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OPINION STATEMENT: Neoadjuvant chemotherapy is safe for patients with locally advanced colon cancer (LACC). The FOxTROT trial demonstrated a reduction in residual and recurrent cancer at 2 years with neoadjuvant chemotherapy for patients with cT3-4 LACC. Preoperative chemotherapy should be avoided, if possible, for patients with dMMR LACC, as over 50% of dMMR cancers have no pathologic response. Early universal testing of MMR status is critical to selecting the appropriate neoadjuvant therapy. Concerns about CT staging of LACC have limited uptake of neoadjuvant chemotherapy, as approximately 25% of patients with cT3-T4 cancer on CT have low-risk stage II disease. Development of CT criteria for malignant nodes should reduce the risk of over-staging. A multidisciplinary approach is needed to identify patients for neoadjuvant therapy. Neoadjuvant immunotherapy is safe and results in dramatic pathologic responses in patients with dMMR LACC. Longer follow-up is needed to determine if the exceptionally high pathologic response rates observed will translate into long-term remission. Remarkably, neoadjuvant immunotherapy has been found to cause major pathologic responses in a subset of patients with pMMR LACC, indicating the potential to cure more patients with this common cancer. Patients with cT4 LACC, whether stage II or III, have a substantial risk of recurrence despite adjuvant fluoropyrimidine plus oxaliplatin chemotherapy. We recommend neoadjuvant systemic therapy for all patients with cT4b LACC (dMMR and pMMR). Features of T4b disease are routinely reported by radiology. We use three cycles of FOLFOX chemotherapy for patients with cT4b pMMR LACC, due to the high rate of compliance and improvement in residual and recurrent disease. Patients with cT4b dMMR LACC should receive neoadjuvant immunotherapy, if there are no contraindications. Clinical trials of neoadjuvant therapy for LACC are of great interest and should provide training for radiologists to identify eligible patients. Results are anticipated from multiple ongoing trials of neoadjuvant chemotherapy, immunotherapy, and targeted therapy for pMMR LACC and immunotherapy for dMMR LACC.
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Neoplasias Encefálicas , Neoplasias do Colo , Neoplasias Colorretais , Recidiva Local de Neoplasia , Síndromes Neoplásicas Hereditárias , Humanos , Prognóstico , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Neoplasias do Colo/terapia , Neoplasias do Colo/tratamento farmacológico , Terapia Neoadjuvante , Reparo de Erro de Pareamento de DNARESUMO
Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N3-methyladenine and N7-methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled-median age 59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m2 daily × 5 may be safely administered with MX 150 mg/m2 intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.
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Antineoplásicos Alquilantes/uso terapêutico , Hidroxilaminas/uso terapêutico , Neoplasias/tratamento farmacológico , Temozolomida/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Área Sob a Curva , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Meia-Vida , Humanos , Hidroxilaminas/administração & dosagem , Hidroxilaminas/efeitos adversos , Hidroxilaminas/farmacocinética , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Temozolomida/efeitos adversos , Temozolomida/farmacocinéticaRESUMO
BACKGROUND: MK-5108 is a potent/highly selective Aurora A kinase inhibitor. METHODS: A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1-2 in 14-21 day cycles either alone (MT; Panel1/n = 18; 200 to 1800 mg) or in combination (CT; Panel2/n = 17; 100 to 225 mg) with IV docetaxel 60 mg/m(2), determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. RESULTS: 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; three patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6 to 13.5 h across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). CONCLUSIONS: MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 µM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aurora Quinase A/antagonistas & inibidores , Ácidos Cicloexanocarboxílicos/administração & dosagem , Neoplasias/tratamento farmacológico , Tiazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Estudos Cross-Over , Ácidos Cicloexanocarboxílicos/efeitos adversos , Ácidos Cicloexanocarboxílicos/farmacocinética , Docetaxel , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Taxoides/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/farmacocinéticaRESUMO
The treatment of patients with localized rectal cancer is complex and requires input from a multidisciplinary team. Baseline local staging and mismatch repair protein testing are vital to develop individualized treatment plans. There are multiple options in terms of treatment modalities and sequencing, including transanal excision, short-course radiation, long-course chemoradiation, chemotherapy doublet or triplet, nonoperative management, and immune checkpoint blockade for patients with mismatch repair deficient tumors. While localized colon cancer is typically treated with surgical resection and consideration of adjuvant chemotherapy, emerging data suggest that neoadjuvant chemotherapy may be beneficial in patients with higher-risk disease. Quality-of-life considerations are imperative to prevent potential chronic effects on psychosocial health, neuropathy, fertility, and bowel, bladder, and sexual function. The omission of radiation or surgery can mitigate these toxicities without diminishing oncologic outcomes. The optimal treatment plan and sequence is not a one-size-fits-all approach but rather should be personalized to the patient's disease burden, tumor location, comorbidities, and preferences.
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Neoplasias Colorretais , Padrão de Cuidado , Humanos , Neoplasias Colorretais/terapia , Gerenciamento Clínico , Terapia Combinada , Qualidade de Vida , Estadiamento de NeoplasiasRESUMO
The incidence of early-onset colorectal cancer (eoCRC) is rising, and its pathogenesis is not completely understood. We hypothesized that machine learning utilizing paired tissue microbiome and plasma metabolome features could uncover distinct host-microbiome associations between eoCRC and average-onset CRC (aoCRC). Individuals with stages I-IV CRC (n = 64) were categorized as eoCRC (age ≤ 50, n = 20) or aoCRC (age ≥ 60, n = 44). Untargeted plasma metabolomics and 16S rRNA amplicon sequencing (microbiome analysis) of tumor tissue were performed. We fit DIABLO (Data Integration Analysis for Biomarker Discovery using Latent variable approaches for Omics studies) to construct a supervised machine-learning classifier using paired multi-omics (microbiome and metabolomics) data and identify associations unique to eoCRC. A differential association network analysis was also performed. Distinct clustering patterns emerged in multi-omic dimension reduction analysis. The metabolomics classifier achieved an AUC of 0.98, compared to AUC 0.61 for microbiome-based classifier. Circular correlation technique highlighted several key associations. Metabolites glycerol and pseudouridine (higher abundance in individuals with aoCRC) had negative correlations with Parasutterella, and Ruminococcaceae (higher abundance in individuals with eoCRC). Cholesterol and xylitol correlated negatively with Erysipelatoclostridium and Eubacterium, and showed a positive correlation with Acidovorax with higher abundance in individuals with eoCRC. Network analysis revealed different clustering patterns and associations for several metabolites e.g.: urea cycle metabolites and microbes such as Akkermansia. We show that multi-omics analysis can be utilized to study host-microbiome correlations in eoCRC and demonstrates promising biomarker potential of a metabolomics classifier. The distinct host-microbiome correlations for urea cycle in eoCRC may offer opportunities for therapeutic interventions.
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Deleterious effects of environmental exposures may contribute to the rising incidence of early-onset colorectal cancer (eoCRC). We assessed the metabolomic differences between patients with eoCRC, average-onset CRC (aoCRC), and non-CRC controls, to understand pathogenic mechanisms. Patients with stage I-IV CRC and non-CRC controls were categorized based on age ≤ 50 years (eoCRC or young non-CRC controls) or ≥ 60 years (aoCRC or older non-CRC controls). Differential metabolite abundance and metabolic pathway analyses were performed on plasma samples. Multivariate Cox proportional hazards modeling was used for survival analyses. All P values were adjusted for multiple testing (false discovery rate, FDR P < 0.15 considered significant). The study population comprised 170 patients with CRC (66 eoCRC and 104 aoCRC) and 49 non-CRC controls (34 young and 15 older). Citrate was differentially abundant in aoCRC vs. eoCRC in adjusted analysis (Odds Ratio = 21.8, FDR P = 0.04). Metabolic pathways altered in patients with aoCRC versus eoCRC included arginine biosynthesis, FDR P = 0.02; glyoxylate and dicarboxylate metabolism, FDR P = 0.005; citrate cycle, FDR P = 0.04; alanine, aspartate, and glutamate metabolism, FDR P = 0.01; glycine, serine, and threonine metabolism, FDR P = 0.14; and amino-acid t-RNA biosynthesis, FDR P = 0.01. 4-hydroxyhippuric acid was significantly associated with overall survival in all patients with CRC (Hazards ratio, HR = 0.4, 95% CI 0.3-0.7, FDR P = 0.05). We identified several unique metabolic alterations, particularly the significant differential abundance of citrate in aoCRC versus eoCRC. Arginine biosynthesis was the most enriched by the differentially altered metabolites. The findings hold promise in developing strategies for early detection and novel therapies.
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Neoplasias Colorretais , Metabolômica , Humanos , Pessoa de Meia-Idade , Citratos , Ácido Cítrico , ArgininaRESUMO
BACKGROUND: Young-onset gastrointestinal malignancies appear to be increasing in incidence. There are limited data on young-onset pancreaticobiliary adenocarcinoma (YO-PBA). METHODS: The study comprised patients with PBA (pancreatic adenocarcinoma, intra-, and extra-hepatic cholangiocarcinoma) and included in the National Cancer Database (NCDB) between 2004 and 2017. YO-PBA was defined as a diagnosis at age less than 50 years. Logistic regression to assess factors associated with YO-PBA status, and cox proportional hazards modeling to associate relevant factors with overall survival was performed. RESULTS: The study cohort comprised 360,764 patients, with 20,822 (5.8%) YO-PBA. YO-PBA was associated with (p-values<0.0001 for all): male sex (6.3% YO-male out of all male patients vs. 5.2% YO-female, OR 1.29, 95% CI 1.25-1.33), Black race (7.9% YO-Black vs. 5.0% YO-White, OR 1.72, 95% CI 1.64-1.80), lower income (6.4% YO-lowest household income based group vs. 5.5% highest, OR 1.08, 95% CI 1.03-1.13). YO-PBA were more likely to present with stage-IV disease (6.4% YO-Stage IV of all stage IV vs. 5.4% YO-Stage I-III, OR 1.25, 95% CI 1.21-1.29 p-value < 0.0001). Factors associated with overall survival (OS) in non-operable patients included-sex - male vs. female, HR 1.12 (95% CI 1.08-1.15); race - Black vs. White, HR 1.23 (95% CI 1.06-1.42); income group - lowest vs. highest, HR 1.33 (95% CI 1.27-1.39), and treatment center type - academic vs. nonacademic center, HR 0.87 (95% CI 0.85-0.90). CONCLUSIONS: Socioeconomic factors significantly impact incidence and outcomes for young-onset pancreaticobiliary adenocarcinoma (YO-PBA). More work is needed to help understand the mechanisms involved while addressing the disparities.
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Adenocarcinoma , Idade de Início , Neoplasias Pancreáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/epidemiologia , Adenocarcinoma/terapia , População Negra , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Fatores Socioeconômicos , População BrancaRESUMO
Importance: The association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited. Objective: To assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer. Design, Setting, and Participants: This cohort study was derived from a National Cancer Institute-sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022. Exposures: Plasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization. Main Outcomes and Measures: The primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression. Results: Of 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103 pg/mL (IQR, 2.3-3.6 × 103 pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14]; P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55]; P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34]; P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival. Conclusions and Relevance: This cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT01150045.
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Proteína C-Reativa , Neoplasias do Colo , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos de Coortes , Estudos Prospectivos , Proteína C-Reativa/uso terapêutico , Interleucina-6/uso terapêutico , Recidiva Local de Neoplasia/patologia , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Recidiva , Biomarcadores , InflamaçãoRESUMO
BACKGROUND: Consumption of a diet with high glycemic indices has been associated with inferior cancer-specific outcomes in patients with early-stage colorectal cancer, but there is limited prospective evidence that alterations in dietary habits improves cancer outcomes. This study aimed to determine the feasibility and acceptability of following a low glycemic load (GL) diet in patients with stage I-III colorectal cancer. METHODS: Patients with stage I-III colorectal cancer, who completed definitive therapy, and consumed an average daily GL >150 participated in a 12-week tailored face-to-face dietary intervention with a target GL. This study followed a 2-stage design, with 4 planned cohorts, each with an assigned GL target and dietary intervention intensity. The primary endpoint of feasibility was determined by participant compliance, defined as an individual following the assigned GL ≥75% of the time. Compliance was determined using 24-hour telephone recalls. A cohort was deemed feasible if at least 67% of participants were compliant. Secondary endpoints included acceptability of the diet, nutritional support resources necessary to follow the diet, and evaluation of the effect of the diet on physical measures and correlative laboratories. RESULTS: Only cohort 1 was required as the primary endpoint of feasibility was met (stringent GL target, low intensity dietary support). The majority of participants experienced a decrease in body mass index (BMI) and waist circumference, 29% experiencing meaningful weight loss (≥5%). The dietitian spent an average of 6.97 hours (SD 2.18) face-to-face time and 1.58 hours (SD 0.68) by phone with each participant. Significant decreases were seen in total cholesterol, very-low-density lipoprotein (VLDL) and triglycerides (all P<0.05). All participants liked the foods and were satisfied with the diet. All participants felt the in-person meetings were helpful, and 62% did not feel a virtual meeting (e.g., Skype, etc.) could replace in-person meetings. CONCLUSIONS: Patients with stage I-III colorectal cancer can follow a low GL diet with a 12-week in-person dietary intervention. Significant changes in physical and laboratory measures suggest relevant biologic effects of the dietary intervention. This study establishes feasibility, and warrants a larger scale prospective intervention trial to evaluate the impact of a low GL diet on cancer outcomes.
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BACKGROUND: The incidence of colorectal cancer (CRC) in patients under age 50 is rising for unclear reasons. We examined the effects of socioeconomic factors on outcomes for patients with early-onset CRC compared to late-onset CRC. METHODS: Patients with CRC from 2004 to 2015 in the National Cancer Database were included and categorized by age (under or over 50 years). Differences in demographic and socioeconomic factors, disease characteristics, and survival outcomes between early-onset versus late-onset CRC patients were assessed by Chi-squared test and Cox models. RESULTS: The study population included 1,061,204 patients, 108,058 (10.2%) of whom were under age 50. The proportion of patients diagnosed under age 50 increased over time: 9.4% in 2004-2006, 10.1% in 2007-2009, 10.5% in 2010-2012, and 10.7% in 2013-2015 (p < 0.0001). Early-onset CRC patients were more likely to be Black (15.1% vs. 11.3%) or Hispanic (8.6% vs. 4.6%) and to present with stage 4 disease (24.9% vs. 17.0%), p < 0.0001 for all. Black patients had the worst median OS (58.3 months) compared to White (67.0 months), Hispanic (91.6 months), or Asian (104.9 months) patients, p < 0.0001. Within the subgroup of early-onset CRC patients with private insurance, Black patients had worse OS compared to White patients, even in communities with higher income and education status. CONCLUSIONS: Early-onset CRC continues to increase. Patients with early-onset CRC are more likely to be Black or Hispanic and to present with stage 4 cancer. Early-onset Black patients showed worse OS compared to White patients in all income subgroups, even with private insurance.
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Neoplasias Colorretais/etnologia , Neoplasias Colorretais/epidemiologia , Fatores Raciais , Classe Social , Idade de Início , Idoso , Povo Asiático/estatística & dados numéricos , População Negra/estatística & dados numéricos , Neoplasias Colorretais/mortalidade , Escolaridade , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Incidência , Renda , Cobertura do Seguro , Seguro Saúde , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricosRESUMO
PIK3CA encodes the p110α catalytic subunit of PI3K and is frequently mutated in human cancers, including â¼30% of colorectal cancer. Oncogenic mutations in PIK3CA render colorectal cancers more dependent on glutamine. Here we report that the glutaminase inhibitor CB-839 preferentially inhibits xenograft growth of PIK3CA-mutant, but not wild-type (WT), colorectal cancers. Moreover, the combination of CB-839 and 5-fluorouracil (5-FU) induces PIK3CA-mutant tumor regression in xenograft models. CB-839 treatment increased reactive oxygen species and caused nuclear translocation of Nrf2, which in turn upregulated mRNA expression of uridine phosphorylase 1 (UPP1). UPP1 facilitated the conversion of 5-FU to its active compound, thereby enhancing the inhibition of thymidylate synthase. Consistently, knockout of UPP1 abrogated the tumor inhibitory effect of combined CB-839 and 5-FU administration. A phase I clinical trial showed that the combination of CB-839 and capecitabine, a prodrug of 5-FU, was well tolerated at biologically-active doses. Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that PIK3CA-mutant patients with colorectal cancer might derive greater benefit from this treatment strategy as compared with PIK3CA WT patients with colorectal cancer. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant colorectal cancers and warrants further clinical evaluation. SIGNIFICANCE: Preclinical and clinical trial data suggest that the combination of CB-839 with capecitabine could serve as an effective treatment for PIK3CA-mutant colorectal cancers.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzenoacetamidas/administração & dosagem , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/administração & dosagem , Tiadiazóis/administração & dosagem , Adulto , Animais , Benzenoacetamidas/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/efeitos adversos , Humanos , Masculino , Dose Máxima Tolerável , Camundongos , Pessoa de Meia-Idade , Tiadiazóis/efeitos adversos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Studies indicate that incidentally discovered thyroid nodules >or=1 cm in size may have a higher rate of malignancy (7% to 29%) than traditionally discovered nodules (5%). We sought to determine the rate of malignancy in incidental thyroid nodules in patients with other malignancies, and examine the accuracy of ultrasound (US) versus computed tomography (CT) in determining nodule size. METHODS: We evaluated 41 patients with history of another known malignancy (gastrointestinal, 23; breast, 11; other, 7) referred with an incidental thyroid nodule. Patients underwent office-based US and biopsy of nodules >or=1 cm. Surgical intervention was based on biopsy results. We compared nodule size at pathology with size seen on CT or US. RESULTS: Thirty-five patients met criteria for biopsy. Of the 35, 20 (57%) had atypical biopsy results warranting resection. Sixteen of those 20 underwent surgery. Pathology yielded 4 papillary thyroid cancers (PTC), 4 microPTC, 2 metastatic cancers, and 7 benign lesions. Ultrasound measurement of nodules compared to size measured at pathology had an r2 correlation value of 0.90 with P value <.0001. CT scan had an r2 value of 0.83 and P value of .005. CONCLUSIONS: Incidental thyroid nodules in patients with another primary malignancy warranted resection in 57%. The rate of malignancy in incidental thyroid nodules was 24%, which is above the expected rate of 5% seen in traditionally discovered nodules. US correlation with nodule size at pathology was excellent and superior to CT scan. Incidentally discovered thyroid nodules >or=1 cm, seen in patients with another malignancy, warrant further evaluation.
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Carcinoma Papilar/epidemiologia , Carcinoma Papilar/cirurgia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/epidemiologia , Nódulo da Glândula Tireoide/cirurgia , Neoplasias dos Ductos Biliares/epidemiologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos , Biópsia , Carcinoma Papilar/patologia , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/secundário , Colangiocarcinoma/epidemiologia , Colangiocarcinoma/secundário , Bases de Dados Factuais , Humanos , Incidência , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Melanoma/epidemiologia , Melanoma/secundário , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability-high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942-9. ©2017 AACR.
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Neoplasias Colorretais/terapia , Imunoterapia , Animais , Neoplasias Colorretais/imunologia , HumanosRESUMO
BACKGROUND: Delayed chemotherapy is associated with inferior survival in stage III colon and stage II/III rectal cancer patients, but similar studies have not been performed in stage II colon cancer patients. We investigate the association between delayed and incomplete chemotherapy, and the association of delayed chemotherapy with survival in stage II colon cancer patients. PATIENTS AND METHODS: Patients (age ≥ 66) diagnosed as stage II colon cancer and received chemotherapy from 1992 to 2005 were identified from the linked SEER-Medicare database. The association between delayed and incomplete chemotherapy was assessed using unconditional and conditional logistic regressions. Survival outcomes were assessed using stratified Cox regression based on propensity score matched samples. RESULTS: 4,209 stage II colon cancer patients were included, of whom 73.0% had chemotherapy initiated timely (≤ 2 months after surgery), 14.7% had chemotherapy initiated with moderate delay (2-3 months), and 12.3% had delayed chemotherapy (≥ 3 months). Delayed chemotherapy was associated with not completing chemotherapy (adjusted odds ratio (OR): 1.33 (95% confidence interval: 1.11, 1.59) for moderately delayed group, adjusted OR: 2.60 (2.09, 3.24) for delayed group). Delayed chemotherapy was associated with worse survival outcomes (hazard ratio (HR): 1.75 (1.29, 2.37) for overall survival; HR: 4.23 (2.19, 8.20) for cancer-specific survival). CONCLUSION: Although the benefit of chemotherapy is unclear in stage II colon cancer patients, delay in initiation of chemotherapy is associated with an incomplete chemotherapy course and poorer survival, especially cancer-specific survival. Causal inference in the association between delayed initiation of chemotherapy and inferior survival requires further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Estimativa de Kaplan-Meier , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Feminino , Humanos , Modelos Logísticos , Masculino , Estadiamento de Neoplasias , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Estados UnidosRESUMO
PURPOSE: Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function. METHODS: Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses). RESULTS: Twenty-four patients participated in the study. After a single brivanib alaninate dose, brivanib exposure was comparable between Groups A, B, and D. Area under the concentration-time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history. CONCLUSIONS: Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend brivanib use in this population.
Assuntos
Alanina/análogos & derivados , Carcinoma Hepatocelular/complicações , Insuficiência Hepática/complicações , Fígado/fisiopatologia , Pró-Fármacos/farmacocinética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Triazinas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/farmacocinética , Alanina/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/fisiopatologia , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Insuficiência Hepática/sangue , Insuficiência Hepática/etiologia , Insuficiência Hepática/fisiopatologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Índice de Gravidade de Doença , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Triazinas/uso terapêuticoRESUMO
PURPOSE: Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy. METHODS: We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale. RESULTS: Two different MTDs were determined. The schedule of gemcitabine 800 mg/m(2) on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m(2) on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m(2) on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily. CONCLUSIONS: This combination is well-tolerated and has significant clinical activity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Sunitinibe , GencitabinaRESUMO
BACKGROUND: Irinotecan and weekly cetuximab (I+C) is a standard second-line regimen for metastatic colorectal cancer (mCRC). This study investigated the safety and efficacy of every 2 weeks I+C in patients with mCRC. PATIENTS AND METHODS: Patients with mCRC refractory to first-line fluoropyrimidine/oxaliplatin regimens and not previously treated with I+C were eligible. Response rate (RR) was the primary endpoint. Cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) were administered intravenously (I.V.) on day 1 every 2 weeks. RESULTS: Patient characteristics (n = 31): male (n = 17), median age 62; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 (n = 30), and PS = 2 (n = 1). Median number of cycles = 3 (range, 1-22). I+C doses were modified in 18 and 12 patients, respectively. Grade 3/4 adverse events: acneiform rash (n = 6); neutropenia (n = 6); and diarrhea (n = 5); there was one grade 5 respiratory failure, possibly related to therapy. Two patients had a partial response, 11 had stable disease, and 18 had progressive disease resulting in an overall RR of 6% and disease control rate of 41.9%. Median overall survival (OS) was 9.3 months (95% CI, 5.1-15), and time to progression (TTP) was 2.4 months (95% CI, 1.3-4.6). K-ras and BRAF mutations were detected in 39% and 9%, respectively, of the patients tested. There was a trend toward longer TTP among patients with wild-type K-ras and BRAF (2.6 vs. 1.7 months; P = 0.16), and OS was significantly longer in those patients (14.1 vs. 5.5 months; P = 0.04). CONCLUSIONS: The RR and TTP were lower than expected and may reflect the reduced dose intensity due to toxicities. While the OS was consistent with previous publications, the efficacy of this combination was not demonstrated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Irinotecano , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies. PATIENTS AND METHODS: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non-small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non-small cell lung) and median overall survival (pancreas). RESULTS: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met. CONCLUSIONS: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens.
Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/mortalidade , Neoplasias/patologia , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To determine tolerability, pharmacokinetics, and pharmacodynamics of PD-0325901, a highly potent, selective, oral mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor in advanced cancer patients. EXPERIMENTAL DESIGN: Sixty-six patients received PD-0325901 at doses from 1 mg once daily to 30 mg twice daily (BID). Cycles were 28 days; three administration schedules were evaluated. Pharmacokinetic parameters were assessed and tumor biopsies were done to evaluate pharmacodynamics. RESULTS: Common adverse events were rash, diarrhea, fatigue, nausea, and visual disturbances including retinal vein occlusion (RVO; n = 3). Neurotoxicity was frequent in patients receiving >or=15 mg BID. The maximum tolerated dose, 15 mg BID continuously, was associated with late-onset RVO outside the dose-limiting toxicity window. An alternative dose and schedule, 10 mg BID 5 days on/2 days off, was therefore expanded; one RVO event occurred. Three of 48 evaluable patients with melanoma achieved confirmed partial responses; 10 had stable disease >or=4 months. PD-0325901 exposure was generally dose proportional. Doses >or=2 mg BID consistently caused >or=60% suppression of phosphorylated ERK in melanoma. Fifteen patients showed significant decreases (>or=50%) in Ki-67. CONCLUSIONS: PD-0325901 showed preliminary clinical activity. The maximum tolerated dose, based on first cycle dose-limiting toxicities, was 15 mg BID continuously. However, 10 and 15 mg BID continuous dosing and 10 mg BID 5 days on/2 days off schedules were associated with delayed development of RVO; thus, further enrollment to this trial was stopped. Intermittent dose scheduling between 2 and 10 mg BID should be explored to identify a recommended dose with long-term PD-0325901 use.