Management of Capecitabine Toxicities in Breast Cancer May Be Better With Dose Reduction

David O. Okonji, MD

David O. Okonji, MD

Toxicities associated with capecitabine may be better managed by dose reductions and/or a week-on/week-off (WOWO) dosing schedule among patients aged 70 years or older with metastatic breast cancer, according to David O. Okonji, MD, clinical research fellow at The Royal Marsden Hospital NHS Foundation Trust in London.

Capecitabine monotherapy is prescribed for patients who have progressed after all available endocrine therapies no longer offer benefit, Okonji said in an interview withTargeted Oncologyduring the 2016 ESMO Congress. It may be administered as a last oral agent option before resorting to intravenous chemotherapy with its attendant potential side effects of alopecia, nausea, vomiting, and fatigue.

“Chemotherapy with capecitabine has been around for about 25 years. Its registration dose of 1250 mg/m²twice daily is very hefty for the elderly, however,” Okonji said.

Its clinical benefit rate (CBR) as a monotherapy is 60% and median time to progression in patients ≥65 years is 4 months. Of those receiving that dose, 27% to 50% require a dose reduction due to toxicity.

The starting dose and schedule for capecitabine at The Royal Marsden Hospital and NHS Foundation Trust is 2000 mg/m²on days 1 to 14, every 3 weeks (2 weeks on/1 week off). However, older patients, and those with a poor performance status, comorbidities, and/or moderate to severe renal impairment may need a further dose reduction.

Because capecitabine is metabolized by the liver and cleared renally, a switch to a WOWO schedule is being substituted in order to improve tolerance in the elderly. The strategy was devised at Memorial Sloan Kettering Cancer Center, but is infrequently used in Europe, Okonji noted.

In a single-center retrospective observational cohort study, led by Okonji, researchers sought to assess the safety and efficacy of low-dose capecitabine monotherapy in elderly patients with metastatic breast cancer, with toxicity as the primary endpoint.¹Eligible patients were 70 years of age or older and had relapsedde novometastatic breast cancer. Those receiving the standard 2 weeks on/1 week off regimen (2000 mg/m²) were compared to those receiving a dose reduction or the WOWO (2000 mg/m²) schedule.

Among a total of 77 patients, those receiving the dose reduction or the WOWO schedule were older (median age 79 versus 73;P<.001), had reduced renal function (P= .016) and lower performance status.

The complete response rates were 7% and 0% for the 2000 mg/m²(n = 43) and <2000 mg/m²(n = 34) groups, respectively, with corresponding partial response rates at 37% and 16%. Progressive disease was reported in 30% of those receiving higher doses of capecitabine and in 50% of those receiving below 2000 mg/m².

The clinical benefit rate was 67% for those receiving 2000 mg/m²and 43% for those receiving less than 2000 mg/m²(P= .05). Okonji commented that this difference might be accounted for by longer treatment duration in the 2000 mg/m²cohort.

At a median follow-up of 28.1 months, the combined time-to-progression was 8.2 months and an overall survival OS of 18.6 months. Time-to-progression was 11.7 months and 6.2 months in the 2000 mg/m²and <2000 mg/m²cohorts, respectively.

Patients in the <2000 mg/m²cohort experienced less grade 3/4 toxicities (3% vs 19%) with fewer subsequent dose reductions.

&ldquo;Patients on the WOWO schedule tolerated capecitabine better because of less diarrhea, less hand inflammation, and little to no reduced white cell counts with their infection risk,&rdquo; Okonji said. &ldquo;This enabled them to stay on their dose for a longer time, despite their poor performance status and impaired kidney function, which is usually a contraindication for this drug.

&ldquo;Capecitabine toxicity can be managed by dose reduction and/or a switch to a WOWO schedule; both strategies enabled continued treatment in those deriving clinical benefit,&rdquo; he concluded.

Additionally, he added that the study&rsquo;s findings revive the use of capecitabine for these patients with metastatic breast cancer.

&ldquo;In many respects, the major conferences are all about getting new drug—which get us very excited for a while&mdash;and then we forget about them sooner or later after a few years. With this modification of the capecitabine regimen, we have given this old drug a new lease on life and allowed it to be used in patients who would not otherwise be able to tolerate it. And, it&rsquo;s off-patent and cheap.&rdquo;

Reference:

Okonji D, Mohammed K, Redana S, et al. Capecitabine monotherapy in patients aged 70 years and older with metastatic breast cancer (MBC).Ann Oncol. doi:10.1093/annonc/mdw365