Variations and Nuances in Colorectal Cancer Drug Dosing

Capecitabine is a frequently used oral oncology agent for colorectal cancer (CRC). It is a fluoropyrimidine prodrug of 5-fluorouracil (5-FU) with similar efficacy to intravenous 5-FU. Due to the convenience of oral administration, capecitabine has become an attractive therapy option for treating CRC. Specialty pharmacists need to fully understand capecitabine’s place in CRC treatment to ensure that it is safely and effectively utilized.

A crucial factor to consider when reviewing the appropriateness of capecitabine dosing is the setting in which it will be used. Treatment goals and dosing regimens can vary greatly depending on tumor stage, concurrent medications, age, and prognosis. In the adjuvant setting, capecitabine is used after curative treatments, such as surgery to reduce the risk of cancer recurrence. Capecitabine can also be used prior to surgery to shrink tumor size and facilitate the complete removal of cancerous tissue in the neoadjuvant chemotherapy setting. Finally, in advanced or metastatic colorectal cancer (mCRC), capecitabine is used to delay disease progression and extend survival.

Three-week cycle

The manufacturer-recommended dose in all settings is 1250 mg/m2 twice daily (BID) for 14 days followed by 7 days of rest (14/7) in repeating cycles. Under most circumstances, an initial dose of 1250 mg/m2 BID is appropriate for CRC; no current data support higher dosing than this using 3-week dosing cycles. Importantly, no adjustments to body surface area (BSA) are needed to calculate total doses in obese patients since there have been no observed differences in toxicity between obese and nonobese patients.

However, clinical experience with this medication shows that the optimal dose and dosing schedule can vary considerably based on age, renal function, concurrent cytotoxic agents, and past tolerability. Pharmacists need to be aware when doses other than 1250 mg/m2 BID in 3-week cycles are appropriate in CRC to reduce the potential for dosing errors, ineffectiveness, and adverse events (AEs).

There are circumstances in which doses lower than 1250 mg/m2 BID are appropriate. For example, when capecitabine is administered for mCRC with other chemotherapy agents, such as oxaliplatin or bevacizumab, the dose should be limited to 1000 mg/m2 BID. Additionally, although standard doses can be used in the elderly population with acceptable tolerability, there is clinical rationale to support a dose of 1000 mg/m2 BID.

An ongoing phase 3 noninferiority trial may determine which dose should be preferred in patients 70 years and older. Renal impairment should also be taken into consideration; capecitabine requires a dose limit of 950 mg/m2 BID in patients with creatinine clearance less than 50 mL/min, and it is contraindicated below 30 mL/min.1 Since renal function declines with age, further caution is needed in elderly patients.

Be fully aware, as well, that some prescribers round the recommended dose to the nearest 500 mg instead of using 150-mg tablets. The clinical rationale for using this technique is that fewer strengths will reduce the chance of medication errors from the prescriber, pharmacy, and/or patient.

Additionally, fewer tablets for the patient to take may improve adherence, although no trials to date have specifically studied the impact of this intervention. Whenever a pharmacist notices that the dosing is inappropriate based on BSA, it is prudent to discuss which dosing parameters the provider is using to prescribe the capecitabine. This may account for variances in dosing when calculating based on BSA.

Genetic differences have been shown to influence the tolerability of capecitabine. Currently, the most clinically significant abnormality identified involves dihydropyrimidine dehydrogenase (DPD), an enzyme involved in fluoropyrimidine metabolism. Patients with known complete or near-complete DPD deficiency should not be started on any fluoropyrimidines due to the risk of severe, potentially lethal, AEs.3 Since no genetic testing is recommended prior to starting therapy, monitoring, particularly at the beginning of therapy, becomes vital. Patients with this disorder tend to present with early onset and unusually severe AEs.3 An estimated 3% to 5% of Caucasians are affected, with even higher prevalence in women and African-Americans. Further investigation into the impact of pharmacogenetics on capecitabine is underway and may in part explain observed regional tolerability differences.11-13 Genetic testing may become more common as assays become more feasible and as mutations that affect safety and efficacy are identified.

BSA-based dosing regimens are the recommended starting point for new patients, but some evidence suggests that BSA may not be a reliable predictor of tolerability. The need for dose adjustments with this approach remains high, with 42% of patients requiring dose reductions and 15% experiencing treatment interruption during phase 3 testing.3

Furthermore, pharmacokinetic analysis has found that drug clearance does not correlate significantly with a patient’s BSA for capecitabine (R = 0.07; P = .71). These data suggest the presence of a large amount of interpatient variability that may not be represented by a specific patient’s BSA. A patient with a high BSA will get a correspondingly high dose of capecitabine but may not eliminate the drug faster than someone with a lower BSA, thereby increasing their risk of toxicity. With this in mind, it becomes important to closely monitor patient tolerability over time and understand that dose modification may be necessary and appropriate.

Two-week cycle

In certain circumstances, prescribers may deviate from 3-week cycles in favor of 2-week cycles: 7 days on followed by 7 days off (7/7). Interest in this dosing schedule originated with mouse models that showed a higher maximum-tolerated dose and higher rates of survival with 7/7 versus standard dosing.

These murine-model findings were supported in a phase 2 study of mCRC. A dose of 1750 mg/m2 BID with a 7/7 schedule used in combination with oxaliplatin every 14 days achieved a significantly higher progression-free survival rate compared with 1000-mg/m2 BID doses of capecitabine with oxaliplatin in 14/7 cycles (10.5 months vs 6.0 months; P = .0013) with similar rates of toxicity. Use of 7/7 cycles in other treatment settings should be questioned, as very little evidence supports this cycle outside of metastatic disease.

Weekly cycle

Another common dosing regimen consists of 5 days on followed by 2 days off (5/2), repeating every week. This common dosing schedule is encountered as part of a neoadjuvant radiotherapy regimen to aid in tumor shrinkage in resectable CRC. The treatments are used synergistically, with capecitabine acting as a radiosensitizing agent and radiation increasing the levels of thymidine phosphorylase, which is the enzyme responsible for converting capecitabine to its active metabolite.

Subsequent models of human colon xenografts found that the combination of radiation and capecitabine was more effective than either treatment alone. These findings were validated in phase 3 trials that established the efficacy and safety of weekly cycles, making it the preferred dosing schedule in the neoadjuvant setting. Lower doses and a defined treatment duration are expected with these cycles.

Trials used a dose of 825 mg/m2 BID only on radiation days (5/2) for 5 weeks, but longer durations may be appropriate depending on the duration of radiation. Use of this cycle at higher doses or for extended durations should prompt clarification. Evidence is weak for this schedule outside of the neoadjuvant setting. One small trial does support its use in mCRC, but more evidence is needed.

Alternate dosing schemes

Other cycle and dosing schemes may be seen in the course of practice, but evidence to support them is lacking. Four-week cycles, 21 days on with 7 days off, have been used in Japan and in pancreatic cancer patients, but remain unsupported within the United States for CRC., Continuous or metronomic dosing has also been used in mCRC, but standard 3-week cycles were found to have a longer time to progression (127 days vs 230 days). Finally, fixed or flat dosing has been found feasible, but only 1 trial has prospectively examined this approach in CRC. Further validation is required for these dosing schemes.

To maximize patient benefit, a specialty pharmacist must be comfortable determining when each specific capecitabine dosing schedule and dosage is appropriate. When a prescription is received, a pharmacist must be able to review the total dose, patient age, prognosis, BSA, and the goals of therapy to determine if the prescribed dosing scheme will benefit the patient. A deeper understanding of where different doses of capecitabine fit into a treatment algorithm will minimize risks, maximize benefits, and lead to better quality of care overall for these patients.

References
  1. Haller, D. G. et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer. Journal of Clinical Oncology 29, 1465–1471 (2011).
  2. Cassidy, J. et al. Randomized Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid Plus Oxaliplatin As First-Line Therapy for Metastatic Colorectal Cancer.Journal of Clinical Oncology 26, 2006–2012 (2008).
  3. Capecitabine [package insert]. Amneal Pharmaceuticals LLC. Bridgewater, NJ. 2016
  4. Griggs, J. J., Mangu, P. B., Temin, S. & Lyman, G. H. Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Oncology Practice 8, e59–e61 (2012).
  5. Hochster, H. S. et al. Safety and Efficacy of Oxaliplatin and Fluoropyrimidine Regimens With or Without Bevacizumab As First-Line Treatment of Metastatic Colorectal Cancer: Results of the TREE Study. Journal of Clinical Oncology 26, 3523–3529 (2008).
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  11. Rosmarin, D. et al. Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis. Journal of Clinical Oncology 32, 1031–1039 (2014).
  12. Lam, S. W., Guchelaar, H. J. & Boven, E. The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treatment Reviews 50, 9–22 (2016).
  13. Haller, D. G. et al. Potential Regional Differences for the Tolerability Profiles of Fluoropyrimidines.Journal of Clinical Oncology 26, 2118–2123 (2008).
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