International Journal of Radiation Oncology*Biology*Physics
Clinical investigationEsophagusConcurrent cisplatin, 5-FU, paclitaxel, and radiation therapy in patients with locally advanced esophageal cancer
Introduction
The prognosis for patients with locally advanced esophageal cancer remains dismal. Therapies are needed that will improve both local and distant disease control. There has been a significant interest in the use of taxanes. Multiple Phase I–II studies have demonstrated that taxanes have significant activity in patients with locally advanced and metastatic esophageal cancer (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). In addition to cytotoxic activity, taxanes act as excellent radiation sensitizers, arresting cells in G2/M, the most radiation-sensitive phase of the cell cycle (12, 13, 14, 15). Thus, adding paclitaxel to standard regimens could potentially benefit esophageal cancer patients treated with definitive chemoradiation or tri-modality therapy by improving local and distant control.
Most patients diagnosed with esophageal cancer in the United States will have locally advanced or metastatic disease (16). Despite the relative frequency of this disease, optimal management for patients with locally advanced disease remains controversial. Surgery alone yields 5-year survival rates in the range of 22% (17, 18, 19, 20, 21). Studies employing tri-modality therapy have not consistently demonstrated a statistically significant survival benefit; however, there is a trend toward improved overall survival with the use of tri-modality therapy (17, 18, 19, 20, 21). At Massachusetts General Hospital, in an effort to improve survival for patients with locally advanced disease, we have adopted a tri-modality approach as the standard treatment for patients who are felt to be able to tolerate aggressive therapy. Because most patients experience disease recurrence despite aggressive therapy, we sought to improve survival by investigating paclitaxel in the neoadjuvant setting in a Phase I–II study (1, 2). Our findings suggested a high pathologic complete response (pCR) rate, but there was significant toxicity (1).
This report updates the results of our experience with neoadjuvant cisplatin, 5-fluorouracil (5-FU), paclitaxel, and radiation (PFT-R), and provides the largest reported experience with the use of this three-drug regimen in esophageal cancer. Additionally, we compare these results to our own institutional experience with cisplatin, 5-FU, and radiation therapy (PF-R) in patients with locally advanced esophageal cancer treated during the same time frame. We examine the pathologic response rates, local control, disease-free survival, and overall survival as well as the significant toxicities in patients treated with either neoadjuvant PF-R or neoadjuvant PFT-R at Massachusetts General Hospital between 1994 and 2002.
Section snippets
Patients and methods
This study was approved by the Internal Review Board at Massachusetts General Hospital.
Demographic data
A total of 164 patients with esophageal/gastroesophageal cancer were treated with curative neoadjuvant chemotherapy (PF = 81 or PFT = 83) and radiation therapy between 1994 and 2002. Patients were more likely to have received paclitaxel during the years of the protocol accrual period, and did not receive paclitaxel before initiation of the protocol. After the protocol closed, patients were less likely to have received paclitaxel as part of their regimen, but paclitaxel use did increase again
Discussion
Phase III data demonstrate that the addition of chemotherapy to radiotherapy improves overall survival in esophageal cancer (22, 23). The ideal chemotherapeutic regimen, however, remains controversial. PF has served as the backbone of the chemotherapeutic regimen for many years. Studies of paclitaxel have suggested a synergistic effect with PF and radiation, offering hope of an opportunity to improve survival for patients with esophageal cancer.
Investigators have been encouraged by the
Acknowledgment
We wish to acknowledge Eileen Sharkey, RHIA, CTR, Massachusetts General Hospital Senior Cancer Registrar, for her valuable assistance in data accumulation.
References (28)
- et al.
Twice-daily radiotherapy as concurrent boost technique during two chemotherapy cycles in neoadjuvant chemoradiotherapy for resectable esophageal carcinomaMature results of a phase II study
Int J Radiat Oncol Biol Phys
(2004) - et al.
Long-term outcome of phase II trial evaluating chemotherapy, chemoradiotherapy and surgery for locoregionally advanced esophageal cancer
Int J Radiat Oncol Biol Phys
(2003) - et al.
Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus
Ann Oncol
(2003) - et al.
A phase II trial of pre-operative combined modality therapy for localized esophageal carcinoma
J Thorac Cardiovasc Surg
(2002) - et al.
Induction therapy for esophageal cancer with paclitaxel and hyperfractionated radiotherapyA phase I and II study
J Thorac Cardiovasc Surg
(1997) - et al.
Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy
J Clin Oncol
(2000) - et al.
Phase I trial of combined modality therapy for localized esophageal cancerEscalating doses of continuous-infusion paclitaxel with cisplatin and concurrent radiation therapy
J Clin Oncol
(2004) - et al.
Activity of Taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus
J Natl Cancer Inst
(1994) - et al.
A phase II trial of paclitaxel (Taxol) in advanced esophageal cancerPreliminary report
Semin Oncol
(1994) - et al.
A three step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction
Cancer
(2001)
Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus
J Clin Oncol
X-ray sensitivity during cell generation cycle of cultured Chinese hamster cells
Radiat Res
Promotion of microtubule assembly in vitro by Taxol
Nature
X-ray sensitivity and DNA synthesis in synchronous population of Hela cells
Science
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