An estimated 12,500 new cases of esophageal cancer will be diagnosed in the Unites States in 1999. 1 Carcinoma of the esophagus has a dismal prognosis; with current therapy, the 5-year overall survival rate is approximately 13%. Combined treatment modalities were developed to improve local–regional control and lengthen overall survival. 2
The addition of chemotherapy to radiotherapy in a preoperative setting has been the subject of several studies. 3–5 In a randomized trial coordinated by the Radiation Therapy Oncology Group (RTOG), 5-fluorouracil, cisplatin, and radiotherapy were compared with radiotherapy alone in 129 patients, 6,7 and demonstrated that the combined-modality group had a superior 5-year survival rate (27% versus 0%;p < 0.0001).
Paclitaxel is an active agent in the treatment of upper gastrointestinal cancers. 8,9 Several investigators have added paclitaxel to platinum-based preoperative chemoradiation treatments;10–17 however, all of those trials reported substantial treatment-related toxicity (Table I). Several trials of paclitaxel and platinum-based chemoradiation regimens have also reported treatment-related deaths. 10,11,13 Grades III and IV nonhematologic toxicity, including severe esophagitis, were common. 10–18 We were interested in determining whether paclitaxel could be used as a radiosensitizer without enhancing the toxicity of 5-fluorouracil-based concurrent chemoradiation.
MATERIALS AND METHODS
All 10 patients had pathologic proof of esophageal and/or gastroesophageal junction carcinoma. Before initiation of treatment, patients had to have a Karnofsky performance status 70 or greater. A complete history, physical examination, and staging workup were done before treatment. The staging evaluation included a measurement of the extension of the tumor (based on computed tomography of the chest and abdomen), a barium esophagography and esophagogastroduodenoscopy with endoscopic ultrasonography, and, for selected patients, a laparoscopy. In addition, patients also had a complete blood cell count (including platelet count) and an SMA-12 with normal liver and renal function tests (serum bilirubin level <1.5 mg/dl, serum creatinine value of <1.5 mg/dl). All patients had a central venous catheter placement for outpatient continuous ambulatory infusional chemotherapy. Patients who underwent a laparoscopy also had placement of a feeding jejunostomy tube for external nutritional support during chemoradiation and in the postchemoradiation preoperative period.
5-Fluorouracil (300 mg/m2/d) was administered by continuous infusion for 5 days per week during weeks 1 through 5 of radiotherapy. Patients also received an infusion of paclitaxel (45 mg/m2) for 3 hours on the first day of each week during the same weeks. Thirty minutes before the treatment with paclitaxel, patients were premedicated with dexamethasone (20 mg), diphenhydramine (25 mg), and cimetidine (300 mg); all premedications were administered intravenously. Patient blood counts were monitored weekly.
External-beam radiation was delivered by 18-MeV (megavoltage) photons. The total dose administered varied between 45 Gy and 50.4 Gy, with a daily dose of 1.8 Gy administered on days 1 through 5 concomitantly with chemotherapy. The treatment fields depended on the tumor location and extension. The anteroposterior/posteroanterior field margins were 5 cm distal and proximal and 2 cm lateral to the tumor. Tumors located at the midesophagus were treated with anteroposterior/posteroanterior fields at 45 Gy. Tumors located at the lower segment involving the gastroesophageal junction were initially treated with anteroposterior/posteroanterior fields at 36 Gy and then continually treated off cord with lateral posterior oblique and right posterior oblique techniques at 45 Gy or 50.4 Gy, depending on the extension of the tumor. Tumors located only at the gastroesophageal junction were treated by a three-dimensional conformal technique to spare vital organs such as the heart, lungs, and spinal cord, and to minimize the radiation dose to the small bowel and liver. The treatment modality is illustrated in Figure 1.
While undergoing treatment, patients were evaluated weekly by a radiation oncologist and biweekly by a medical oncologist. Five weeks after the completion of treatment, all patients were restaged based on an esophagogastroduodenoscopy with biopsy, computed tomography, endoscopic ultrasonography, and blood counts. Then, all patients who were medically operable and considered to have resectable cancer were offered the option of surgery. Patients were then observed regularly as per National Cancer Comprehensive Network guidelines. 19
Clinical complete response is defined as complete disappearance of measurable tumor by computed tomography and esophagogastroduodenoscopy. Pathologic complete response is defined as no evidence of tumor in the resected specimen. Pathologic partial response is defined as less than 10% necrosis of tumor in resected specimen.
From August 1998 to February 1999, 10 patients with stage II–IV esophageal and/or gastroesophageal junction carcinomas were entered in the study. The median age was 61 years (range, 48–71 years). Nine patients were men and one was a woman. Karnofsky scores at the initiation of treatment ranged from 70 to 90. Two patients had squamous cell carcinoma, seven had adenocarcinoma, and one had a mixed histology. The patients’ characteristics are summarized in Table 2.
After therapy, the patients were reevaluated. Three were found to have metastatic disease: one with liver metastasis, another with brain and right adrenal metastases, and the third with metastasis to the supraclavicular lymph nodes. One patient had stable disease and remained surgically unresectable. One patient had no evidence of cancer according to esophagogastroduodenoscopy and computed tomography but refused surgery. Five patients underwent surgery. Of those, one patient had a pathologically complete response, from a T3N0M0 classification to pT0N0M0 One patient had the initial clinical diagnosis of T3N1M0 confirmed. Another patient with a T3N0M1 (diaphragmatic implant by 2 separate laparoscopy) was restaged pT3N0M0. Two other patients had more than 90% necrosis in the resected specimens after surgery.
Overall, the toxicity reported in the study was mild and consisted mostly of nonhematologic grades I and II events. Leukopenia and thrombocytopenia were not observed. Only one patient who experienced grade II nausea and vomiting had a delay of therapy. The patients’ performance statuses were well preserved during treatment, with an average decrease in Karnofsky score of only 10% points. Weight was well maintained; weight loss was less than 5% in 7 patients and less than 15% in 3 patients. Only two patients had grade II radiation dermatitis consisting of bright erythema. No grade III or IV skin toxicities were observed. Dysphagia was a common complaint at the time of presentation, because of the nature of the tumors. During treatment, three patients had grade II and six had grade I dysphagia. No patient was hospitalized for toxicity management, and there were no treatment-related deaths. The toxicities, according to Radiation Therapy Oncology Group criteria, are summarized in Table 3.
Paclitaxel was chosen for this study because it is known to synchronize cells in the G2/M phase of the cell cycle, which is the most radiosensitive phase. Thishler et al., 20 Choy et al., 21 and Steren et al. 22 demonstrated that in various human cancer cell lines, paclitaxel arrested cells in the G2/M phase of the cell cycle. Sinclair 23 has shown that the G2/M phase is the most radiosensitive phase of the cell cycle. These results led to the use of paclitaxel as a radioenhancer. Herskovic et al., 6 Al Sarraf et al., 7 and others 10–18 have shown that chemoradiation is superior to radiation alone in the treatment of esophageal cancers. However, severe side effects have been associated with chemoradiation. The challenge is to develop effective but less toxic chemoradiotherapy regimens.
In our pilot study, the toxicities observed were mild esophagitis, nausea, vomiting, and abdominal pain. No patient was hospitalized for toxicity, and the treatment was effectively administered in the outpatient setting. All patients remained fully active while receiving therapy, and their performance statuses were maintained throughout the treatment period.
The pathologic responses observed suggest that this regimen could be as effective as any previously described. The number of patients studied in our pilot was small; however, these patients were supervised by the same physicians, who reviewed any toxic side effects in detail each week. We believe this is a unique aspect of our data collection.
In conclusion, continuous infusion of 5-fluorouracil with weekly paclitaxel, given concurrently with external-beam radiation, is well tolerated. The surgical and pathology reports of the patients who underwent surgery after the completion of treatment were encouraging. We have already started a preoperative study to investigate the response to this regimen of patients with gastric cancer referred to The University of Texas M.D. Anderson Cancer Center.
Acknowledgment: We thank Adam Frome, M.P.H. and Reeni John, B.S. for their assistance with the manuscript.
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