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PURPOSE: This study aimed to evaluate the effects of adjuvant chemotherapy (AC) on oncologic outcomes for patients with stage IIA upper rectal cancer and to investigate whether AC is associated with improved survival outcomes. METHODS: This retrospective study comprised 432 patients with rectal cancer above the peritoneal reflection who had undergone curative resection without preoperative chemoradiotherapy between 2008 and 2016. This study cohort was divided according to whether AC was received (AC group) or not (no-AC group). Risk factors included obstruction, perforation, poorly-differentiated tumor, lympho-vascular invasion, perineural invasion, resection margin involvement, and < 12 lymph nodes harvested. RESULTS: Among the 432 patients, 279 (64.6%) had received AC. The AC group had significantly higher 5-year overall survival (OS) rates than those of the no-AC group (93.2% vs. 84.6%, P = .001). Among patients with ≥ 1 risk factors, the AC group (n = 123) had significantly higher rates of 5-year recurrence-free survival (RFS) (81.6% vs. 64.1%, P = .01) and 5-year OS (88.8% vs. 69.0%, P = .001) than those of the no-AC group (n = 59). No significant difference in survival outcomes was observed between the 2 groups in patients aged > 65 years. CONCLUSION: AC was significantly associated with better 5-year RFS and 5-year OS rates in patients with stage IIA rectal cancer above peritoneal reflection who did not receive preoperative chemoradiotherapy, especially in those with ≥ 1 risk factors.
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BACKGROUND: The randomized, open-label, phase III LYNK-003 study assessed the efficacy of first-line maintenance olaparib, alone or in combination with bevacizumab, versus bevacizumab plus a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer (mCRC). We present results of the prespecified interim futility analysis. METHODS: Eligible participants were ≥18 years of age with unresectable or mCRC that had not progressed after induction with first-line bevacizumab plus 5-fluorouracil plus oxaliplatin plus leucovorin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX). Participants were randomly assigned 1:1:1 to olaparib plus bevacizumab, olaparib alone, or bevacizumab plus a fluoropyrimidine (5-fluorouracil or capecitabine). The primary end point was progression-free survival (PFS) per RECIST v1.1 by central review. RESULTS: Between August 2020 and May 2022, 309 participants were assigned to olaparib plus bevacizumab (n = 104), olaparib (n = 107), or bevacizumab plus fluoropyrimidine (n = 98). At interim analysis, with a median follow-up of 7.6 months (range 0.1-19.7 months), the median PFS was 3.7 months (95% CI 2.8-5.3) with olaparib plus bevacizumab (HR 1.52; 95% CI 1.02-2.27; P = 0.982) and 3.5 months (95% CI 2.0-3.7) with olaparib (HR 2.11; 95% CI 1.39-3.18; P = 0.999) versus 5.6 months (95% CI 3.8-5.9) with bevacizumab plus fluoropyrimidine. Treatment-related adverse events occurred in 64 (62%), 52 (50%), and 57 (59%) participants, respectively. There were no treatment-related deaths. CONCLUSION: The LYNK-003 study was stopped prematurely as criteria for futility were met. Maintenance olaparib with or without bevacizumab did not demonstrate clinical efficacy compared with bevacizumab plus a fluoropyrimidine. GOV REGISTRATION: NCT04456699.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Fluoruracila , Ftalazinas , Piperazinas , Humanos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Ftalazinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Adulto , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Quimioterapia de Manutenção/métodos , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Capecitabina/uso terapêutico , Idoso de 80 Anos ou mais , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
PURPOSE: This study aimed to report the results from an early-phase study of rivoceranib, an oral tyrosine kinase inhibitor highly selective for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. MATERIALS AND METHODS: In this open-label, single-arm, dose-escalating, multicenter three-part phase 1/2a trial, patients had advanced solid tumors refractory to conventional therapy. Part 1 evaluated the safety and pharmacokinetics of five ascending once-daily doses of rivoceranib from 81 mg to 685 mg. Part 2 evaluated the safety and antitumor activity of once-daily rivoceranib 685 mg. Part 3 was conducted later, due to lack of maximum tolerated dose determination in part 1, to evaluate the safety and preliminary efficacy of once-daily rivoceranib 805 mg in patients with unresectable or advanced gastric cancer. RESULTS: A total of 61 patients were enrolled in parts 1 (n=25), 2 (n=30), and 3 (n=6). In parts 1 and 2, patients were white (45.5%) or Asian (54.5%), and 65.6% were male. The most common grade ≥ 3 adverse events were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The objective response rate (ORR) was 15.2%. In part 3, dose-limiting toxicities occurred in two out of six patients: grade 3 febrile neutropenia decreased appetite, and fatigue. The ORR was 33%. CONCLUSION: The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily, which showed adequate efficacy with a manageable safety profile (NCT01497704 and NCT02711969).
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Inibidores da Angiogênese , Neoplasias , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adulto , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Resultado do Tratamento , Dose Máxima Tolerável , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinéticaRESUMO
PURPOSE: The female sex is reported to have a higher risk of adverse events (AEs) from cytotoxic chemotherapy. Few studies examined the sex differences in AEs and their impact on the use of medical services during adjuvant chemotherapy. This sub-study aimed to compare the incidence of any grade and grade ≥ 3 AEs, healthcare utilization, chemotherapy completion rate, and dose intensity according to sex. MATERIALS AND METHODS: This is a sub-study of a multicenter cohort conducted in Korea that evaluated the impact of healthcare reimbursement on AE evaluation in patients who received adjuvant chemotherapy between September 2013 and December 2016 at four hospitals in Korea. RESULTS: A total of 1,170 patients with colorectal, gastric, or non-small cell lung cancer were included in the study. Female patients were younger, had fewer comorbidities, and experienced less postoperative weight loss of > 10%. Females had significantly higher rates of any grade AEs including nausea, abdominal pain, stomatitis, vomiting, and neutropenia, and experienced more grade ≥ 3 neutropenia, nausea, and vomiting. The dose intensity of chemotherapy was significantly lower in females, and they also experienced more frequent dose reduction after the first cycle. Moreover, female patients receiving platinum-containing regimens had significantly higher rates of unscheduled outpatient visits. CONCLUSION: Our study found that females experienced a higher incidence of multiple any-grade AEs and severe neutropenia, nausea, and vomiting, across various cancer types, leading to more frequent dose reductions. Physicians should be aware of sex differences in AEs for chemotherapy decisions.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neutropenia , Humanos , Masculino , Feminino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/etiologia , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Náusea/tratamento farmacológico , Vômito/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante/efeitos adversosRESUMO
PURPOSE: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). MATERIALS AND METHODS: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. RESULTS: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0). CONCLUSION: GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.
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Anticorpos Monoclonais Humanizados , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Irinotecano/uso terapêutico , Fluoruracila/efeitos adversos , Leucovorina/efeitos adversos , Camptotecina/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Lutetium (Lu)-177 peptide receptor radionuclide therapy (PRRT) is one of the standard treatments for somatostatin receptor-positive well-differentiated neuroendocrine tumors (NETs). However, limited Asian representation in the pivotal NETTER-1 trial and a lack of real-world data for Lu-177 PRRT from Asian regions exist. OBJECTIVE: This retrospective study aimed to evaluate the efficacy and safety of Lu-177 PRRT in Korean patients with advanced NETs. PATIENTS AND METHODS: This study analyzed 64 patients treated with Lu-177 DOTATATE PRRT at the Asan Medical Center, Seoul, Korea, between November 2019 and December 2022. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), and safety profile. RESULTS: The median age of patients was 55 years. Prior to PRRT, patients received a median of two lines (range 0-6) of systemic therapy. Fifty (78%) patients received the planned four cycles of Lu-177 DOTATATE PRRT. The median PFS was 21.7 months (95% confidence interval 16.7-not available) and the ORR was 20%. With a median follow-up of 15.7 months (range 1.0-39.3), the median OS was not reached and the 1-year OS rate was 88%. The median PFS was better in patients with grade 1-2 NETs than in those with grade 3 NET (not reached vs. 14.2 months; hazard ratio 3.15; p = 0.0058). Hematological toxicities were the common adverse events, including grade ≥ 3 anemia (7.8%), neutropenia (10.9%), and thrombocytopenia (9.4%). CONCLUSIONS: In Korean patients with advanced NETs, Lu-177 DOTATATE PRRT showed efficacy and safety outcomes, consistent with those in the NETTER-1 trial and previous Western real-world studies.
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Tumores Neuroendócrinos , Compostos Organometálicos , Tomografia por Emissão de Pósitrons , Cintilografia , Humanos , Pessoa de Meia-Idade , Lutécio , Tumores Neuroendócrinos/radioterapia , Octreotida/efeitos adversos , Compostos Organometálicos/efeitos adversos , Radioisótopos , Receptores de Peptídeos , República da Coreia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Carcinoembryonic antigen (CEA) is the most widely used tumor marker in metastatic colorectal cancer (mCRC). However, its potential as a predictive marker of progression in mCRC during systemic chemotherapy, particularly in patients receiving monoclonal antibodies as a combination therapy, has remained of interest. Herein, we investigated whether CEA changes could predict disease progression and clinical outcomes in patients with mCRC cotreated with systemic chemotherapy and/or biologic agents. A total of 1261 patients with mCRC undergoing a first-line systemic treatment were included in this retrospective study. We analyzed the optimal cut-off value for CEA changes to predict progression at the first response evaluation by the treatment arm (chemotherapy alone, chemotherapy plus anti-vascular endothelial growth factor (VEGF) monoclonal antibody [mAb], and chemotherapy plus anti-epidermal growth factor receptor [EGFR] mAb). These cut-off values were then used to predict overall survival (OS) and progression-free survival (PFS). When stratified by their treatment arm, 891 (70.6%), 266 (21.0%), and 104 (8.2%) of the study patients were included in the chemotherapy alone-, anti-VEGF mAb, and anti-EGFR mAb groups, respectively. The optimal CEA cut-off values were 16.5% and 38.9% increase in the whole cohort and anti-EGFR mAb group, respectively, and these values showed high sensitivity and specificity for predicting disease progression. The patients in the entire population and anti-EGFR mAb group with CEA changes below these cut-off values showed significantly better OS and PFS outcomes compared those whose changes were above cut-off values. Among the patients with mCRC treated with anti-VEGF mAb, no associations were found between OS or PFS outcomes and CEA changes. CEA is potentially a good surrogate marker for predicting disease progression and survival outcomes in patients with mCRC receiving first-line systemic chemotherapy alone or chemotherapy with anti-EGFR mAb, whereas it is less effective in those treated with anti-VEGF mAb.
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Antineoplásicos , Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Antígeno Carcinoembrionário , Neoplasias Colorretais/patologia , Estudos Retrospectivos , Receptores ErbB/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Progressão da Doença , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVE: This study aimed to develop and validate post- and preoperative models for predicting recurrence after curative-intent surgery using an FDG PET-CT metabolic parameter to improve the prognosis of patients with synchronous colorectal cancer liver metastasis (SCLM). METHODS: In this retrospective multicenter study, consecutive patients with resectable SCLM underwent upfront surgery between 2006 and 2015 (development cohort) and between 2006 and 2017 (validation cohort). In the development cohort, we developed and internally validated the post- and preoperative models using multivariable Cox regression with an FDG metabolic parameter (metastasis-to-primary-tumor uptake ratio [M/P ratio]) and clinicopathological variables as predictors. In the validation cohort, the models were externally validated for discrimination, calibration, and clinical usefulness. Model performance was compared with that of Fong's clinical risk score (FCRS). RESULTS: A total of 374 patients (59.1 ± 10.5 years, 254 men) belonged in the development cohort and 151 (60.3 ± 12.0 years, 94 men) in the validation cohort. The M/P ratio and nine clinicopathological predictors were included in the models. Both postoperative and preoperative models showed significantly higher discrimination than FCRS (p < .05) in the external validation (time-dependent AUC = 0.76 [95% CI 0.68-0.84] and 0.76 [0.68-0.84] vs. 0.65 [0.57-0.74], respectively). Calibration plots and decision curve analysis demonstrated that both models were well calibrated and clinically useful. The developed models are presented as a web-based calculator ( https://cpmodel.shinyapps.io/SCLM/ ) and nomograms. CONCLUSIONS: FDG metabolic parameter-based prognostic models are well-calibrated recurrence prediction models with good discriminative power. They can be used for accurate risk stratification in patients with SCLM. KEY POINTS: ⢠In this multicenter study, we developed and validated prediction models for recurrence in patients with resectable synchronous colorectal cancer liver metastasis using a metabolic parameter from FDG PET-CT. ⢠The developed models showed good predictive performance on external validation, significantly exceeding that of a pre-existing model. ⢠The models may be utilized for accurate patient risk stratification, thereby aiding in therapeutic decision-making.
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Neoplasias Colorretais , Neoplasias Hepáticas , Masculino , Humanos , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/secundário , Estudos Retrospectivos , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologiaRESUMO
INTRODUCTION: Colorectal cancer with peritoneal metastasis (PM) has been considered a non-curative disease. PM is associated with reduced overall survival (OS) and worse prognosis compared with metastasis at other sites. We aimed to investigate the treatment outcome and recurrence after curative resection of colorectal PM during a long-term follow-up. METHODS: Patients who were diagnosed with colorectal PM and underwent surgery between December 2001 and December 2019 were included (n = 309). Curative resection was defined as PM resection without residual disease after surgery (complete macroscopic resection). RESULTS: Of 309 patients, 208 (67.8%) had PM as an initially metastatic disease. Curative (R0/1) resection was achieved in 155 (50.2%) patients, while non-curative operation (R2 resection or palliative operation including colostomy) was performed in 154 (49.8%) patients. Compared with patients who underwent non-curative operation, those with curative resection more often had a single PM on preoperative imaging (34.2% vs. 20.8%, p = 0.011) and postoperative results (59.4% vs. 22.7%, p < 0.001) and less often had concurrent metastasis (distant lymph node, liver, or lung) at the time of surgery (p < 0.001). During a median follow-up of 90.4 months, 80.6% (125/155) patients had recurrence in the curative resection group; the peritoneum was the most common site (56.0%). The median OS was 47.7 months (95% CI, 39.2-56.2) in the curative resection group and 24.8 months (95% CI, 20.8-28.9) in the non-curative resection group, respectively (p < 0.001). In particular, twenty-six patients without recurrence showed long-term survival after curative resection (median OS, 87.1 months; range, 40.1-127.5). CONCLUSION: Surgical resection can be considered for selected patients with colorectal PM because a significant number of them could seize the cure changes during their treatment continuum.
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Neoplasias Colorretais , Neoplasias Peritoneais , Humanos , Peritônio/patologia , Seguimentos , Neoplasias Peritoneais/secundário , Neoplasias Colorretais/patologia , Resultado do Tratamento , Prognóstico , Estudos Retrospectivos , Recidiva Local de NeoplasiaRESUMO
A better understanding of the effects of preoperative chemoradiotherapy (CRT) on tumor immune microenvironment (TIME) is essential to improve the treatment outcomes of patients with locally advanced rectal cancer (LARC). In this context, we performed a multiplex immunofluorescence staining to evaluate the TIME in 158 patients with LARC who underwent preoperative CRT followed by surgery and adjuvant chemotherapy in the ADORE trial. We found that higher levels of T-cell subsets (CD3+, CD4+, and CD8+) and dendritic cells in the tumor compartment of pretreatment biopsy samples were associated with good response to preoperative CRT. After CRT, there was a significant increase in the densities of CD3+ T cells, CD8+ T cells, and dendritic cells, while that of CD4+FoxP3+ regulatory T cells decreased, indicating that CRT changed the TIME into a more immune-active status. However, CRT also conferred an immunosuppressive effect by polarizing the tumor-associated macrophages from pro-inflammatory M1 macrophage to immune-suppressive M2 macrophages and decreasing the density of B cells. High delta values of CD3+ T cells and PD-L1+ lymphocytes after CRT were associated with good disease-free survival (DFS), while that of CD4+FoxP3+ regulatory T cells was associated with poor DFS. These findings provide a framework for future studies incorporating strategies to modulate the TIME in patients with LARC.
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Segunda Neoplasia Primária , Neoplasias Retais , Humanos , Linfócitos T CD8-Positivos , Microambiente Tumoral , Quimiorradioterapia , Neoplasias Retais/terapia , Fatores de Transcrição ForkheadRESUMO
PURPOSE: The combination of oxaliplatin and fluoropyrimidine for 6 months is one of the standard options for adjuvant therapy for high-risk stage II and III colorectal cancers (CRCs). The optimal duration of oxaliplatin to diminish neurotoxicity without compromising efficacy needs to be clarified. PATIENTS AND METHODS: This open-label, randomized, phase III, noninferiority trial randomly assigned patients with high-risk stage II and III CRC to 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine groups (3- and 6-month arms, respectively). The primary end point was disease-free survival (DFS), and the noninferiority margin was a hazard ratio (HR) of 1.25. RESULTS: In total, 1,788 patients were randomly assigned to the 6-month (n = 895) and 3-month (n = 893) arms, and 83.6% in the 6-month arm and 85.7% in the 3-month arm completed the treatment. The neuropathy rates with any grade were higher in the 6-month arm than in the 3-month arm (69.5% v 58.3%; P < .0001). The 3-year DFS rates were 83.7% and 84.7% in the 6-month and 3-month arms, respectively, with an HR of 0.953 (95% CI, 0.769 to 1.180; test for noninferiority, P = .0065) within the noninferiority margin. Among patients with stage III CRC treated by capecitabine plus oxaliplatin, the 3-year DFS of the 3-month arm was noninferior as compared with that of the 6-month arm with an HR of 0.713 (95% CI, 0.530 to 0.959; P = .0009). However, among patients with high-risk stage II and stage III CRC treated by infusional fluorouracil, leucovorin, and oxaliplatin, the noninferiority of the 3-month arm compared with the 6-month arm was not proven. CONCLUSION: This study suggests that adding 3 months of oxaliplatin to 6 months of capecitabine could be considered an alternative adjuvant treatment for stage III CRC (ClinicalTrials.gov identifier: NCT01092481).
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Neoplasias do Colo , Compostos Organoplatínicos , Oxaliplatina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/uso terapêuticoRESUMO
Background: BRAF-mutated colorectal cancers (BRAF-MT CRCs) are known to have poor prognoses. BRAF-MT CRC was reported to be possibly related to the immune-activated phenotype. Objectives: This study aimed to investigate the association between the immune microenvironment and prognosis of BRAF-MT CRC. Methods: We evaluated clinical outcomes and investigated the immune profile of the BRAF-MT CRC tumors using the multiplex immunohistochemistry of immune-related markers: cytokeratin, programmed death ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), and a cluster of differentiation 8 (CD8). Results: Out of 2313 tumors, 123 were BRAF-MT tumors. Among them, 86 tumors with available tissue were included. Out of 86 patients, 75 patients were non-good responders (GR), whereas 11 patients were GR. Median progression-free survival after first-line chemotherapy (4.6 vs. 12.4 months, p = 0.008) and overall survival (11.8 vs. 45.0 months) were longer in the GR group (p < 0.001). Median CD8+ T cell (254.29 vs. 656.0, p = 0.092), PD-L1+ tumor cell (0.95 vs.15.56, p = 0.050), PD-L1+ stromal cell (3.17 vs. 72.38, p = 0.025), PD-L1+ tumor and stromal cell (5.08 vs. 74.92, p = 0.032), and PD-1+ stromal cell (45.08 vs. 325.40, p = 0.046) counts were greater in the GR group. Conclusion: The clinical outcomes of unselected patients with BRAF-MT CRC were generally similar to those in previous studies. Based on the immune profile analysis, higher PD-L1 expression and CD8-positive cell infiltration were observed in BRAF-MT tumors with a good prognosis.
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BACKGROUND: Few studies to date have investigated morphological changes after neoadjuvant treatment (NAT) and their implications in total mesorectal excision (TME). This study was primarily designed to evaluate whether tissue changes associated with NAT affected the quality of TME and additionally to suggest a more objective method evaluating TME quality. METHODS: This study enrolled 1322 consecutive patients who underwent curative robot-assisted surgery for rectal cancer. Patients who did and did not receive NAT were subjected to propensity-score matching, yielding 402 patients in each group. RESULTS: NAT independently reduced complete achievement of TME [odds ratio (OR) = 2.056, p = 0.017]. Intraoperative evaluation identified seven tissue changes significantly associated with NAT, including tumor perforation, mucin pool, necrosis, fibrosis, fat degeneration, and rectal or perirectal edema NAT (p < 0.001-0.05). Tumor perforation (OR = 5.299, p = 0.001) and mucin pool (OR = 14.053, p = 0.002) were independently associated with inappropriate (near-complete + incomplete) TME. Complete TME resulted in significantly reduced local recurrence (4.3% vs 15.3%, p = 0.003) and increased 5-year DFS rate (80.6% vs 67.6%, p = 0.047) compared with inappropriate one. By contrast, two tiers of complete and near-complete TMEs vs incomplete TME did not. Notably, among patients with complete TME, those who received NAT had a lower 5-year DFS than those who did not (77.8% vs 83.3%, p = 0.048). CONCLUSIONS: NAT-associated tissue changes, somewhat interrupting complete TME, may provide unsolved clue to the relative inability of NAT to improve overall survival. The conventional three-tier grading of TME seems to be simplified into two tiers as complete and inappropriate.
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Neoplasias Retais , Procedimentos Cirúrgicos Robóticos , Humanos , Mucinas , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Neoplasias Retais/patologia , Reto/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Young-onset colorectal cancer (YOCR) is increasing. This study aimed to determine the difference between advanced YOCR and non-YOCR patient outcomes. METHODS: We retrospectively included patients with recurrent/metastatic colorectal cancer treated with palliative systemic therapy between 2016 and 2018. Diagnosis at < 50 years was defined as YOCR. Targeted sequencing was used to assess the mutational status. RESULTS: Among the 969 patients included, 210 (21.7%) were YOCR. The median progression-free survival with first-line chemotherapy (PFS1) was 9.7 vs 9.4 months (P = .755), and the median overall survival (OS) was 25.9 vs 22.3 months (P = .581) in the YOCR and the non-YOCR group, respectively. However, the youngest patients diagnosed at < 30 years showed poorer survival outcomes (median PFS1, 3.9 months; median OS, 8.6 months) compared with other age groups. PFS1 did not differ between YOCR and non-YOCR by choice of treatment regimen. Among the 340 patients with targeted sequencing results, YOCR had fewer APC mutations (61% vs 80%), but had similar KRAS (53% vs 48%), NRAS (7% vs 3%), and BRAF class I mutations (4% vs 6%). The median tumor mutational burden (TMB) was 10.9 vs 12.5 mut/Mb in YOCR and non-YOCR patients, respectively (P = .064). TMB increased with age in tumors with high microsatellite instability (Pearson's R = .69, P = .028), but not in microsatellite-stable tumors (R = .02, P = .658). CONCLUSIONS: Survival outcomes with palliative systemic therapy were similar between recurrent/metastatic YOCR and non-YOCR with an age cut-off of 50 years. However, patients diagnosed at < 30 years of age showed poorer outcomes compared with other age groups.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Biomarcadores Tumorais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Cuidados Paliativos , Proteínas Proto-Oncogênicas B-raf/genética , Estudos RetrospectivosRESUMO
The aim of our study is to evaluate the clinical efficacy of durvalumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) or polymerase epsilon (POLE)-mutated metastatic or unresectable colorectal cancer (mCRC) who had disease progression after standard chemotherapy. This prospective, open-label, multicenter, phase II study enrolled patients with mCRC harboring MSI-H/dMMR or POLE mutations treated with at least one prior line of therapy. The participants received durvalumab (1500 mg) every 4 weeks intravenously. The primary endpoint was the objective response rate (ORR). Of the 33 patients, 30 had MSI-H/dMMR and 3 had POLE-mutated microsatellite stable (MSS) CRC. With a median follow-up duration of 11.2 months (95% confidence interval [CI]: 7.3-15.0), the ORR was 42.4% (95% CI: 25.5-60.8). Among three patients with POLE-mutated CRC, one patient who had an exonuclease domain mutation (EDM) achieved an objective response, but the others with mutations in the non-exonuclease domain had progressive disease. Overall, the median duration of response was not reached and 85.7% of the responses were ongoing at data cutoff. The progression-free survival rate of 12 months was 58.2% (95% CI: 39.0-73.1) and the 12-month overall survival rate was 68.3% (95% CI: 48.8-81.7). Grade 3 treatment-related adverse events occurred in 36.4% of the patients and were manageable. In conclusion, durvalumab showed promising clinical activity with encouraging response rates and satisfactory survival outcomes in mCRC patients with MSI-H/dMMR or POLE EDM. In patients with POLE-mutated mCRC, clinical response to durvalumab may be restricted to those with EDM.
Assuntos
Neoplasias Colorretais , Instabilidade de Microssatélites , Anticorpos Monoclonais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Humanos , Estudos ProspectivosRESUMO
We aimed to investigate the dynamic changes of gene expression profiles and immune microenvironment linked to resistance to cetuximab-based treatments in patients with metastatic colorectal cancer (mCRC). A total of 106 patients with RAS-wild type mCRC who were treated with cetuximab-based treatments were included as the study population. RNA-sequencing and multiplexed immunohistochemistry were performed using paired or unpaired pre-treatment and post-treatment tumor tissues. Differentially expressed gene analysis of paired pre-treatment and post-treatment tumor tissues that develop acquired resistance (AR) identified the AR signature. Gene ontology analysis of the AR signature indicated enrichment of immune-related pathway genes. Among the immune subsets whose abundance was estimated by CIBERSORT, M2 macrophages showed the most prominent positive correlation with the expression of the AR signature. Among the post-treatment samples, progressive disease (PD) tumors showed a significantly higher abundance of M2 macrophages compared to non-PD tumors. These findings were validated by multiplexed immunohistochemistry analysis: the density of CD68+CD206+ M2 macrophages significantly increased at the time of PD following cetuximab-based treatment, whereas it did not consistently change in the tumor pairs of non-PD. In conclusion, a dynamic increase of M2 macrophages is associated with disease progression during cetuximab-based treatment of mCRCs. Targeting M2 macrophages is a promising immunotherapeutic strategy in this clinical context.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antineoplásicos Imunológicos/efeitos adversos , Cetuximab/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Fenótipo , Intervalo Livre de Progressão , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Estudos Retrospectivos , Fatores de Tempo , Transcriptoma , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Adulto JovemRESUMO
PURPOSE: Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instabilityâhigh (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC. MATERIALS AND METHODS: MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning-based classification model was built to predict treatment response among MSI-H CRCs patients. RESULTS: A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, PRAME had the highest fold change in the responder group. Higher expression of PRAME was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response. CONCLUSION: We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Inibidores de Checkpoint Imunológico , Interferon gama , Instabilidade de Microssatélites , Receptor de Morte Celular Programada 1RESUMO
BACKGROUND: This study was conducted to compare the reported adverse event (AE) profiles and unexpected use of medical services during chemotherapy between before and after the healthcare reimbursement of AE evaluation in patients with cancer. PATIENTS AND METHODS: Using the electronic medical record database system, extracted patients with breast, lung, gastric, and colorectal cancers receiving neoadjuvant or adjuvant chemotherapy between September 2013 and December 2016 at four centers in Korea were matched using the 1:1 greedy method: pre-reimbursement group (n = 1084) and post-reimbursement group (n = 1084). Unexpected outpatient department (OPD), emergency room (ER) visit, hospitalization rates, and chemotherapy completion rates were compared between the groups. RESULTS: The baseline characteristics were well-balanced between the groups. By chemotherapy cycle, hospitalization (1.8% vs. 2.3%; p = 0.039), and ER visit rates (3.3% vs. 3.9%; p = 0.064) were lower in the post-reimbursement group than that in the pre-reimbursement group. In particular, since cycle 2, ER visit and hospitalization rates were significantly lower in the post-reimbursement group than those in the pre-reimbursement group (2.6% vs. 3.3%; p = 0.020 and 1.4% vs. 2.0%; p = 0.007, respectively), although no significant differences were observed during cycle 1. The OPD visit rates were similar between both groups, regardless of cycles. The post-reimbursement group had a higher proportion of patients who completed chemotherapy as planned than the pre-reimbursement group (93.5% vs. 90.1%; p = 0.006). Post-reimbursement group had more AEs reported, including alopecia, fatigue, diarrhea, anorexia, and peripheral neuropathy, during cycle 1 than the pre-reimbursement group, which significantly decreased after cycle 2. CONCLUSION: The introduction of healthcare reimbursement for AE evaluation may help physicians capture and appropriately manage AEs, consequently, decreasing hospital utilization and increasing chemotherapy completion rates.
Assuntos
Hospitalização , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Hospitais , Humanos , Terapia Neoadjuvante/efeitos adversos , Estudos RetrospectivosRESUMO
Next-generation sequencing (NGS) is becoming essential in the fields of precision oncology. With implementation of NGS in daily clinic, the needs for continued education, facilitated interpretation of NGS results and optimal treatment delivery based on NGS results have been addressed. Molecular tumor board (MTB) is multidisciplinary approach to keep pace with the growing knowledge of complex molecular alterations in patients with advanced solid cancer. Although guidelines for NGS use and MTB have been developed in western countries, there is limitation for reflection of Korea's public health environment and daily clinical practice. These recommendations provide a critical guidance from NGS panel testing to final treatment decision based on MTB discussion.