Dihydropyrimidine dehydrogenase (DPYD) gene polymorphisms profiling in colon cancer patients treated with adjuvant chemotherapy in the randomized phase III TOSCA trial

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.

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Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients

British Journal of Cancer ◽

10.1038/bjc.2017.289 ◽

2017 ◽

Vol 117 (9) ◽

pp. 1269-1277 ◽

Cited By ~ 20

Author(s):

A Ruzzo ◽

F Graziano ◽

Fabio Galli ◽

Francesca Galli ◽

E Rulli ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Cancer Patients ◽

Dihydropyrimidine Dehydrogenase ◽

Phase Iii

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Capecitabine (X) is resource saving compared with i.v. bolus 5-FU/LV in adjuvant chemotherapy for Dukes' C colon cancer patients: Medical resource utilization (MRU) data from a large phase III trial (X-ACT)

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.3578 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 3578-3578 ◽

Cited By ~ 3

Author(s):

J. J. McKendrick ◽

J. Cassidy ◽

S. Chakrapee-Sirisuk ◽

G. Fountzilas ◽

T. Iveson ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Phase Iii ◽

Medical Resource ◽

Resource Saving ◽

Phase Iii Trial ◽

Medical Resource Utilization ◽

Large Phase ◽

Dukes C

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Assessing the representativeness of trial populations for contemporary real-world cancer patients: A case study of adjuvant chemotherapy for colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.306 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 306-306

Author(s):

Jennifer Leigh Lund ◽

Michael Webster-Clark ◽

Emily W. Bratton

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Real World ◽

Performance Status ◽

Stage Ii ◽

Phase Iii ◽

Stage Iii ◽

Marketing Approval ◽

Trial Participants

306 Background: Randomized controlled trials are the gold standard for assessing the efficacy of new cancer therapies and are required for marketing approval. However, participants enrolled into trials are often not representative of the more diverse populations in whom treatment will ultimately be delivered. Real-world data can be used to potentially bridge this gap by evaluating the effectiveness and safety of therapies in more generalizable populations. In this study, we describe differences in demographic and clinical characteristics between participants enrolled in a phase III trial of adjuvant chemotherapy for colon cancer and a contemporary comparator cohort using structured oncology electronic medical records (EMR) data. Methods: We drew upon publications from the Multicenter International Study of Oxaliplatin/5 Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) recruiting patients primarily from Western Europe with stage II or III colon cancer from October 1998-January 2001. This trial established FOLFOX (oxaliplatin + 5-FU) as the standard of care over 5FU alone in treating stage III colon cancer and led to US marketing approval. For comparison, we identified patients diagnosed with stage II or III colon cancer (September 2014-2020) who received FOLFOX in the IQVIA US Oncology EMR database via E360, IQVIA’s Real World Discovery and Analytics platform. In the two populations, we described distributions of prognostic factors including age, sex, stage of disease, body mass index (BMI), and Eastern Cooperative Group (ECOG) performance status. Results: The MOSAIC trial included 2,246 participants; we identified 4,566 patients starting FOLFOX in the EMR comparator. Median age was similar: 61 versus 62 years, but the range differed (19-75 years versus 18-85 years) in the trial and EMR comparator, respectively. Female sex was similar at 44% and 48%, while the proportion of patients with stage III disease differed considerably at 60% and 84% for trial and EMR comparator, respectively. Half (51%) of all EMR patients were missing ECOG status; among those with a reported ECOG status, 96% had a score of 0-1, while 87% of trial participants had an ECOG of 0-1. BMI was missing in 34% of patients in the EMR comparator; among those with a reported BMI, 28% had a BMI < 25, while 54% of trial participants had a BMI < 25. Conclusions: Colon cancer patients receiving FOLFOX in an EMR comparator had a similar age and sex distribution as MOSAIC trial participants, but were more likely to have stage III disease. Missing ECOG and BMI data were common in the EMR comparator, which limited comparisons. Structured oncology EMR data represent an important resource for generating real-world evidence; future data enrichment efforts focused on critical patient-level variables via unstructured EMR extraction may improve data completeness and quality.

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Capecitabine (X) is resource saving compared with i.v. bolus 5-FU/LV in adjuvant chemotherapy for Dukes' C colon cancer patients: Medical resource utilization (MRU) data from a large phase III trial (X-ACT)

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.90140.3578 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 3578-3578 ◽

Cited By ~ 1

Author(s):

J. J. McKendrick ◽

J. Cassidy ◽

S. Chakrapee-Sirisuk ◽

G. Fountzilas ◽

T. Iveson ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Phase Iii ◽

Medical Resource ◽

Resource Saving ◽

Phase Iii Trial ◽

Medical Resource Utilization ◽

Large Phase ◽

Dukes C

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Adjuvant colon cancer care quality, risk, value, and level one data and guideline compliance among the elderly privately insured in southeastern USA.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.30_suppl.249 ◽

2014 ◽

Vol 32 (30_suppl) ◽

pp. 249-249 ◽

Cited By ~ 1

Author(s):

William J. Hrushesky ◽

Anmol Baranwal ◽

Dinah Faith Q. Huff ◽

William S. Shimp ◽

Avinash Mamgain ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Older Persons ◽

Performance Status ◽

Stage Ii ◽

Phase Iii ◽

Disease Stage ◽

Nccn Guidelines ◽

Time Period

249 Background: Oxaliplatin-containing regimens are among the most efficacious adjuvant treatments for locally-advanced colon cancer, although significant toxicity can occur. Because of relevant level I data, the NCCN revised its guidelines in 2012, recommending omission of oxaliplatin from combination adjuvant chemotherapy regimens for older patients (>70yo) with colon cancer. We examined prescribing behavior of oncologists between 2009 and 2014 to evaluate how rapidly NCCN guidelines were adopted into practice. Methods: This is a retrospective observational study of chemotherapy request data from more than 2,000 community oncologists in the southeastern United States. We examined 57 consecutive months of chemotherapy requests for stage II and III colon cancer patients 70 years and older, based on three epochs. During the middle epoch, one phase III trial evaluating oxaliplatin-containing regimens as adjuvant chemotherapy (NSABP C-07), and a revised 2012 NCCN guidelines, each supported omission of oxaliplatin from adjuvant chemotherapy regimens for older persons with colon cancer. Multivariate analyses evaluated associations among patient characteristics (age, gender, and performance status), disease stage, and time-period, with the odds of receiving oxaliplatin-containing regimens as adjuvant chemotherapy. Results: Among 266 persons with stage II or III colon cancer 70 years of age and older, over the six-year span, most adjuvant chemotherapy requests (184/266, 69.2%) contained oxaliplatin. Older age, male gender, and poor performance status were associated with significantly lower odds of receiving oxaliplatin-containing adjuvant chemotherapy regimens (p<0.05), while time period (epoch) was not significantly associated with temporal changes in patterns of use. Conclusions: Use of oxaliplatin containing adjuvant chemotherapy regimens among older persons with colon cancer did not decrease following publication of phase III clinical trial data and revised NCCN guidelines recommending against oxaliplatin use in this setting. Focused quality improvement initiatives for this population of cancer patients may be helpful.

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Phase II study of an oxaliplatin-based regimen for relapsed colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (INSPIRE study)

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-021-04232-2 ◽

2021 ◽

Author(s):

Keiichiro Ishibashi ◽

Toru Aoyama ◽

Masahito Kotaka ◽

Hironaga Satake ◽

Yasushi Tsuji ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Sensory Neuropathy ◽

Progression Free Survival ◽

First Line ◽

Secondary Endpoints ◽

Grade 3 ◽

Peripheral Sensory ◽

Line Chemotherapy

Abstract Background The aim of this study was to evaluate the efficacy and safety of first-line chemotherapy with re-introduction of oxaliplatin (OX) more than 6 months after adjuvant chemotherapy including OX. Methods Stage II/III colon cancer patients with neuropathies of grade ≤ 1 who relapsed more than 6 months after adjuvant chemotherapy including OX were considered eligible. Eligible patients were treated with 5-fluorouracil, l-leucovorin and OX plus molecularly targeted agents or capecitabine and OX plus bevacizumab (BV) or S-1 and OX plus BV. The primary endpoint was the progression-free survival (PFS), and the secondary endpoints were the overall survival (OS), response rate (RR) and toxicity. Results A total of 50 patients were enrolled between September 2013 and May 2019. Twelve patients received 5-fluorouracil, l-leucovorin and OX (FOLFOX) plus BV, 21 patients received capecitabine and OX plus BV, 10 patients received S-1 and OX plus BV and 7 patients received FOLFOX plus cetuximab or panitumumab. The median PFS was 11.5 months (95% confidence interval [CI] 8.3–16.0), the median OS was 45.4 months (95% CI 37.4–NA), and the RR was 56.0% (95% CI 42.3–68.8). Adverse events of grade ≥ 3 that occurred in ≥ 5% of cases were neutropenia in 6 patients (12%), peripheral sensory neuropathy in 5 patients (10%), diarrhea in 4 patients (8%), hypertension in 4 patients (8%), anorexia in 3 patients (6%) and allergic reactions in 3 patients (6%). Conclusions First-line chemotherapy with re-introduction of OX more than 6 months after adjuvant chemotherapy including OX can be used safely with expected efficacy for relapsed colon cancer patients.

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