Pharmacy

Li-Ju Chen, Pharmacist
Division of Clinical Epidemiology and Ageing Research
German Cancer Research Center

Im Neuenheimer Feld 581
D-69120 Heidelberg

Phone: +49 (0)6221 42 1304
li-ju.chen(at)dkfz-heidelberg.de

2. Affiliation: Netzwerk AlternsfoRschung, Fellow: Ben Schöttker, PhD

Polypharmacy and potentially inappropriate medication in older colorectal cancer patients

Summary of PhD thesis

Potentially inappropriate medication (PIM) is defined as prescriptions in older adults, which have a negative benefit-risk ratio. An instrument to assess PIM is the FORTA list, which does not only capture PIM use but also medication overuse and underuse. Polypharmacy, most defined as concomitant use of 5 or more medications, is incorporated in most comprehensive geriatric assessment tools (CGA) to assess the health status of frail older patients. However, the associations of polypharmacy and PIM with relevant clinical outcomes in older (colorectal) cancer patients was unclear. One aim of the dissertation was to perform a systematic review and meta-analysis of observational studies on the associations of PIM use and polypharmacy with adverse outcomes in older cancer patients. In my own data analyses, I assessed the associations of PIM use, medication overuse and underuse (all assessed with the FORTA list), and polypharmacy with survival outcomes and chemotherapy-related adverse drug reactions (ADRs) in a large cohort of older colorectal cancer (CRC) patients. Furthermore, I investigated whether adding functional status, Charlson comorbidity index (CCI), frailty index (FI), polypharmacy, or the total FORTA score improves the predictive value of a reference model containing age, sex, tumor stage, and tumor location for CRC survival.

Relevant studies for the systematic review were retrieved from the databases PubMed and Web of Science. Meta-analyses were conducted with a random effects model. At first, 42 publications were included in the systematic review. Meta-analyses could be performed on 39 studies about polypharmacy and 13 studies about PIM. Polypharmacy was found to be statistically significant-ly associated with all-cause mortality (risk ratio [95% confidence interval]: 1.37 [1.25–1.50]), hospitalization (1.53 [1.37–1.71]), chemotherapy-related toxicity (1.22 [1.01–1.47]), and postoperative complications (1.73 [1.36–2.20]). The association of polypharmacy with prolongation of hospitalization was not statistically significant at the p<0.05 significance level (1.62 [0.98–2.66]). With respect to PIM, a statistically significant association with all-cause mortality (1.43 [1.08–1.88]) was observed but not with other adverse outcomes. However, these results should be interpreted with caution because about three-quarters of the studies identified did not adjust for comorbidity and are prone to confounding by indication.

For my own analysis on co-medication quality, the data of 3,239 CRC patients aged 65 years and older from the DACHS study were used for survival analyses and 1,209 patients for analyses on chemotherapy-related adverse drug reactions. The hazard ratios (HRs) [95%-confidence intervals (95%CI)] for the total FORTA score ≥ 7 vs. 0-1 points were 1.83 [1.40-2.40] and 1.76 [1.22-2.52] for 5-year overall survival (OS) and CRC-specific survival (CSS), respectively. Worse 5-year OS and CSS was also evident for FORTA sub-scores for PIM use and overuse, whereas no association was observed for underuse. Although results for the total FORTA score and PIM sub-score were much stronger among patients receiving chemotherapy, no significant associations with chemotherapy-related adverse drug reactions were observed. Moreover, associations were particularly strong among men and rectal cancer patients as compared to women and colon cancer patients. For analyses on polypharmacy, the same study population retrieved from the DACHS study was used. The prevalence of polypharmacy (concurrent use of 5 or more drugs) was 54.7% and that of excessive polypharmacy (EPP, concurrent use of 8 or more drugs) was 24.2%. During up to 5 years of follow-up, 1,070 participants died, among whom 615 died of CRC, and 296 died of other causes than cancer. EPP was statistically significantly associated with poorer up to 5-year OS (HR [95%CI]: 1.23 [1.02–1.47]) and CSS (1.31 [1.03-1.68]). The HR point estimate for non-cancer-specific survival was higher than 1 (1.22) but not statistically significant.

The analysis on CRC survival prediction was done with n=3,410 patients of all ages from the DACHS study. The reference model plus functional status was identified as the best model for prediction of OS among all CRC patients (area under the curve (AUC): 0.768) and younger CRC patients (AUC: 0.820). In older CRC patients, CCI should additionally be added (AUC: 0.747). For non-disease-specific survival (nDSS), the reference model plus CCI and FI had the best predictive performance in all CRC patients (AUC: 0.776). For the outcomes disease-free survival (DFS) (AUC: 0. 727), disease-specific survival (DSS) (AUC: 0. 838), and recurrence-free survival (RFS) (AUC: 0. 784), the reference model was already the best model in all CRC patients be-cause no significant net reclassification improvements were observed. The pattern “The less CRC-specific the survival outcome and the older the CRC patients, the more relevant the inclusion of geriatric assessments like functional status, CCI, and FI in CRC survival prognosis scores is” was observed. Co-medication-related factors (polypharmacy and FORTA score), however, did not play as important roles as functional status, CCI, and FI in prognosis of CRC survival.

Overall, based on the evidence summarized in my systematic review and the findings of my original data analyses, I recommend physicians to perform a medication review for older (colorectal) cancer patients with 5 drugs or more. Such a medication review could be included in a broader CGA and should not only focus on reducing the number of medications (by de-prescribing drugs without an indication), but also check the appropriateness of indicated drugs for older adults and look for underuse of indicated drugs. The FORTA list could be a suitable tool for this managing of the co-medication of older (colorectal) cancer patients. However, as the current state of evidence is based on observational studies, randomized controlled trials are further needed to test whether such improved co-medication management improves survival of older (colorectal) cancer patients.

 

Publications

  • Trares, K., Chen, L.J., & Schöttker, B. (2022). Association of F2-isoprostane levels with Alzheimer’s disease in observational studies: A systematic review and meta-analysis. Ageing Research Reviews, 74, 101552. https://doi.org/https://doi.org/10.1016/j.arr.2021.101552
  • Chen L.J., Trares K, Laetsch DC, Nguyen TNM, Brenner H, Schöttker B. Systematic review and meta-analysis on the associations of polypharmacy and potentially inappropriate medication with adverse outcomes in older cancer patients. J Gerontol A Biol Sci Med Sci 2021;76 (6), 1044-1052.
  • Chen, L. J., Nguyen, T. N. M., Chang-Claude, J., Hoffmeister, M., Brenner, H. and Schöttker, B. Association of Polypharmacy with Colorectal Cancer Survival Among Older Patients. Oncologist 2021; 26 (12), e2170-e2180
  • Chen, L. J., Nguyen, T. N. M., Laetsch, D. C., Chang-Claude, J., Hoffmeister, M., Brenner, H. and Schöttker, B. Association of co-medication quality with chemotherapy-related adverse drug reactions and survival in older colorectal cancer patients. J Gerontol A Biol Sci Med Sci 2022; [epub ahead of print].
  • Chen, L. J., Nguyen, T. N. M., Chang-Claude, J., Hoffmeister, M., Brenner, H. and Schöttker, B. Comparison and combination of functional status, comorbidity, frailty, polypharmacy, and a co-medication quality score in the prediction of colorectal cancer survival; 2022 [submitted].

 

Vita

02/2019-01/2022 PhD student, Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center, Heidelberg and Member of Junior Research Group of Ben Schöttker, Network Ageing Research (NAR), Heidelberg University
2018-2018 Research Associate, Health Data Research Center, National Taiwan University, Taipei, Taiwan
2017-2018 Research Assistant, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
2014-2017 Pharmacist, Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan
2012-2014 Master of Science in Clinical Pharmacy, National Taiwan University, Taipei, Taiwan
2008-2012 Bachelor of Science in Pharmacy, National Taiwan University, Taipei, Taiwan

 

 

 

 

 

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Latest Revision: 2022-02-15
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