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Factors Impacting Treatment Choice in the First-Line Treatment of Colorectal Cancer

Introduction To investigate the factors that affect the choice of 5-fluorouracil (5-FU) or its oral alternative, capecitabine, as first-line treatment in patients with colorectal cancer (CRC). Methods Patients treated with 5-FU or capecitabine for CRC between January 1, 2011 and December 31, 2013 in a teaching hospital in the Sydney metropolitan area, Australia were identified using the hospital’s database MOSAIQ®. The electronic medical record of each patient was manually reviewed to extract factors potentially affecting treatment choice. Logistic regression was used to assess which patient and/or treatment factors could explain the choice between 5-FU or capecitabine. Where it was available in the medical correspondence, the explicit reason for the choice made was extracted. Results 170 CRC patients were included; 119 on 5-FU, and 51 on capecitabine. The odds of receiving capecitabine as a first-line treatment were positively associated with giving patients a choice in the decision (OR = 17.51, 95% CI: 5.37–57.08). Qualitative data suggest treatment choices were motivated by convenience (oral administration) and tolerability. Time from diagnosis to treatment commencement (OR = 1.02 per month, 95% CI 1.00–1.04) was also found to be positively associated with the choice of capecitabine. The odds of being treated with capecitabine were lower for patients who lived further from the treating hospital (OR = 0.22, 95% CI 0.05–0.94). Conclusion This study suggests that patient choice, favoring oral capecitabine over i.v. 5-FU, was a key factor influencing first-line treatment for CRC in this cohort. To respect their autonomy, patients should be involved in the clinical decision making process. Electronic supplementary material The online version of this article (doi:10.1007/s40487-016-0020-4) contains supplementary material, which is available to authorized users.

in the Sydney metropolitan area, Australia were identified using the hospital's database MOSAIQ Ò . The electronic medical record of each patient was manually reviewed to extract factors potentially affecting treatment choice.
Logistic regression was used to assess which patient and/or treatment factors could explain the choice between 5-FU or capecitabine. Where it was available in the medical correspondence, the explicit reason for the choice made was Fluoropyrimidines, 5-FU (intravenously administered) and capecitabine (tablet formulated prodrug of 5-FU), are generally used as the backbone of treatment modalities, either alone or in combination with other agents [2,3]. Numerous studies have compared the efficacy and safety of 5-FU and capecitabine, alone or in combination therapy.
Capecitabine, and the combination of capecitabine and oxaliplatin (XELOX or CAPOX) have been shown to be non-inferior to either 5-FU/LV or the combination of 5-FU/ LV and oxaliplatin (FOLFOX or FLOX) [2,4].
However, the decision to use one or the other of these drugs has implications for both the patient and treating institution; most notably, for health care resource use due to the difference in the mode of administration.
While intravenous (i.v.) treatment with 5-FU typically requires the use of indwelling catheters, pumps for continuous infusion and several hospital visits by the patient or home visits by medical personnel, capecitabine is self-administered orally. Thus, the use of 5-FU would be expected to result in increased health care service utilization associated with treatment administration compared with capecitabine [5][6][7][8][9][10][11][12], as well as the costs to the patient for traveling to, and remaining at the hospital for treatment [6,10,11,13]. Given these differences in the mode of administration and potential accessibility of treatment, several studies have noted a preference by patients for capecitabine over 5-FU on the basis of convenience [14,15].
Studies specifically evaluating patient preferences for oral versus i.v. chemotherapy (mostly for CRC) generally show a preference for oral treatment [14][15][16][17][18][19]. Before and after treatment, the main drivers of preference for oral chemotherapy were convenience of home administration [14][15][16][17][18], the avoidance of i.v. line problems [16,18], fewer adverse events (AEs) [17,18] and oral administration [14,15,17]. Interestingly, Twelves et al. [14] found fewer occurrences of AEs to be a driver of preference for 5-FU. Other studies have shown that home-based chemotherapy treatments were preferred by the patients [20,21] and led to significant [21] or greater treatment satisfaction [22]. The reasons associated with this preference were convenience, traveling less, lower anxiety, not having to trouble carers and family, having a greater ability to perform other tasks and having a relative close-by [20,21].

Setting and Study Population
This was a retrospective, single center study conducted at a teaching hospital in the Sydney

Patient Characteristics
Review of the MOSAIQ database revealed that a total of 170 CRC patients were eligible for inclusion in this analysis; 119 patients had received initial treatment with 5-FU (14 as single agent), while 51 commenced treatment with a capecitabine-based regimen (     One option discussed ' '… he is not very keen (…) as he does not want to take time off work to allow for the 2 days that he will need to attend every fortnight' ' Patient ' 'We have advised that he receive oral capecitabine, concurrent with the radiotherapy, as this tends to be better tolerated than intravenous 5-fluorouracil (5-FU)' ' Physician recommended ' 'I thought it was reasonable to offer her palliative systemic chemotherapy but, in an attempt to reduce the risk of significant toxicity, I thought it appropriate to start with single agent oral 5-fluorouracil analogue capecitabine'' Physician ' 'In view of the equal efficacy of both the agents the patient would prefer, from a convenience point of view, to have treatment with capecitabine'' Patient ' '… given the fact that she already has metastasis, she is eligible for the oral version of analogue of 5-fluorouracil capecitabine' '

Physician
Our results show that the time from diagnosis to commencement of treatment was significantly associated with choosing capecitabine. While it is possible that the increased time interval between diagnosis and commencement of treatment, which was noted to be significant, was a surrogate marker for performance status or increased co-morbidities, it would be speculative to state that this was the case for all patients. Unfortunately ECOG performance was not available for patients in this sample: performance status was not always sequentially recorded in the electronic health record, MOSAIQ. The number of comorbidities was available, but initial univariate testing showed no association between the number of comorbidities and treatment choice so this was excluded from subsequent multivariate analyses.
A caveat to this result is that the records used to inform our analysis did not consistently capture the time of disease recurrence where it occurred, such that the actual interval between newly emergent disease requiring treatment and treatment starting may be shorter than calculated. This could not be clarified further with the available data. Data issues notwithstanding, we found it difficult to explain that the longer a treatment decision appeared to be deferred, the higher was the chance that a patient was treated with a capecitabine-based regimen. We explored the possibility that the timing of public subsidy for capecitabine played a part, given that it was not Indeed, patient participation in the medical decision making process has been shown to influence patient satisfaction [32]. Women with breast cancer who were not given the opportunity to make a choice fared less well psychologically (they expressed a diminished positive attitude) than women who were offered a choice between treatment options. In addition, final decision making by the patient rather than the physician led to greater psychological wellbeing [32]. Other studies have shown that a majority of patients prefer to make either an autonomous or a shared decision (i.e., together with their physician) [16,33,34]. In a recent review of patient preferences related to the choice of treatment and mode of decision making, Damm et al. [35] found that the majority of CRC patients expressed a preference for a passive role in the decision making process . This is consistent with our data in which approximately 60% of decisions were the result of a direct choice by the physician, or indicate some degree of physician direction. Nonetheless, our results suggest that patient involvement in treatment choice is a significant predictor of the use of capecitabine compared with 5-FU. It might be reasonable to expect therefore that if more patients were able to be actively involved in treatment decision making, the use of capecitabine might be higher than we have observed.
There are several limitations to this study.  [36,37]. Both assessed factors associated with treatment choices for single agent as well as combination therapy (CAPOX/ XELOX vs. FOLFOX) as first-line treatment in (metastatic) CRC patients from the USA and Australia. In the study by Satram-Hoang et al. [36], the population who received capecitabine rather than 5-FU was older, and a higher proportion was female, had lower CRC stage at diagnosis but a higher tumor grade, and had higher incomes. Comorbidity score and race were not associated with a specific single agent treatment. CAPOX treatment was associated with a higher overall CRC stage at diagnosis and a trend was observed toward people in this group being older. Comorbidity, sex, race, income and tumor grade were not associated with a specific multi-agent therapy. Compared to those receiving i.v. treatment, more patients receiving capecitabine or CAPOX were living in western USA, and a higher proportion had at least a college degree [36]. Finally, in Australia, patient age at diagnosis was found to be significant, with older patients more often receiving single agent capecitabine, as well as primary tumor site, with colon cancer patients more often receiving FOLFOX [37].
Notably, these studies focused only on patient and disease characteristics as determinants of treatment modality and not the source of the treatment decision. It is likely that in making their treatment choice, patients and physicians alike evaluate some of the disease and patient characteristics considered in those larger studies. However, using the information available in patients' charts, we were able to identify that convenience is an additional underlying reason which influences preferences.