Pharmacogenetic Predictors of Adverse Events and Response to Chemotherapy in Metastatic Colorectal Cancer: Results From North American Gastrointestinal Intergroup Trial N9741

Purpose With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets. Patients and Methods Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing. Results All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study. Conclusion This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.

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Efficacy of aspirin for stage III colorectal cancer: a randomized double-blind placebo-controlled trial (JCOG1503C, EPISODE-III trial)

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyz106 ◽

2019 ◽

Vol 49 (10) ◽

pp. 985-990 ◽

Cited By ~ 1

Author(s):

Kenichi Miyamoto ◽

Atsuo Takashima ◽

Junki Mizusawa ◽

Yuya Sato ◽

Yasuhiro Shimada ◽

...

Keyword(s):

Colorectal Cancer ◽

Adjuvant Chemotherapy ◽

Adverse Events ◽

Curative Resection ◽

Disease Free Survival ◽

Phase Iii ◽

Stage Iii ◽

Double Blind ◽

Free Survival ◽

Double Blind Placebo

Abstract Adjuvant chemotherapy is the current standard treatment for stage III colorectal cancer after curative resection. However, the prognosis of stage III colorectal cancer is still poor even after curative resection and adjuvant chemotherapy. Several observational studies suggested that the anti-tumor effect of aspirin. Therefore, we planned a randomized double-blind placebo-controlled phase III trial, which commenced in Japan in March 2018, to confirm the superiority of aspirin over placebo added to adjuvant chemotherapy in terms of disease-free survival (DFS) for stage III colorectal cancer patients after curative resection. A total of 880 patients will be accrued from 20 Japanese institutions within 3 years. The primary endpoint is DFS and the secondary endpoints are overall survival, relapse-free survival, relative dose intensity, adverse events, and serious adverse events. This trial has been registered at Japan Registry of Clinical Trials as jRCTs031180009 (https://jrct.niph.go.jp/detail/589).

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Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability, and CIMP status: Prognostic implications and response to chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.668 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 668-668

Author(s):

Oscar Murcia ◽

Miriam Juárez ◽

Eva Hernández-Illán ◽

Maria Rodriguez-Soler ◽

Mar Giner-Calabuig ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Braf Mutation ◽

Kras Mutation ◽

Cpg Island ◽

Disease Free Survival ◽

Molecular Classification ◽

Hazard Ratio ◽

Tnm Stage ◽

Response To Chemotherapy

668 Background: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy. Methods: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). Conclusions: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.

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Acute adverse events associated with the administration of Crotalidae polyvalent immune Fab antivenom within the North American Snakebite Registry

Clinical Toxicology ◽

10.1080/15563650.2018.1464175 ◽

2018 ◽

Vol 56 (11) ◽

pp. 1115-1120 ◽

Cited By ~ 7

Author(s):

Kurt Kleinschmidt ◽

Anne-Michelle Ruha ◽

Sharan Campleman ◽

Jeffrey Brent ◽

Paul Wax ◽

...

Keyword(s):

Adverse Events ◽

North American ◽

The North

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Retrospective Study of Adverse Events of Chemotherapy in Cats

Acta Scientiae Veterinariae ◽

10.22456/1679-9216.81801 ◽

2018 ◽

Vol 46 (1) ◽

pp. 12

Author(s):

Simone Carvalho dos Santos Cunha ◽

Franciele Basso Silva ◽

Katia Barão Corgozinho ◽

Kássia Valéria Gomes Coelho da Silva ◽

Ana Maria Reis Ferreira

Keyword(s):

Adverse Event ◽

Adverse Effects ◽

Adverse Events ◽

Case Series ◽

Grading System ◽

Oncology Group ◽

Chemotherapy Drugs ◽

Chemotherapy Administration ◽

Response To Chemotherapy ◽

Grade Ii

Background: Clients who seek veterinary care for pets with cancer are often concerned about the potential negative impact of chemotherapeutic treatments on their animals’ quality of life. A consensus currently exists in veterinary oncology regarding the quantification and rating of adverse treatment effects in dogs and cats in response to chemotherapy agents. This grading system is referred to as Veterinary Cooperative Oncology Group - Common Terminology Criteria for Adverse Events. The purpose of this retrospective case series was to investigate the delayed acute effects of chemotherapy drugs in cats receiving cancer treatment.Materials, Methods & Results: Medical records were reviewed to determine the chemotherapy agent used and delayed adverse effects. Side effects were classified according to Veterinary Co-operative Oncology Group grading. All cats were evaluated after the first chemotherapy administration, after a single dose. The reported effects included hematologic effects (e.g., neutropenia, thrombocytopenia, increases in liver enzymes, and azotemia), gastrointestinal effects (e.g., vomiting, diarrhea, and inappetence), and sepsis. All of the cats in this study received ondansetron and omeprazol in the first five days following chemotherapy administration. If vomiting occurred with oral medication, maropitant was administered subcutaneously for three consecutive days. If diarrhea (> grade II) occurred, probiotics were administered for seven days. Hematologic examination was performed 3-14 days after chemotherapy. If neutropenia (> grade III) occurred, Human granulocyte colony stimulating factor was administered subcutaneously for three consecutive days together with prophylactic antibiotics. Lomustine, carboplatin, vincristine, doxorubicin, cyclophosphamide, mitoxantrone, and vinblastine were administered in 33%, 19%, 16%, 5%, 16%, 10% and 2% of the cases examined, respectively. The most common adverse events were vomiting, inappetence, neutropenia, and thrombocytopenia. Vomiting occurred in 6% cases, most of them associated with cyclophosphamide. Inappetence/anorexia affected 12% of the cases, mostly those involving cyclophosphamide or doxorubicin. Neutropenia was observed in 22% of the cases, with cyclophosphamide, followed by carboplatin and lomustine. According to the current grading system of adverse effects induced by chemotherapy, grade I toxicity was observed in 83% of the cases, whiles grade II-IV were observed in 7%, 8%, and 2% of the cases examined, respectively.Discussion: In general, the chemotherapy regimens in the cases examined were well tolerated. The toxicity experienced was infrequent and mostly mild, thereby resulting in satisfactory tolerability of the chemotherapy regimens. According to the current grading system for the adverse effects of chemotherapy, 83% of the cases examined included grade I, indicating that most of the cats experienced asymptomatic, or mild symptoms, and medical intervention was not needed. In previous studies of dogs and cats, a severe adverse event following chemotherapy was reported for fewer than 1 in 4 animals, and approximately 3-5% experienced a serious adverse event that led to hospitalization. In the present study, 2% of the cats experienced serious or life threatening adverse events. The only chemotherapeutic agent that was associated with inappetence, vomiting, and neutropenia was cyclophosphamide. Based on the data examined, we would recommend that cyclophosphamide should be used with caution for the treatment of cancer in cats, with adequate antiemetic and nutritional support available if needed. In addition, febrile neutropenia/sepsis may be avoided by using a fractionated schedule.

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The role of endoscopy and findings in COVID-19 patients, an early North American Cohort

BMC Gastroenterology ◽

10.1186/s12876-021-01796-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Gabriela Kuftinec ◽

◽

B. Joseph Elmunzer ◽

Sunil Amin

Keyword(s):

Adverse Events ◽

North American ◽

Secondary Analysis ◽

Gastrointestinal Manifestations ◽

Endoscopic Procedures ◽

Systematic Assessment ◽

The North ◽

The Usa ◽

Enteral Access

Abstract Background and aims Gastrointestinal manifestations in patients with COVID-19 are common but the role of endoscopy in this patient population remains unclear. We investigated the need for endoscopic procedures, their findings, and impact on patient care in a systematic and geographically diverse sample of patients hospitalized with COVID-19. Methods As part of the North American Alliance for the Study of Digestive Manifestations of COVID-19, we identified consecutive patients hospitalized with COVID-19 at 36 medical centers in the USA and Canada. We performed a secondary analysis of patients who underwent endoscopy, collecting information on endoscopic indications, findings, interventions, staffing, procedure location, anesthesia utilization, and adverse events. Results Data were collected on 1992 patients; 24 (1.2%) underwent 27 endoscopic procedures (18 upper endoscopies, 7 colonoscopies, 2 endoscopic retrograde cholangiopancreatographies). The most common indications were: gastrointestinal bleeding (13) and enteral access (6). The most common findings were erosive or inflammatory changes. Ten patients underwent an endoscopic intervention for hemostatic therapy (2), enteral access (6), or biliary obstruction (2). Half of cases employed anesthesiology support; no sedation-related adverse events were reported. One-third of cases were performed in the intensive care setting and one quarter in the endoscopy unit. Conclusions In this large, systematic, geographically diverse cohort of patients hospitalized with COVID-19 in North America, very few patients underwent endoscopy despite a high prevalence of gastrointestinal manifestations. Almost all endoscopic findings and interventions were thought related to critical illness rather than direct viral injury. This systematic assessment of endoscopic necessity and outcomes may help guide resource allocation in the event of ongoing and future surges.

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Associations between oncogenic risk markers and clinical outcomes among black and white colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16078 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16078-e16078

Author(s):

Victoria Starks ◽

Edith P. Mitchell

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Clinical Outcomes ◽

Disease Free Survival ◽

Risk Markers ◽

Braf Mutations ◽

Black And White ◽

Response To Chemotherapy ◽

Incidence And Mortality ◽

Colorectal Cancer Patients

e16078 Background: Blacks have a 25% higher incidence of colorectal cancer compared to their white societal counterparts1. Additionally, the overall mortality rate among black colorectal cancer patients is 50% higher than that of whites2. However, little is known about the biomarkers prevalent among blacks and their possible correlation to treatment response and patient outcomes. Objective: The objective of this study is to explore disease trends that may unveil a correlation between molecular markers, pathologic stage at presentation and poor clinical outcomes among black colorectal cancer patients. Methods: De-identified patient data was obtained from The Oncology Data Services Department (Cancer Registry) of TJUH. The population cohort (n = 836) included newly diagnosed colorectal cancer patients treated at TJUH from 2000-2019, & included information regarding patient race, sex, age at presentation, stage at presentation, histological code, tumor markers: KRAS, NRAS, BRAF, MS1, treatment received, surgical findings: tumor size, lymph node involvement, presence of distant metastases at first surgery, response to chemotherapy & disease-free survival. Results: Findings reveal a higher prevalence of BRAF mutations among whites compared to blacks within this population, while black patients were diagnosed later according to AJCC pathological stage at presentation. Future analysis of this cohort will further divide the population by age ( < 50, 50-65, & > 65). This facet of the study will explore relationships between age & stage at presentation among patients of different races. Conclusions: Both oncogenic risk markers and AJCC stage at presentation differ between black and white colorectal cancer patients within this population. Additional analysis regarding age at presentation will further inform us as to how these findings may contribute to the comparatively higher incidence and mortality rates among black colorectal cancer patients. Researchers should continue to explore possible etiologies for the prevalent racial disparities seen among black colorectal cancer patients.

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Associations between age and stage at presentation among black and white colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15542 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15542-e15542

Author(s):

Victoria Starks ◽

Edith P. Mitchell

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Disease Free Survival ◽

Distant Metastases ◽

Lymph Node Involvement ◽

University Hospital ◽

Black And White ◽

Response To Chemotherapy ◽

Node Involvement ◽

Colorectal Cancer Patients

e15542 Background: Blacks have a 25% higher incidence of colorectal cancer compared to their white societal counterparts. Additionally, the overall mortality rate among black colorectal cancer patients is 50% higher than that of whites. It is suggested that the etiology of this disparity may be inadequate screening for colorectal cancer among racial communities. However, little is known about the correlations between age and stage at presentation among black and white colorectal cancer patients at Thomas Jefferson University Hospital (TJUH). Objective: The objective of this study is to explore diagnostic trends that may unveil differences in age and stage at presentation between black and white colorectal cancer patients. Methods: De-identified patient data was obtained from The Oncology Data Services Department (Cancer Registry) of TJUH. The population cohort (n= 529) included newly diagnosed colorectal cancer patients treated at TJUH from 2015-2019 and included information regarding race, sex, age at presentation, stage at presentation, histological code, tumor markers: KRAS, NRAS, BRAF, MS1, treatment received, surgical findings: tumor size, lymph node involvement, presence of distant metastases at first surgery, response to chemotherapy & disease-free survival. The cohort was divided by age (<50, 50-65, >65). Patient age was compared against AJCC stage at presentation. Results: Findings reveal 12.38% of blacks & 14.29% of whites presented before age 50. 36.19% of blacks and 30.19% of whites presented between ages 50-65. 51.43% of blacks & 55.42% of whites presented after age 65. Additionally, the average age at presentation among blacks was 62.71 years vs. 65.71 years among whites. Lastly, the average stage at presentation among blacks was between 2C and 3A while the average stage at diagnosis among whites was between least 2B and 2C. Conclusions: Within this population, similarities exist among age at presentation between black and white patients, however, differences in stage at presentation exist between blacks and whites. Further research is needed explore how these findings inform the poor clinical outcomes seen among black colorectal cancer patients. Future analysis of this cohort will explore trends regarding time to treatment and treatment received after diagnosis, as similar studies have found differences among racial populations.

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Quantifying the risk of insertion-related peritoneal dialysis catheter complications following laparoscopic placement: Results from the North American PD Catheter Registry

Peritoneal Dialysis International ◽

10.1177/0896860819893813 ◽

2020 ◽

Vol 40 (2) ◽

pp. 185-192

Author(s):

Matthew J Oliver ◽

Jeff Perl ◽

Rory McQuillan ◽

Peter G Blake ◽

Arsh K Jain ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Adverse Events ◽

North American ◽

The United States ◽

Catheter Insertion ◽

Peritoneal Dialysis Catheter ◽

Invasive Procedures ◽

Exit Site ◽

Flow Restriction ◽

The North

Background: Peritoneal dialysis (PD) is a more cost-effective therapy to treat kidney failure than in-center hemodialysis, but successful therapy requires a functioning PD catheter that causes minimal complications. In 2015, the North American Chapter of the International Society for Peritoneal Dialysis established the North American PD Catheter Registry to improve practices and patient outcomes following PD catheter insertion. Aims: The objective of this study is to propose a methodology for defining insertion-related complications that lead to significant adverse events and report the risk of these complications among patients undergoing laparoscopic PD catheter insertion. Methods: Patients undergoing laparoscopic PD catheter insertion were enrolled at 14 participating centers in Canada and the United States and followed using a Web-based registry. Insertion-related complications were defined as flow restriction, exit-site leak, or abdominal pain at any point during follow-up. We also included infections or bleeding within 30 days of insertion, and any immediate postoperative complications. Adverse events were categorized as PD never starting or termination of PD therapy, delay in the start of PD therapy or interruption of PD therapy, an emergency department visit or hospitalization, or need for invasive procedures. Cause-specific cumulative incidence functions were used to estimate risk. Results: Five hundred patients underwent laparoscopic PD catheter insertion between 10 November 2015 and 24 July 2018. The cumulative risk of insertion-related complications 6 months from the date of insertion that led to an adverse event was 24%. The risk of flow restriction, exit-site leak, and pain at 6 months was 10.2%, 5.7%, and 5.3%, respectively. PD was never started or terminated in 6.4% of patients due to an insertion-related complication. Leaks and flow restrictions were most likely to delay or interrupt PD therapy. Flow restrictions were the primary cause of invasive procedures. Fifty percent of the complications occurred before the start of PD therapy. Conclusions: Insertion-related complications leading to significant adverse events following laparoscopic placement of PD catheters are common. Many complications occur before the start of PD. Insertion-related complications are an important area of focus for future research and quality improvement efforts.

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Tamoxifen and Anastrozole As a Sequencing Strategy: A Randomized Controlled Trial in Postmenopausal Patients With Endocrine-Responsive Early Breast Cancer From the Austrian Breast and Colorectal Cancer Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2011.36.8993 ◽

2012 ◽

Vol 30 (7) ◽

pp. 722-728 ◽

Cited By ~ 57

Author(s):

Peter C. Dubsky ◽

Raimund Jakesz ◽

Brigitte Mlineritsch ◽

Sabine Pöstlberger ◽

Hellmut Samonigg ◽

...

Keyword(s):

Breast Cancer ◽

Colorectal Cancer ◽

Adverse Events ◽

Controlled Trial ◽

Disease Free Survival ◽

Phase Iii ◽

Study Group ◽

Free Survival ◽

Cancer Study ◽

Cancer Study Group

Purpose Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor–positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients. Patients and Methods Endocrine receptor–positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated. Results Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of follow-up was available for this analysis. Median age was 63.8 years, 75% were node negative, and 75% had T1 tumors. Sequencing of ANA after identical 2-year treatment with TAM in both arms did not result in a statistically significant improvement of RFS (hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.01; P = .06). Exploratory analyses of distant relapse-free survival indicated a 22% improvement (HR, 0.78; 95% CI, 0.60 to 1.00). On-treatment adverse events and serious adverse events were consistent with known toxicity profiles of ANA and TAM treatment. Conclusion Despite a low overall rate of recurrence in a population with breast cancer at limited risk of relapse, the a priori sequence strategy of 2 years of TAM followed by 3 years of ANA led to small outcome and toxicity benefits.

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