International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationA Phase 2 Study of Preoperative Capecitabine and Concomitant Radiation in Women With Advanced Breast Cancer
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.
Section snippets
Patient eligibility
This study was a single-center, phase 2 study (study schema in Fig. E1; available online at www.redjournal.org). Eligible subjects were women with invasive breast cancer with measurable disease that had progressed on standard chemotherapy. This includes: (1) those with inoperable disease after chemotherapy; (2) patients with residual nodal disease after definitive surgical resection; and (3) those with an unresectable chest wall or nodal recurrence after a prior mastectomy. Of note, in all
Statistical Analysis
The primary endpoint was disease response (complete response or partial response) as evaluated by RECIST by a single physician (W.A.W.). Those who did not complete treatment or with unknown response were considered nonresponders. All analyses included patients who received at least 1 dose of CAP.
Secondary efficacy endpoints were rates of CTO and clinical and pathologic complete response after completion of all specified therapy among patients who proceeded to surgery and locoregional control of
Results
From 2009 to 2012, 32 patients were accrued, and 26 received protocol-specific treatment. Six patients did not receive protocol-specified treatment. One patient withdrew from study owing to lack of insurance clearance for protocol participation; 2 patients were taken off study before any treatment owing to the severe pre-existing peripheral neuropathy. Two patients withdrew after having mild side effects (1 with nausea, another with mild foot pain/diarrhea). In 1 patient, RT was stopped early
Discussion
This study provides prospective results investigating disease response to concurrent CAP and RT in patients with inoperable, chemotherapy-resistant, or oligometastatic disease. Local disease burden is often associated with high morbidity and distress in these patients, for whom therapeutic options are limited.
Previously, CAP has been offered as concurrent neoadjuvant treatment with RT at our institution. In an unpublished retrospective review of 64 patients treated at our institution with
Conclusion
Capecitabine can be safely administered as a concurrent chemoradiation regimen on RT days with careful clinical monitoring for patients with inflammatory breast cancer, or inoperable, chemo-refractory, locally recurrent, or gross residual disease after mastectomy. In this small, prospective and selected cohort, concurrent chemoradiation with CAP was associated with a high risk of distant disease progression among TN patients despite good radiographic response. Other treatment strategies should
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This study was funded with National Institutes of Health National Cancer Institute R01 grant CA138239, awarded to W.A.W.
W.A.W. and P.F. contributed equally to this work.
Conflict of interest: B.D.S. receives grant funding from Varian Medical Systems, outside the present work.