Tolerability of and adherence to combination oral therapy with gefitinib and capecitabine in metastatic breast cancer

Abstract

Summary Purpose This phase I study explored gefitinib (G) and capecitabine (C) in metastatic breast cancer (MBC). Methods Sequential cohorts (n=3) received G and escalating C on a 14 day on/7 day off schedule, with a validation cohort (n=10) at the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) was defined in cycle 1. The primary endpoint was safety; secondary endpoints included response and adherence. Results 19 patients were treated for a median of 5 cycles. No patients in sequential cohorts experienced DLT; C MTD was 2000 mg/m2/day when paired with daily G 250 mg. In the validation cohort, 4 experienced serious toxicities, including diarrhea, mucositis, and palmarplantar dysesthesia. At the MTD, 6 (46%) required a C dose reduction, and 3 (23%) came off study for toxicity. One partial response was observed (8%, 95% CI 0.2–38.5%); 5 had stable disease > 24 weeks (26%, 95% CI 9–51%). Patients missed few drug doses, with the suggestion of overadherence to therapy. Conclusions In this phase I study of G and C in MBC, a C MTD was identified, and significant toxicity was observed. 8% demonstrated a response, with 26% maintaining stable disease. The possibility of overadherence, as suggested in this study, may have implications for other trials of oral antineoplastic therapy.

Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells

“…A previous study has shown that gefitinib combined with the antimetabolite drugs gemcitabine or capecitabine had significant activity against breast cancer. [18][19][20] Moreover, dasatinib, as a second-generation c-abl oncogene (ABL) tyrosine kinase inhibitor (TKI) has been approved by the FDA for the treatment of chronic myelogenous leukemia. A combination of dasatinib and capecitabine or gemcitabine has been shown to have potential for the treatment of breast cancer.…”

The Challenges of Oral Agents as Antineoplastic Treatments

“…24,91 In a randomized control drug trial with adherence as a secondary endpoint, researchers found over adherence: days of taking medications beyond the end of an expected cycle; taking extra doses in one day; and missing a day and compensating with a double dose the next day. 92 The high rate of over adherence found may cause toxicity or lead to adverse events.…”

Assessment and Measurement of Adherence to Oral Antineoplastic Agents

“…This includes MEMS, pill counts, self-report or diaries, medical record review, and pharmacy record review. 7,[51][52][53][54] Several 'tightly' controlled drug trials noted over adherence or overdosing when medications were not stopped or resumed at the proper time. Overall, minimal attention has been paid to the potential hazards related to overdosing.…”

“…7,20,21,[23][24][25]38,39,50,51,[55][56][57][58][59] Although the MEMS is touted as a "gold standard" measurement in medication compliance, only 6 of the adult studies 8,48,52,53,60 and one pediatric study 61 used this method of measurement. MEMS is not considered to be a practical tool in the clinical setting due to its excessive cost.…”