A Phase 2 Study of Preoperative Capecitabine and Concomitant Radiation in Women With Advanced Breast Cancer

Purpose

To examine the response rate of gross chemo-refractory breast cancer treated with concurrent capecitabine (CAP) and radiation therapy in a prospective Phase II study.

Methods and Materials

Breast cancer patients with inoperable disease after chemotherapy, residual nodal disease after definitive surgical resection, unresectable chest wall or nodal recurrence after a prior mastectomy, or oligometastatic disease were eligible. Response by RECIST criteria was assessed after 45 Gy. Conversion to operable, locoregional control, and grade ≥3 toxicities were assessed. The first 9 patients received CAP 825 mg/m² twice daily continuously. Because of toxicity, subsequent patients received CAP only on radiation days. Kaplan-Meier analysis was used to estimate overall survival (OS) and locoregional recurrence–free survival.

Results

From 2009 to 2012, 32 patients were accrued; 26 received protocol-specified treatment. Median follow-up was 12.9 months (interquartile range, 7.10-42.9 months). Nineteen patients (73%) had partial or complete response. Fourteen patients (53.9%) experienced grade 3 non-dermatitis toxicity (7 of 9 continuous dosing). Three of four inoperable patients converted to operable. One-year actuarial OS in the treated cohort was 54%. The trial was stopped early after interim analysis suggested futility independent of response. Treatment was deemed futile (ie, conversion to operable but M1 disease immediately postoperatively) in 9 of 10 patients with triple-negative (TN) versus 6 of 16 with non-TN disease (P=.014). Median OS and 1-year locoregional recurrence–free survival among non-TN versus TN patients was 22.8 versus 5.1 months, and 63% versus 20% (P=.007).

Conclusions

Capecitabine can be safely administered on radiation days with careful clinical monitoring and was associated with encouraging response in this chemo-refractory cohort. However, patients with TN breast cancer had poor outcomes even when response was achieved. Further study in non-TN patients may be warranted.

Introduction

Locally advanced breast cancer can be painful and distressing owing to high local symptom morbidity, and current therapeutic options are limited 1, 2, 3, 4. In particular, patients with inoperable tumors and chemo-resistant disease tend to have particularly poor prognosis with current definitive therapies. Alternatively some patients develop progressive or inoperable breast cancer as a recurrence after definitive therapy for breast cancer or present or recur with distant disease and are often not surgical candidates but may benefit from palliative radiation to the primary tumor to reduce what would be otherwise significant morbidity from local disease. This study was a prospective, single-arm trial of radiation therapy (RT) and capecitabine (CAP), oral chemotherapy that is also a functional radiosensitizer, to improve response rates in these patients with advanced disease after inadequate response to systemic therapy.

Although the optimal treatment strategy has not been established, preoperative therapies that render patients candidates for mastectomy can improve locoregional control and reduce morbidity. Among 38 patients treated with radiation with concurrent chemotherapy for inoperable breast cancer resistant to anthracycline-containing primary chemotherapy on 5 consecutive trials at our institutional without evidence of distant metastases at diagnosis, 32 (84%) were able to undergo mastectomy after RT, with an overall survival (OS) of 46% at 5 years (5). Locoregional control was modestly improved for patients who were able to undergo mastectomy, and was 73% versus 64% at 5 years (5). Despite the high conversion to operable (CTO) rate with RT alone, the 5-year postoperative complication rate was 53%, and preoperative radiation doses ≥54 Gy were significantly associated with complications requiring surgical revision. Therefore, pursuing an alternative strategy such as addition of CAP to RT to achieve CTO allowing for response with a lower radiation dose was warranted.

Capecitabine is a fluoropyrimidine carbamate that undergoes sequential conversion via a triple enzyme pathway to 5-fluorouracil (5-FU) with documented antineoplastic activity approved as a first-line agent for the treatment of metastatic breast cancer resistant to anthracycline and taxane therapy (6). The final enzyme in the pathway is thymidine phosphorylase, which is preferentially expressed in tumor cells as opposed to normal tissue cells, thereby increasing the therapeutic index (7). Radiation therapy has been demonstrated to up-regulate thymidine phosphorylase levels, which is the final and rate-limiting enzyme in the CAP pathway, leading to a synergistic improvement in therapeutic index when used concurrently with radiation 8, 9. Use of preoperative RT and CAP for rectal cancer has led to significant preliminary experience at our institution using concurrent preoperative CAP and RT for inoperable breast cancer, with >90% CTO, and a small published phase 2 trial 10, 11 as well as a French retrospective study (12) support this approach for breast cancer patients resistant to first-line chemotherapy to improve operability.

Therefore, we conducted a phase 2 study to prospectively examine the efficacy and toxicity of CAP and RT in a larger group of patients with gross disease despite systemic therapy for whom radiation was to be used for disease control and in whom radiosensitization was desirable.