Table 3Characteristics of Included Non-Randomized Studies

Study citation, country, funding sourceStudy designPopulation characteristicsRelevant intervention and comparator(s)Relevant clinical outcomes, length of follow-up
Gallois et al. (2022)13

France

Funding source: No specific funding received for this report

Retrospective multicentre study with data since 2006Patients with metastatic colorectal cancer (N = 75)
  • Subgroup relevant for this report: patients with a history of fluoropyrimidine-induced cardiotoxicity (n = 36)
Characteristics of relevant subgroup (N = 36):
  • Mean age, years: 65.4
  • WHO-PS 0 to 1 rate: 94%
Characteristics of full sample (N = 75):
  • Male, n (%): 51 (68)
  • Location of primary tumour, n (%):
    • Right colon: 20 (27)
    • Right + left colon: 3 (4)
    • Transverse colon: 2 (3)
    • Left colon: 48 (66)
  • Median serum CEA, ng/mL (range): 15 (0 to 2,169)
Intervention: Raltitrexed, single-agent or combination chemotherapy; combinations were raltitrexed with:
  • oxaliplatin
  • irinotecan
  • bevacizumab
  • oxaliplatin and bevacizumab
  • irinotecan and bevacizumab
From entire sample:
  • Mean number of cycles (SD): 7.9 (5.1)
  • Dosage: 3 mg/m2 every 3 weeks or 2.5 mg/m2 every 2 weeks
Comparators:
  • Fluoropyrimidines (before-after)
  • No comparator
Outcomes:
  • Overall survival
  • Progression-free survival
  • Cardiac adverse events
Median follow-up from full sample, months (95% CI): 51.3 months (41.9 to not reached); until death or last follow-up
Batra et al. (2021)14

Canada

Funding source: NR

Retrospective, population-based review of provincial administrative data from 2004 to 2018Patients with metastatic colorectal cancer, initially treated with fluoropyrimidine-based systemic therapy and developed serious cardiac and/or non-cardiac adverse events (N = 86)
  • Cardiac events (n = 32, 37.6%)
  • Non-cardiac events (n = 64, 63.4%)
Median age, years (IQR): 66.5 (42 to 86)

Male patients, n (%): 50 (58.1%)

Primary cancer site, n (%):

  • Left colon: 33 (38.4)
  • Transverse colon: 5 (5.8)
  • Right colon: 24 (27.9)
  • Rectum: 21 (24.4)
Previous lines of systemic therapy, n (%):
  • 1 or 2: 49 (57.0)
  • > 2: 37 (43.0)
ECOG performance status (N = 84), n (%):
  • 0 or 1: 68 (81.0)
  • 2 or 3: 16 (19.0)
Median serum CEA (N = 26), ug/L (IQR): 35.5 (5.4 to 470)

Intervention: Raltitrexed (single-agent or combination with irinotecan)
  • 1 patient received combination; all other patients received raltitrexed alone
  • Median number of cycles (range): 3 (1 to 23)
  • Dose: 3 mg/m2 every 3 weeks (except 1 patient who received raltitrexed and irinotecan)
Comparators:
  • Fluoropyrimidines (before-after)
  • No comparator
Outcomes:
  • Overall survival
  • Progression-free survival
  • Adverse events (cardiac and non-cardiac)
  • Treatment-related deaths
Median follow-up, months: 46.7
Khan et al. (2018)15

UK

Funding source: Unclear; reported support and research funding received by authors, but unclear which funding sources supported this study.

Retrospective single-centre cohort study with data from 1998 to 2011Patients with gastrointestinal cancer (N = 247)
  • Subgroup relevant for this report: patients who had cardiac side effects following 5-FU or capecitabine (n = 155)
Characteristics of full sample (N = 247):
  • Female, n (%): 179 (72.5)
  • Mean age (range), years: 65.5 (31 to 88)
  • Type of cancer, n (%):
    • Upper GI: 75 (30.4)
    • Lower GI: 162 (65.6)
    • Miscellaneous: 10 (4.0)
    • Early-stage: 140 (56.7)
    • Advanced metastatic: 107 (43.3)
Intervention: Raltitrexed (single-agent or combination chemotherapy; combinations not reported)
  • Median number of cycles (range) from subgroup: 5 (1 to 8)
From entire sample:
  • Approximately 31% and 68% received single-agent and combination respectively
  • Standard dose: 3 mg/m2 as a 15-minute infusion; 22% received reduced doses (1.3 to 2.8 mg/m2); 44% received higher doses (3.10 to 6.60 mg/m2)
Comparator: Fluoropyrimidines (5-FU- or capecitabine-containing chemotherapy; before-after)		Outcome: Cardiac adverse events

Median follow-up (IQR), months from full sample: 47.1 (32.4 to 65.7)

Ransom et al. (2014)16

Australia

Funding source: Astra Zeneca

Retrospective multicentre review of pharmacy and medical records from 2004 to 2012Patients with cancer who had cardiac toxicity with 5-FU or capecitabine (N = 42)

Median age (range), years: 62 (36 to 81)

Patients by type and stage of cancer at time of initiating raltitrexed, n:

  • Colorectal (stage II or III): 14
  • Colorectal (stage IV): 25
  • Esophageal (stage II or IV): 2
  • Ampullary (stage IV): 1

Intervention: Raltitrexed (single agent [N = 11] or combination [N = 31])
  • Combination was usually with irinotecan or oxaliplatin
  • Median number of cycles (range): 6 (1 to 21).
Comparator: Fluoropyrimidines (5-FU or capecitabine, alone or combination; historical control)		Outcome: Rate of further cardiac events attributed to chemotherapy

Follow-up: up to 30 days after last dose of raltitrexed

Kelly et al. (2013)12

UK

Funding source: Unclear; mentions financial support from Hospira UK Ltd., but unclear if this was for conducting the study or for editorial assistance

Retrospective review of medical records at 2 treatment centres from 2008 to 2011Patients with gastrointestinal tumours (N = 111):
  • Subgroup relevant for this report: patients who experienced vascular complications associated with 5-FU or capecitabine (n = 63)
    • Cardiovascular complications: n = 60
    • Cerebrovascular complications: n = 3
Characteristics from full sample (N = 111):
  • Male, n (%): 82 (74%)
  • Median age (range), years: 68 (33 to 85)
  • Type of cancer, n:
    • Metastatic colorectal: 67
    • Colorectal, no distant metastases: 40
    • Anal: 2
    • Mucinous appendicular: 1
    • Lower esophageal: 1
Intervention: Raltitrexed (unclear if single-agent and/or combination)

Comparator: Fluoropyrimidines (5-FU or capecitabine; before-after)

Reported outcomes: Cardiovascular or cerebrovascular complications

Follow-up: NR

5-FU = 5-fluorouracil; CEA = carcinoembryonic antigen; ECOG = Eastern Cooperative Oncology Group; NR = not reported; WHO-PS: WHO Performance Status.

Note: For serum CEA measurements: ng/mL and ug/L are equivalent.

From: Raltitrexed in Patients With Dihydropyrimidine Dehydrogenase Deficiency

Cover of Raltitrexed in Patients With Dihydropyrimidine Dehydrogenase Deficiency
Raltitrexed in Patients With Dihydropyrimidine Dehydrogenase Deficiency: Rapid Review [Internet].
Vu T, Spry C; Authors.
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