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Identifying patients with stage II and III colon cancer who will benefit from 5-fluorouracil (5-FU)-based adjuvant chemotherapy is crucial for the advancement of personalized cancer therapy. We employ a semi-supervised machine learning approach to analyze a large dataset with 933 stage II and III colon cancer samples. Our analysis leverages gene regulatory networks to discover an 18-gene prognostic signature and to explore a 10-gene signature that potentially predicts chemotherapy benefits. The 10-gene signature demonstrates strong prognostic power and shows promising potential to predict chemotherapy benefits. We establish a robust clinical assay on the NanoString nCounter platform, validated in a retrospective formalin-fixed paraffin-embedded (FFPE) cohort, which represents an important step toward clinical application. Our study lays the groundwork for improving adjuvant chemotherapy and potentially expanding into immunotherapy decision-making in colon cancer. Future prospective studies are needed to validate and establish the clinical utility of the 10-gene signature in clinical settings.
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Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.
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Neoplasias do Colo , Humanos , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/terapia , Neoplasias do Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Oncologia/normas , Oncologia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estados UnidosRESUMO
PURPOSE: We examined the concordance of genetic mutations between pretreatment tumor tissue and posttreatment circulating tumor DNA (ctDNA) in patients with metastatic squamous cell carcinoma of the anal canal (SCCA) and assessed the impact of therapy on this concordance. METHODS: We analyzed next-generation sequencing reports from pretreatment tumor tissue and posttreatment ctDNA in 11 patients with metastatic SCCA treated at Vanderbilt University Medical Center between 2017 and 2021. RESULTS: Among the mutations identified in posttreatment ctDNA, 34.5% were also found in pretreatment tumor tissue, while 47.6% of pretreatment tumor tissue mutations were found in posttreatment ctDNA. Four patients had preservation of potentially actionable mutations in both pretreatment tissue and posttreatment ctDNA, while 7 patients had newly identified mutations in posttreatment ctDNA that were not present in pretreatment tumor tissue. CONCLUSION: Patients with SCCA demonstrate a high degree of temporal mutational heterogeneity. This supports the hypothesis that ctDNA can serve as a real-time tracking mechanism for solid tumors' molecular evolution in response to therapy. Our findings highlight the potential of ctDNA in identifying emerging actionable mutations, supplementing information from tissue-based genomic assessments. Further research, ideally with larger and multi-institutional cohorts, is needed to validate our findings in this relatively rare tumor type.
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Neoplasias do Ânus , Carcinoma de Células Escamosas , DNA Tumoral Circulante , Humanos , Canal Anal , Mutação , DNA Tumoral Circulante/genética , Carcinoma de Células Escamosas/genética , Neoplasias do Ânus/genética , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Advances in multimodal management of locally advanced rectal cancer (LARC), consisting of preoperative chemotherapy and/or radiotherapy followed by surgery with or without adjuvant chemotherapy, have improved local disease control and patient survival but are associated with significant risk for acute and long-term morbidity. Recently published trials, evaluating treatment dose intensification via the addition of preoperative induction or consolidation chemotherapy (total neoadjuvant therapy [TNT]), have demonstrated improved tumor response rates while maintaining acceptable toxicity. In addition, TNT has led to an increased number of patients achieving a clinical complete response and thus eligible to pursue a nonoperative, organ-preserving, watch and wait approach, thereby avoiding toxicities associated with surgery, such as bowel dysfunction and stoma-related complications. Ongoing trials using immune checkpoint inhibitors in patients with mismatch repair-deficient tumors suggest that this subgroup of patients with LARC could potentially be treated with immunotherapy alone, sparing them the toxicity associated with preoperative treatment and surgery. However, the majority of rectal cancers are mismatch repair-proficient and less responsive to immune checkpoint inhibitors and require multimodal management. The synergy noted in preclinical studies between immunotherapy and radiotherapy on immunogenic tumor cell death has led to the design of ongoing clinical trials that explore the benefit of combining radiotherapy, chemotherapy, and immunotherapy (mainly of immune checkpoint inhibitors) and aim to increase the number of patients eligible for organ preservation.
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Neoplasias Encefálicas , Segunda Neoplasia Primária , Neoplasias Retais , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Quimioterapia AdjuvanteRESUMO
This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.
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Neoplasias do Ânus , Carcinoma de Células Escamosas , Humanos , Biópsia , OncologiaRESUMO
Gastrointestinal (GI) cancers, including esophageal, gastroesophageal junction, gastric, duodenal and distal small bowel, biliary tract, pancreatic, colon, rectal, and anal cancer, comprise a heterogeneous group of malignancies that impose a significant global burden. Immunotherapy has transformed the treatment landscape for several GI cancers, offering some patients durable responses and prolonged survival. Specifically, immune checkpoint inhibitors (ICIs) directed against programmed cell death protein 1 (PD-1), either as monotherapies or in combination regimens, have gained tissue site-specific regulatory approvals for the treatment of metastatic disease and in the resectable setting. Indications for ICIs in GI cancer, however, have differing biomarker and histology requirements depending on the anatomic site of origin. Furthermore, ICIs are associated with unique toxicity profiles compared with other systemic treatments that have long been the mainstay for GI cancer, such as chemotherapy. With the goal of improving patient care by providing guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of GI cancer. Drawing from published data and clinical experience, the expert panel developed evidence- and consensus-based recommendations for healthcare professionals using ICIs to treat GI cancers, with topics including biomarker testing, therapy selection, and patient education and quality of life considerations, among others.
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Neoplasias Gastrointestinais , Qualidade de Vida , Humanos , Neoplasias Gastrointestinais/tratamento farmacológico , Imunoterapia , Sociedades MédicasRESUMO
BACKGROUND: HER2 is an actionable target in metastatic colorectal cancer. We assessed the activity of tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer. METHODS: MOUNTAINEER is a global, open-label, phase 2 study that enrolled patients aged 18 years and older with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer at 34 sites (clinics and hospitals) in five countries (Belgium, France, Italy, Spain, and the USA). Initially, the study was designed as a single-cohort study, which was expanded following an interim analysis to include more patients. Initially, patients were given tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg as an initial loading dose, then 6 mg/kg every 21 days; cohort A) for the duration of treatment (until progression), and after expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumour location, to either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C). The primary endpoint was confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined and was assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least one dose of study treatment). Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03043313, and is ongoing. FINDINGS: Between Aug 8, 2017, and Sept 22, 2021, 117 patients were enrolled (45 in cohort A, 41 in cohort B, and 31 in cohort C), of whom 114 patients had locally assessed HER2-positive disease and received treatment (45 in cohort A, 39 in cohort B, and 30 in cohort C; full analysis set), and 116 patients received at least one dose of study treatment (45 in cohort A, 41 in cohort B, and 30 in cohort C; safety population). In the full analysis set, median age was 56·0 years (IQR 47-64), 66 (58%) were male, 48 (42%) were female, 88 (77%) were White, and six (5%) were Black or African American. As of data cutoff (March 28, 2022), in 84 patients from cohorts A and B in the full analysis set, the confirmed objective response rate per BICR was 38·1% (95% CI 27·7-49·3; three patients had a complete response and 29 had a partial response). In cohorts A and B, the most common adverse event was diarrhoea (55 [64%] of 86), the most common grade 3 or worse adverse event was hypertension (six [7%] of 86), and three (3%) patients had tucatinib-related serious adverse events (acute kidney injury, colitis, and fatigue). In cohort C, the most common adverse event was diarrhoea (ten [33%] of 30), the most common grade 3 or worse adverse events were increased alanine aminotransferase and aspartate aminotransferase (both two [7%]), and one (3%) patient had a tucatinib-related serious adverse event (overdose). No deaths were attributed to adverse events. All deaths in treated patients were due to disease progression. INTERPRETATION: Tucatinib plus trastuzumab had clinically meaningful anti-tumour activity and favourable tolerability. This treatment is the first US Food and Drug Administration-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer. FUNDING: Seagen and Merck & Co.
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Neoplasias do Colo , Neoplasias Retais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Trastuzumab/efeitos adversos , Receptor ErbB-2/genética , Estudos de Coortes , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Diarreia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Rationale and Objectives: Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Methods: Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction. Measurements and Main Results: It was found that 14.9-23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere-related genes. New candidate genes were identified in a small number of families-including SYDE1, SERPINB8, GPR87, and NETO1-and tools were developed for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single-cell transcriptomics with prioritized candidate genes, expression of RV-containing genes was discovered to be enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells. Conclusions: In the most comprehensive FPF genetic study to date, the prevalence of RVs in known FPF-related genes was defined, and new candidate genes and pathways relevant to FPF were identified. However, new RV-containing genes shared across multiple kindreds were not identified, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.
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Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Humanos , Fibrose Pulmonar/genética , Células Endoteliais , Doenças Pulmonares Intersticiais/genética , Fatores de Risco , Telômero , Predisposição Genética para Doença/genética , Receptores de Ácidos Lisofosfatídicos/genéticaRESUMO
Data on diet and survival among people with metastatic colorectal cancer are limited. We examined dietary fat in relation to all-cause mortality and cancer progression or death among 1149 people in the Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group (SWOG) 80405 trial who completed a food frequency questionnaire at initiation of treatment for advanced or metastatic colorectal cancer. We examined saturated, monounsaturated, total and specific types (n-3, long-chain n-3 and n-6) of polyunsaturated fat, animal and vegetable fats. We hypothesized higher vegetable fat intake would be associated with lower risk of all-cause mortality and cancer progression. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Over median follow-up of 6.1 years (interquartile range [IQR]: 5.3, 7.2 y), we observed 974 deaths and 1077 events of progression or death. Participants had a median age of 59 y; 41% were female and 86% identified as White. Moderate or higher vegetable fat was associated with lower risk of mortality and cancer progression or death (HRs comparing second, third and fourth to first quartile for all-cause mortality: 0.74 [0.62, 0.90]; 0.75 [0.61, 0.91]; 0.79 [0.63, 1.00]; P trend: .12; for cancer progression or death: 0.74 [0.62, 0.89]; 0.78 [0.64, 0.95]; 0.71 [0.57, 0.88]; P trend: .01). No other fat type was associated with all-cause mortality and cancer progression or death. Moderate or higher vegetable fat intake may be associated with lower risk of cancer progression or death among people with metastatic colorectal cancer.
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Doenças Cardiovasculares , Neoplasias do Colo , Neoplasias Retais , Feminino , Animais , Masculino , Gorduras na Dieta , Dieta , Causas de MorteRESUMO
PURPOSE: To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC). METHODS: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria. RECOMMENDATIONS: Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti-vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti-epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive RAS wild-type mCRC; chemotherapy and anti-vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair RAS wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated BRAF V600E-mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/terapia , Neoplasias Colorretais/tratamento farmacológico , Fatores de Crescimento Endotelial/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Guias de Prática Clínica como AssuntoRESUMO
The global incidence of colorectal adenocarcinoma is stable or decreasing overall; however, the incidence of colorectal cancer in patients aged <50 years is increasing. Although some of this increase is due to hereditary cancer syndromes, this is not the sole explanation. Patients with early-onset rectal cancer in particular have unique disease patterns and face distinct challenges in their treatment. Molecular patterns of disease in this patient cohort are noteworthy and often represent an opportunity to target these cancers more effectively. Recent and ongoing trials focusing on minimizing toxicities and necessary therapy modalities and maximizing response and patient outcome are of paramount importance in this patient population. Additional resources are needed for this patient population, including fertility counseling and preservation, financial guidance, genetic counseling, and psychosocial support.
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Adenocarcinoma , Neoplasias Colorretais , Neoplasias Retais , Adenocarcinoma/patologia , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Humanos , Incidência , Neoplasias Retais/diagnóstico , Neoplasias Retais/epidemiologia , Neoplasias Retais/terapiaRESUMO
This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a "watch-and-wait" nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.
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Neoplasias Retais , Humanos , Oncologia , Terapia Neoadjuvante , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , Neoplasias Retais/terapiaRESUMO
With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.
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Neoplasias Colorretais , Instabilidade de Microssatélites , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/terapia , Reparo de Erro de Pareamento de DNA , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Repetições de Microssatélites , Microambiente Tumoral/genéticaRESUMO
The social stigma surrounding an anal cancer diagnosis has traditionally prevented open discussions about this disease. However, as recent treatment options and an increasing rate of diagnoses are made worldwide, awareness is growing. In the United States alone, 9,090 individuals were expected to be diagnosed with anal cancer in 2021. The US annual incidence of squamous cell carcinoma of the anus continues to increase by 2.7% yearly, whereas the mortality rate increases by 3.1%. The main risk factor for anal cancer is a human papillomavirus infection; those with chronic immunosuppression are also at risk. Patients with HIV are 19 times more likely to develop anal cancer compared with the general population. In this review, we have provided an overview of the carcinoma of the anal canal, the role of screening, advancements in radiation therapy, and current trials investigating acute and chronic treatment-related toxicities. This article is a comprehensive approach to presenting the existing data in an effort to encourage continuous international interest in anal cancer.
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Neoplasias do Ânus , Carcinoma de Células Escamosas , Infecções por HIV , Infecções por Papillomavirus , Canal Anal/patologia , Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/epidemiologia , Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/terapia , Infecções por HIV/epidemiologia , Humanos , Doenças Raras/complicações , Doenças Raras/patologiaRESUMO
BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAFV600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAFV600E-mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAFV600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.
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Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Each year, gastric cancer claims the lives of hundreds of thousands of patients worldwide. Despite surgical resection, the risk of residual disease, micrometastatic disease, and disease recurrence remain elevated. Herein, we review systemic therapy strategies in the neoadjuvant, adjuvant, and metastatic settings, including novel uses of immunotherapy, targeted therapies and cytotoxic chemotherapies, for the treatment of gastric cancer.
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Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Gastrectomia , Humanos , Terapia Neoadjuvante , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgiaRESUMO
The 5-year overall survival rate of a patient with unresectable metastatic colorectal cancer is poor at approximately 14%. Similarly, historical data on liver transplantation (LT) in those with colorectal liver metastases (CRLM) showed poor outcomes, with 5-year survival rates between 12% and 21%. More recently, limited data have shown improved outcomes in select patients with 5-year overall survival rates of approximately 60%. Despite these reported survival improvements, there is no significant improvement in disease-free survival. Given the uncertain benefit with this therapeutic approach and a renewed investigational interest, we aimed to conduct a contemporary systematic review on LT for CRLM. A systematic review of the literature was performed according to the preferred reporting items for systematic reviews and meta-analysis statement. English articles reporting on data regarding LT for CRLM were identified through the MEDLINE (via PubMed), Cochrane Library, and ClinicalTrials.gov databases (last search date: December 16th, 2021) by 2 researchers independently. A total of 58 studies (45 published and 13 ongoing) were included. Although early retrospective studies suggest the possibility that some carefully selected patients may benefit from LT, there is minimal prospective data on the topic and LT remains exploratory in the setting of CRLM. Additionally, several other challenges, such as the limited availability of deceased donor organs and defining appropriate selection criteria, remain when considering the implementation of LT for these patients. Further evidence from ongoing prospective trials is needed to determine if and to what extent there is a role for LT in patients with surgically unresectable CRLM.
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Neoplasias Colorretais , Neoplasias Hepáticas , Transplante de Fígado , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Hepatectomia , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Importance: Despite the benefit of peptide receptor radionuclide therapy (PRRT) for patients with well-differentiated neuroendocrine tumors (WD NETs), no clinical metric to anticipate benefit from the therapy for individual patients has been previously defined. Objective: To assess whether the prognostic ability of the clinical score (CS) could be validated in an external cohort of patients with WD NETs. Design, Setting, and Participants: This multicenter cohort study's analysis included patients with WD NETs who were under consideration for peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-dotatate between March 1, 2016, and March 17, 2020. The original cohort included patients from Vanderbilt-Ingram Cancer Center. The validation cohort included patients from Ochsner Medical Center, Markey Cancer Center, and Rush Medical Center. Patients with paragangliomas, pheochromocytomas and neuroblastomas were excluded. Statistical analysis was performed from June to November 2021. Exposures: PRRT with 177Lu-dotatate or alternate therapies such as everolimus, sunitinib, or capecitabine plus temozolomide. Main Outcomes and Measures: The primary outcome was progression-free survival (PFS) and was estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusting for primary tumor site, tumor grade, and number of PRRT doses administered was used to analyze association between CS and outcomes. Results: A total of 126 patients (median age [IQR] age: 63.6 [52.9-70.7] years; 64 male individuals) were included in the validation cohort, and the combined cohort (validation and original cohorts combined) had a total of 248 patients (median [IQR] patient age: 63.3 [53.3-70.3] years; 126 male individuals). In the validation cohort, on multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.61; 95% CI, 1.64-4.16). After finding an association of the CS with PFS in the validation cohort, the original and validation cohorts were combined into the cohort for this analysis. On multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.52; 95% CI, 1.89-3.36). Conclusions and Relevance: Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT.
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Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/radioterapia , Radioisótopos/uso terapêutico , Receptores de Peptídeos/uso terapêutico , Índice de Gravidade de Doença , Idoso , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Compostos Organometálicos/uso terapêutico , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Cintilografia , Resultado do TratamentoRESUMO
Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Noninvasive imaging via PET may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. l-[5-11C]-glutamine (11C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of 11C-glutamine for oncologic PET imaging. Methods: Nine patients with confirmed metastatic colorectal cancer underwent PET/CT imaging. Patients received 337.97 ± 44.08 MBq of 11C-glutamine. Dynamic PET acquisitions that were centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. After the dynamic acquisition, a whole-body PET/CT scan was acquired. Volume-of-interest analyses were performed to obtain estimates of organ-based absorbed doses of radiation. Results:11C-glutamine was well tolerated in all patients, with no observed safety concerns. The organs with the highest radiation exposure included the bladder, pancreas, and liver. The estimated effective dose was 4.46E-03 ± 7.67E-04 mSv/MBq. Accumulation of 11C-glutamine was elevated and visualized in lung, brain, bone, and liver metastases, suggesting utility for cancer imaging. Conclusion: PET using 11C-glutamine appears safe for human use and allows noninvasive visualization of metastatic colon cancer lesions in multiple organs. Further studies are needed to elucidate its potential for other cancers and for monitoring response to treatment.