for hypoxia-induced FTO degradation. FTO inhibited CRC metastasis both in vitro and in vivo. Mechanistically, FTO exerted a tumor suppressive role by inhibiting metastasis-associated protein 1 (MTA1) expression in an m6A-dependent manner. Methylated MTA1 transcripts were recognized by an m6A "reader", insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which then stabilized its mRNA. Together, our findings highlight the critical role of FTO in CRC metastasis and reveal a novel epigenetic mechanism by which the hypoxic tumor microenvironment promotes CRC metastasis.
Assuntos
Neoplasias Colorretais , Regulação para Baixo , Adenosina , Anexina A2 , Humanos , Proteínas de Ligação a RNARESUMO
BACKGROUND: The impact of HER2 somatic mutations in colorectal carcinoma (CRC) has not been well studied and its relationship with microsatellite instability-high (MSI-H) is yet to be fully elucidated. MATERIALS AND METHODS: From February 2017 to February 2020, the data of patients with CRC who underwent next-generation sequencing and had detailed record of clinicopathological information were investigated. HER2 alteration and its relationship with MSI-H were analyzed. RESULTS: Among 731 patients who underwent sequencing, 55 patients (7.5%) had HER2 alteration, including 29 (4.0%) with HER2 somatic mutations, 24 (3.3%) with HER2 gene amplification, and 2 patients (0.2%) with both HER2 mutations and amplification. R678Q was the most common mutated kinase domain, and no HER2 kinase domain in-frame insertions/deletions were found in HER2 mutated cases. MSI-H was found in 5.2% of our cohort and 36.8% of MSI-H patients had HER2 mutation. For HER2 mutated cases, 48.3% were MSI-H, whereas none of the HER2 amplification cases were MSI-H. MSI-H patients with HER2 mutation had significantly worse median progression-free survival for programmed death-1 (PD-1) antibody than those without HER2 alteration (p = .036). CONCLUSION: High MSI-H rate was found in HER2 mutated cases, but no MSI-H was found in HER2 amplification cases. MSI-H patients with HER2 mutated had worse progression-free survival for PD-1 antibody than those without. IMPLICATIONS FOR PRACTICE: This study highlights the high microsatellite instability-high (MSI-H) rate in HER2 mutated cases but no MSI-H in HER2 amplification cases. Moreover MSI-H patients with HER2 mutated had worse progression-free survival for programmed death-1 antibody than those without. Further research to explore the internal relationship between HER2 alteration and MSI-H is needed.
Assuntos
Adenocarcinoma , Neoplasias Colorretais , Adenocarcinoma/genética , Neoplasias Colorretais/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Instabilidade de Microssatélites , Mutação , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Liver metastasis is an indicator of unfavorable responses to immunotherapy in colorectal cancer patients. However, the difference of immune microenvironment between primary tumors and liver metastases has not been well understood. PATIENTS AND METHODS: Fifty-four colon cancer with liver metastasis patients who received resection of both primary and metastasis lesions have been analyzed. The immune score is based on the density of infiltrating immune cells (CD3+ cell, CD8+ cell, CD11b+ cell, CD11c+ cell, and CD33+ cell) in the center and margin of the tumor. The expression of immune markers between the primary tumor and hepatic metastases was analyzed using Wilcoxon's signed rank test. RESULTS: All the five markers had higher expression in tumor margins than center tumor in both primary tumor and hepatic metastases lesions. The expression of CD11c and CD11b had no difference between metastatic lesions and primary tumor. In tumor margins, except CD11b, all the other 4 markers expressed significantly higher in hepatic metastases than in primary tumor. Intra-tumor, CD3 had higher expression in primary tumor than in hepatic metastases, while CD33 had higher expression in hepatic metastases than in primary tumor. CD8+ CD3+ cells of the total CD8+ cell population in primary tumor was significantly higher than in hepatic metastases (36.42% vs. 24.88%, p = 0.0069). CONCLUSIONS: The immune microenvironment between primary tumor and hepatic metastasis is different. More immunosuppressing cells in liver may partially explain why immunotherapy in colon cancer is less effective with liver metastatic disease.
Assuntos
Biomarcadores , Neoplasias do Colo/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Microambiente Tumoral/fisiologia , Neoplasias do Colo/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
BACKGROUND: Inherited susceptibility accounts for nearly one-third of colorectal cancer (CRC) predispositions and has an 80%-100% lifetime risk of this disease. However, there are few data about germline mutations of hereditary CRC-related genes in Chinese patients with CRC. This study aimed to assess the prevalence of gene mutations related to cancer susceptibility among Chinese patients with CRC, differences between Chinese and Western patients, and the phenotype-genotype correlation. METHODS: We retrospectively collected tumor samples from 526 patients with CRC under 70 years old who underwent hereditary CRC genetic testing. A series of bioinformatic analyses, as well as statistical comparisons, were performed. RESULTS: We found that 77 patients (14.6%) harbored functional variants of the 12 genes. The mutation frequencies of the top 5 mutated genes were 6.5% for MutL homolog 1 (MLH1), 5.1% for MutS homolog 2 (MSH2), 1.0% for MSH6, 0.8% for PMS1 homolog 2 (PMS2), and 0.8% for APC regulator of the WNT signaling pathway (APC). Our data showed much higher rates of mutations of MSH6 and PMS2 genes among all mismatch repair (MMR) genes as compared with those in Western populations. Mutations in MLH1, MSH2, and MSH6 were found to be mutually exclusive. Patients with MLH1 or MSH2 mutations had higher frequencies of personal history of cancer (MLH1: 20.6% vs. 8.7%; MSH2: 25.9% vs. 8.6%) and family history of cancer than those without these mutations (MLH1: 73.5% vs. 48.4%; MSH2: 70.4% vs. 48.9%), and the lesions were more prone to occur on the right side of the colon than on the left side (MLH1: 73.5% vs. 29.3%; MSH2: 56.0% vs. 31.0%). The proportion of stage I/II disease was higher in patients with MLH1 mutations than in those without MLH1 mutations (70.6% vs. 50.7%), and the rate of polyps was higher in patients with APC mutations than in those with wild-type APC (75.0% vs. 17.4%). CONCLUSION: These results provide a full-scale landscape of hereditary susceptibility over 12 related genes in CRC patients and suggest that a comprehensive multi-gene panel testing for hereditary CRC predisposition could be a helpful analysis in clinical practice.
Assuntos
Neoplasias Colorretais , Mutação em Linhagem Germinativa , Idoso , China , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Feminino , Células Germinativas , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Estudos RetrospectivosRESUMO
Adjuvant chemotherapy after surgery is the standard treatment modality for stage III and part of stage II or stage IV colorectal cancer (CRC) patients. However, the 5-year overall survival (OS) rate remains unsatisfactory. Thus, developing combination therapies is essential to improve the prognosis of patients with CRC. The present study aimed to determine the effect of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for patients with CRC. 122 patients with CRC treated with postoperative adjuvant chemotherapy were retrospectively included in this study. Among them, 62 patients received adjuvant chemotherapy only (control group), while the other 60 patients, with similar demographic and clinical characteristics, received adjuvant chemotherapy and sequential CIK cell immunotherapy (CIK group). Survival analysis showed significantly improved disease free survival (DFS) and OS rates in the CIK group compared with the control group (log-rank test, P = .0024; P = .008, respectively). Univariate and multivariate analyses indicated that sequential CIK cell treatment was an independent prognostic factor for patients' DFS and OS. Subgroup analyses showed that sequential CIK cell treatment significantly improved the DFS and OS of patients with high-risk T4 stage and insufficient chemotherapy duration. In conclusion, these data indicate that sequential adjuvant CIK cell treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with CRC, particularly for patients with high-risk T4 stage and insufficient chemotherapy duration.
Assuntos
Neoplasias Colorretais , Células Matadoras Induzidas por Citocinas , Quimioterapia Adjuvante , Neoplasias Colorretais/terapia , Terapia Combinada , Procedimentos Cirúrgicos do Sistema Digestório , Feminino , Humanos , Imunoterapia Adotiva , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
BACKGROUND: The accurate detection of cancer-associated venous thromboembolism (VTE) can avoid unnecessary diagnostic imaging or laboratory tests. OBJECTIVE: We sought to determine clinical and cancer-related risk factors of VTE that can be used as predictors for oncology patients presenting to the emergency department (ED) with suspected VTE. METHODS: We retrospectively analyzed all consecutive patients who presented with suspicion of VTE to The University of Texas MD Anderson Cancer Center ED between January 1, 2009, and January 1, 2013. Logistic regression models were used to identify risk factors that were associated with VTE. The ability of these factors to predict VTE was externally validated using a second cohort of patients who presented to King Hussein Cancer Center ED between January 1, 2009, and January 1, 2016. RESULTS: Cancer-related covariates associated with the occurrence of VTE were high-risk cancer type (odds ratio [OR] 3.64 [95% confidence interval {CI} 2.37-5.60], p < 0.001), presentation within 6 months of the cancer diagnosis (OR 1.92 [95% CI 1.62-2.28], p < 0.001), active cancer (OR 1.35 [95% CI 1.10-1.65], p = 0.003), advanced stage (OR 1.40 [95% CI 1.01-1.94], p = 0.044), and the presence of brain metastasis (OR 1.73 [95% CI 1.32-2.27], p < 0.001). When combined, these factors along with other clinical factors showed high prediction performance for VTE in the external validation cohort. CONCLUSIONS: Cancer risk group, presentation within 6 months of cancer diagnosis, active and advanced cancer, and the presence of brain metastases along with other related clinical factors can be used to predict VTE in patients with cancer presenting to the ED.
Assuntos
Neoplasias , Tromboembolia Venosa , Serviço Hospitalar de Emergência , Humanos , Neoplasias/complicações , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologiaRESUMO
OBJECTIVE: Knowledge about the impact of metabolic disturbances and parenteral nutrition (PN) characteristics on the survival of cancer patients receiving PN is limited. We aimed to assess the association between clinical and PN characteristics and survival in colorectal-cancer patients receiving PN support. METHODS: Our study included 572 consecutive colorectal-cancer patients who had received PN support between 2008 and 2013. Patient characteristics, body mass index, weight, medical/surgical history, indication for PN, PN data and survival were recorded. Associations between clinical and PN characteristics and survival were analysed with important confounding factors. RESULTS: The final cohort included 437 evaluable patients, with a mean age of 57 years. Eighty-one percent of the study population had advanced stage of colorectal cancer. Unstable weight (weight change ≥2.5%) prior to PN initiation [hazard ratio (HR) = 1.41, P = 0.023] was adversely associated with survival after adjusting for multiple factors including cancer stage. Bowel obstruction (HR = 1.75, P = 0.017) as a PN indication was associated with worse survival when compared with without bowel obstruction. Higher PN amino acid by ideal body weight (gâ¢kg-1) (HR = 0.59, P = 0.029) was associated with longer survival, whereas a higher percentage of non-PN intravenous calories (HR = 1.04, P = 0.011) was associated with shorter survival independently of confounding factors. CONCLUSIONS: Body mass index and weight stability can be useful nutritional indices for survival prediction in cancer patients receiving PN. PN planning should take into account of non-PN calories to achieve optimal energy support and balance. Future research is needed to define optimal PN amino-acid requirement and energy balance.
RESUMO
BACKGROUND: In a Phase II clinical trial, we reported the effectiveness and safety of a sandwich neoadjuvant treatment based on a modified oxaliplatin plus capecitabine (XELOX) regimen for locally advanced rectal cancer (LARC). The pathologic complete response (pCR) rate was 42.2%, and no patient presented Grade 4 acute toxicities. This study was performed to evaluate whether the high pCR rate could translate into an improved long-term survival benefit by analyzing the 5-year follow-up results of the trial. METHODS: Fifty-one patients with LARC were initially enrolled in the trial. Of these, 2 cases were eliminated due to distant metastasis before treatment. In addition, 4 cases were eliminated for refusing surgery after neoadjuvant chemoradiotherapy (NACRT). Finally, a total of 45 patients were treated with the sandwich NACRT plus total mesorectal excision. We followed up these patients and calculated their overall survival (OS) and disease-free survival (DFS) through a Kaplan-Meier approach. A log-rank test and multivariate survival analysis based on a Cox proportional hazard model were performed to explore the risk factors influencing distant metastasis. RESULTS: The median follow-up time was 60.8 months, and among the 45 patients analyzed, 1 (2.2%) patient suffered local recurrence, and 9 (20.0%) suffered distant metastasis. The 3-year OS and DFS were 95.6% and 84.4%, respectively. In addition, the 5-year OS and DFS were 91.1% and 80.0%, respectively. In the multivariate analysis, postsurgical pathological N stage and carbohydrate antigen 19-9 before treatment maintained statistical significance on distant metastasis. CONCLUSIONS: The sandwich NACRT with XELOX regimen might reduce distant metastasis and improve the survival of LARC patients. However, long-term benefits should be verified through further Phase III clinical trials.
RESUMO
BACKGROUND: The necessity for adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) patients who achieve pathological complete response (pCR) after pre-operative chemoradiotherapy (CRT) is still not identified. We aimed to investigate the therapeutic value of ACT in these patients. METHODS: Clinical data were retrospectively collected from 105 consecutive LARC patients who achieved pCR after pre-operative CRT and underwent radical tumor resection between December 2008 and April 2014 in a comprehensive cancer center. Perioperative chemotherapy (CT) was administered by combining oxaliplatin with capecitabine (XELOX regimen). Disease-free survival (DFS) and overall survival (OS) rates of patients with or without ACT were compared. RESULTS: Eighty-three (79.0%) patients received ACT and 22 (21.0%) did not. With a median follow-up of 49 months, the ACT group had a significantly higher 3-year DFS rate (92.8 vs 86.4%, p = 0.029) and 3-year OS rate (95.1 vs 86.1%, p = 0.026) than the non-ACT group. In multivariable analyses, the presence of ACT was an independent prognostic factor for DFS (hazard ratio [HR]: 0.271; 95% confidence interval (CI): 0.080-0.916; p = 0.036) but not for OS. This benefit was more obvious in patients younger than 60 years via subgroup analysis (adjusted HR: 0.106; 95% CI: 0.019-0.606; p = 0.012). CONCLUSIONS: Oxaliplatin-containing ACT may confer survival benefits to patients with pCR, particularly younger patients. However, the routine use of ACT in patients with pCR needs further validation.
RESUMO
Mountain of studies has showed that right-sided colon cancer (RSCC) and left-sided colon cancer (LSCC) have different clinical presentation and biologic features and should be considered as two distinct disease entities. The survival difference between RSCC and LSCC remains controversial. Using Surveillance, Epidemiology, and End Results (SEER) database, we identified colon adenocarcinoma patients from 2004 to 2013. The 5-year cause-specific survival (CSS) was our primary endpoint. All statistical analyses were performed using the Intercooled Stata 13.0. All statistical tests were two-sided. The study included 95,847 (58.72%) RSCC and 67,385 (41.28%) LSCC patients. RSCC patients were older, more often females, more Caucasian, more unmarried, more advanced T and N stage, larger tumor sizes, and more poorly differentiated tumor, while LSCC patients had more stage IV diseases. Location was an independent prognostic factor in the multivariable analysis. Compared with RSCC patients, the hazard ratio for LSCC was 0.87, 95% CI: 0.85-0.89 P < 0.001. There was no survival difference between RSCC and LSCC in the following situations: older than 68 years old, T3-4, N0, poorly differentiated, and undifferentiated diseases. We firstly reported that RSCC patients had a better prognosis than LSCC in mucinous adenocarcinoma/signet ring cell carcinoma patients. RSCC patients also had a better prognosis than LSCC in stage II disease. There is a need for further subdivisions when analyzing the survival difference between RSCC and LSCC patients. RSCC had lower mortality rate than LSCC in stage II disease and mucinous adenocarcinoma/signet ring cell carcinoma patients.
Assuntos
Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/terapia , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Vigilância em Saúde Pública , Programa de SEERRESUMO
OBJECTIVE: Increased expression of programmed death-ligand 1 (PD-L1) on tumor cells can be found in various malignancies; however, very limited information is known about its role in anal squamous cell carcinoma (ASCC). This study explored PD-L1 expression in ASCC patients and its association with patients' clinicopathological features, CD8+ T cell infiltration, and prognosis. METHODS: Formalin-fixed paraffin-embedded tumor samples from 26 patients with ASCC were retrieved. The levels of PD-L1 expression on the membrane of both tumor cells and tumor-infiltrating mononuclear cells (TIMCs) were evaluated by immunohistochemistry. CD8+ T cell densities, both within tumors and at the tumor-stromal interface, were also analyzed. Baseline clinicopathological characteristics, human papilloma virus (HPV) status, and outcome data correlated with PD-L1-positive staining. RESULTS: PD-L1 expression on tumor cells and TIMCs was observed in 46% and 50% of patients, respectively. Nineteen patients (73%) were HPV positive, with 7 showing PD-L1-positive staining on tumor cells and 9 showing PD-L1-positive staining on TIMCs. Increasing CD8+ density within tumors, but not immune stroma, was significantly associated with decreased PD-L1 expression by both tumor cells and TIMCs (P=0.0043 and P=0.0007). Patients with negative PD-L1 expression had significantly better progression-free survival (P=0.038 and P=0.0443) and a non-statistically significant trend toward longer overall survival (P=0.0882 and P=0.1222) compared with patients with positive PD-L1 expression. CONCLUSION: PD-L1 is widely expressed on the membrane of tumor cells and TIMCs in ASCCs. Its negative impact on prognosis may be due to the diminished CD8+ T cell infiltration within tumors.
RESUMO
Research indicates that cancer-triggered inflammation plays a pivotal role in carcinogenesis. Here, we aimed to evaluate the correlation of lymphocyte-to-monocyte ratio (LMR) before neoadjuvant chemoradiotherapy (CRT) with clinical outcomes in patients with locally advanced rectal cancer (LARC). We retrospectively enrolled 317 consecutive patients with LARC between 2004 and 2013. The optimal cutoff values of LMR were determined using receiver operating curve analysis. Overall survival (OS) and disease-free survival related to the LMR were analyzed using the log-rank test and multivariate Cox regression methods. We found that a low LMR (≤4.91) was prominently correlated with worse prognostic features and a shorter 3-year survival rate of LARC. Moreover, multivariate Cox analysis revealed that elevated LMR was an independent factor for better OS (hazard ratio 0.538, 95% confidence interval 0.292-0.991, P=0.047). In addition, univariate logistic regression analysis showed that the LMR was not associated with tumor pathologic regression. In conclusion, LMR is identified as a valuable prognostic marker for predicting the OS of LARC patients receiving CRT.
RESUMO
PURPOSE: The safety and efficacy of intraoperative chemotherapy in colorectal cancer have not yet been extensively investigated. This randomized control trial was designed to compare the safety and efficacy of intraoperative chemotherapy in combination with surgical resection to those of traditional surgical resection alone. METHODS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled in this study: 341 patients were randomly assigned to the intraoperative chemotherapy, which consist of portal vein chemotherapy, intraluminal chemotherapy and intraperitoneal chemotherapy, plus surgery group, whereas 344 patients were randomized to the control group to undergo surgery alone. Eleven patients withdrew consent. RESULTS: Intraoperative chemotherapy did not increase the rate of surgical complications, and no severe chemotherapy-associated side effects were observed. Four patients in each of the intraoperative chemotherapy and the control groups experienced anastomotic leakage and underwent a second operation (1.2 vs. 1.2%, P = 0.99). There were no deaths within 90 days after surgery in the chemotherapy group, whereas one patient died in the control group. Intraoperative chemotherapy did not decrease the rate of patients who received postoperative chemotherapy between the intraoperative group and control group (29.3 vs. 30.2%, P = 0.795). CONCLUSIONS: Intraoperative chemotherapy can be safely performed during colorectal surgery; however, follow-up is necessary for a better assessment of its efficacy. ClinicalTrial.gov Register Number: NCT01465451.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Humanos , Cuidados Intraoperatórios/métodos , Complicações Intraoperatórias/etiologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos ProspectivosRESUMO
PURPOSE: The aim of this study was to characterize the patterns of recurrence in patients achieving pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer. METHODS: Patients with locally advanced rectal cancer treated with neoadjuvant CRT and who achieved pCR from January 2004 to December 2012 were collected. The primary outcome measurement was the patterns of recurrence. RESULTS: Among 195 patients who achieved pCR, 18 developed recurrence. Furthermore, local recurrence occurred in 1.5% of patients (3/195), while distant metastases occurred in 7.7% of patients (15/195), which included 7 lung metastases, 1 liver metastasis, and 8 metastases in other locations. CONCLUSIONS: Our study indicated that patients achieving pCR following neoadjuvant CRT have a favorable prognosis, with distant metastases predominating in all recurrences. Among patients with distant metastases, non-liver metastases were the predominant pattern.