Annals of Surgical Oncology, 13(2): 214)220
DOI: 10.1245/ASO.2006.01.001
Induction Cisplatin and Paclitaxel Followed by Combination Chemoradiotherapy with 5-Fluorouracil, Cisplatin, and Paclitaxel Before Resection in Localized Esophageal Cancer: A Phase II Report Leonard R. Henry, MD,1 Melvyn Goldberg, MD,1 Walter Scott, MD,1 Andre Konski, MD,2 Neal J. Meropol, MD,3 Gary Freedman, MD,2 Louis M. Weiner, MD,3 Perry Watts, MSIS,4 Mary Beard, BA, CTR, CCRP,5 Susan McLaughlin, RN, CCRP,5 and Jonathan D. Cheng, MD3
1
Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111 Department of Radiation Oncology, Fox Chase Cancer Center 333 Cottman Avenue, Philadelphia, Pennsylvania 19111 3 Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111 4 Department of Biostatistics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111 5 Office of Protocol Management, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111
2
Background: Multimodality therapy for esophageal cancer holds promise for improving outcome in this lethal disease. On the basis of encouraging data from a phase I trial, we conducted a phase II study of preoperative chemotherapy, followed by concurrent chemoradiotherapy and surgery. Methods: Patients with clinically staged resectable esophageal cancer were treated with induction cisplatin and paclitaxel, followed by 45 Gy of external beam radiation with concurrent infusional 5-fluorouracil and weekly cisplatin and paclitaxel. Four to eight weeks after multimodality induction, esophagectomy was performed in suitable patients. Study end points were survival, pathologic complete response, and toxicity. Results: Twenty-one patients were enrolled with a median age of 58 years, and all patients were clinically staged II or III. Sixteen (76.2%) patients completed the trial, of whom four (25%) had a pathologic complete response. One patient died from postoperative complications. Grade 3 or 4 toxicity was observed in 76% of patients, and dose-limiting toxicity was seen in 6 of the first 14 patients, thus necessitating a planned dose reduction of paclitaxel. At a median follow-up of 30 months, 13 patients remain alive. The 2-year disease-specific survival for the study population was 78%. Conclusions: This regimen of multimodality therapy before resection resulted in an encouraging 2-year survival rate but a disappointing rate of pathologic complete response and was toxic, necessitating a predetermined paclitaxel dose reduction. The incorporation of taxanes into induction strategies for esophageal cancer seems promising, but the optimal schedule remains undefined. Key Words: Esophageal cancer—Induction—Neoadjuvant—Management—Toxicity.
Received January 6, 2005; accepted August 16, 2005; published online January 18, 2006. Address correspondence and reprint requests to: Jonathan D. Cheng, MD; E-mail:
[email protected].
Cancer of the esophagus, although less common in the United States, remains a lethal malignancy. With mortality rates roughly equivalent to incidence, significant improvements are needed in current treatment regimens. Surgical resection, chemoradiation,
Published by Springer Science+Business Media, Inc. Ó 2006 The Society of Surgical Oncology, Inc.
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or trimodality therapy of surgery and chemoradiation are the accepted treatment options for localized esophageal cancer. Although treatment provides varying degrees of local tumor control and palliation of symptoms, long-term survival, unfortunately, remains poor. Given that most patients with localized esophageal cancer succumb to their initially occult metastatic disease, one of the principal benefits of delivering optimal chemotherapy before definitive local treatment in esophageal cancer is the early treatment of occult distant micrometastasis at presentation. This may be advantageous because the probability of a tumorÕs resistance to chemotherapy likely increases with increasing tumor size.1 In addition, giving systemic therapy up front may also benefit patients who might not be able to tolerate it after an esophagectomy. Local failure rates after surgery alone are high. Esophageal cancer is characterized by extensive local growth, invasion, and a propensity for regional lymph node metastasis. Radiotherapy decreases the risk of local failure. The use of radiosensitizing doses of chemotherapy during radiotherapy (concurrent chemoradiotherapy) has been demonstrated to further increase both local control and survival.2–4 Walsh et al.5 demonstrated an improved survival with induction chemoradiotherapy for esophageal cancer in a randomized controlled trial. Bosset et al.6 similarly showed an improved disease-free survival in patients treated with induction therapy, although overall survival was not changed. Furthermore, using induction strategies allows assessment of the efficacy of treatment by examining the resected histological specimens. Studies suggest that a pathologic complete response (CR) to induction chemotherapy and radiotherapy accurately predicts improved disease-free survival and overall survival in patients undergoing esophageal resection.7,8 The optimal regimen of induction therapy would yield a high rate of pathologic CR while not exposing the patient to untoward toxicity. Traditionally, 5fluorouracil (5-FU) and cisplatin have been the standard agents. Paclitaxel has demonstrated efficacy against esophageal cancer in patients with metastatic disease.9 The search for a more effective induction regimen with acceptable toxicity has recently resulted in the publication of several small trials incorporating new agents (such as paclitaxel) in the preoperative treatment of patients with esophageal cancer. These trials have demonstrated encouraging results with regard to therapeutic index, pathologic CR, and early overall survival.10–13
We have also explored the use of paclitaxel in an induction strategy for patients with esophageal cancer. Goldberg et al.14 recently reported the results of a phase I study that demonstrated an encouraging 4-year disease-free survival of 45% in patients treated with an intensive regimen of preoperative chemoradiation (60 Gy plus 5-FU, paclitaxel, and cisplatin) with consolidation chemotherapy (paclitaxel and cisplatin) after resection. Acute toxicity and postoperative complications were common and thought to be due to the aggressive three-drug chemotherapy regimen and high radiation dose of 60 Gy. Furthermore, only 3 of 22 patients tolerated postoperative adjuvant chemotherapy in this study, and this prompted the change of the chemotherapy administration to the preoperative setting, as well as dosage adjustments. This study was a phase II trial that used lower radiation doses and delivered all chemotherapy before surgery in an attempt to build on the encouraging survival results from our phase I trial with less toxicity. The end points were overall survival, disease-free survival, pathologic CR, and toxicity.
PATIENTS AND METHODS Criteria for eligibility included biopsy-proven, potentially resectable (T2/3, N0/1) adenocarcinoma, squamous cell carcinoma, adenosquamous or undifferentiated carcinoma involving the esophagus or gastroesophageal junction, and ability to give informed consent. The presence of a positive celiac node by computed tomographic (CT) scan was exclusionary unless the node was histologically confirmed to harbor no cancer. Additional exclusionary criteria included neutropenia (absolute neutrophil count 3 times the upper limit of normal). The Institutional Review Board at Fox Chase Cancer Center approved the protocol. Informed consent was obtained for all patients. Treatment Schema CT scanning of the chest, abdomen, and pelvis and endoscopic ultrasonography (EUS) were used to stage the primary tumor. However, EUS was not successfully performed in 7 of the first 10 patients. Liver function tests and barium swallow were also Ann. Surg. Oncol. Vol. 13, No. 2, 2006
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obtained in all patients. Additional studies were obtained at the discretion of the attending physicians. Treatment was initiated with cisplatin (75 mg/m2) and paclitaxel (175 mg/m2) given every 3 weeks for two cycles. Repeat CT scanning of the chest, abdomen, and pelvis was obtained. In patients without disease progression, concurrent chemoradiation began 3 weeks after completion of induction chemotherapy and consisted of 45 Gy (1.8-Gy fractions) given Monday through Friday for 5 weeks. 5-FU (200 mg/m2/day) was administered via continuous infusion throughout the duration of radiotherapy. Cisplatin (25 mg/m2) and paclitaxel (50 mg/m2/day) were administered weekly on days 1, 8, 15, 22, and 29 of radiotherapy. Patients with resectable disease (T0 to T3, any N, M0) then underwent resection 5 to 8 weeks after completion of combined chemoradiotherapy. Tissue was obtained and reviewed from biopsy samples at diagnosis, before chemoradiation, and from the operatively resected specimen. Toxicity, Complications, and Dose Adjustments Toxicity data were gathered prospectively on all patients. Operative complication data were collected prospectively on the 16 patients who underwent esophagectomy on study. Operative death was defined as death within 30 days of operation or within the initial postoperative hospitalization. The Common Toxicity Criteria Version 2.0 scored toxicity. Dose-limiting toxicity (DLT) was defined as toxicity necessitating a 2-week interruption of treatment, grade 3 toxicity persisting over 2 weeks, or any grade 4 nonhematological toxicity. Paclitaxel dose modification was planned after evaluation of the first 14 patients and was targeted to achieve DLT in 20% of patients. If no DLTs were observed in the first 14 patients, the dose of paclitaxel would be increased to 60 mg/m2. Conversely, if 5 or 6 DLTs were observed, the paclitaxel dose would be decreased from 50 to 40 mg/m2, and more than 6 DLTs would have resulted in termination of the trial after 14 patients. Assessment of Response A clinical CR was defined as complete resolution of all clinically detectable disease by radiographic imaging. A partial response indicated >50% reduction in the tumor mass in bidimensional measurement. Stable disease was assessed as primary tumor reduction of 40 mg/m2 of paclitaxel, when given weekly with radiotherapy in esophageal cancer, may engender excessive toxicities. Furthermore, we demonstrated the value and feasibility of planned interim toxicity assessments with predetermined dose modification schemata in this phase II trial and encourage their routine incorporation in other studies derived from phase I experiences.
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