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© 2000 American Society for Clinical Oncology Does Paclitaxel Improve the Chemoradiotherapy of Locoregionally Advanced Esophageal Cancer? A Nonrandomized Comparison With Fluorouracil-Based TherapyFrom the Departments of Hematology and Medical Oncology, Thoracic and Cardiovascular Surgery, Biostatistics and Epidemiology, Radiation Oncology, and Gastroenterology, The Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to David J. Adelstein, MD, Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, Desk T40, 9500 Euclid Ave, Cleveland, OH 44195; email adelstd{at}ccf.org
PURPOSE: A phase II trial of accelerated fractionation radiation with concurrent cisplatin and paclitaxel chemotherapy was performed to investigate the role of the paclitaxel, when substituted for fluorouracil (5-FU), in the chemoradiotherapy of esophageal cancer. PATIENTS AND METHODS: Patients with an esophageal ultrasound stage of T3 or N1 or M1 (nodal) esophageal cancer were treated with two courses of a cisplatin infusion (20 mg/m2/d for 4 days) and paclitaxel (175 mg/m2 over 24 hours) concurrent with a split course of accelerated fractionation radiation (1.5 Gy bid to a total dose of 45 Gy). Surgical resection was performed 4 to 6 weeks later followed by a single identical postoperative course of chemoradiotherapy (24 Gy) in patients with significant residual tumor at surgery. Toxicity and results of this treatment were retrospectively compared with our previous 5-FU and cisplatin chemoradiotherapy experience. RESULTS: Between September 1995 and July 1997, 40 patients were entered onto this study. Although dysphagia proved worse in our 5-FU–treated patients, profound leukopenia and a need for unplanned hospitalization were significantly more common in the paclitaxel group. Thirty-seven patients (93%) proved resectable for cure. The 3-year projected overall survival is 30%, locoregional control is 81%, and distant metastatic disease control is 44%. When compared with a similarly staged cohort of 5-FU–treated patients, there was no advantage for any survival function studied. CONCLUSION: This paclitaxel-based treatment regimen for locoregionally advanced esophageal cancer produced increased toxicity with no improvement in results when compared with our previous 5-FU experience. Paclitaxel-based treatments must be carefully and prospectively studied before their incorporation into the standard management of esophageal cancer.
THE USE OF chemotherapy in conjunction with definitive radiation and/or surgery for esophageal cancer has been under study for more than 20 years.1,2 Although preoperative induction chemotherapeutic approaches have produced encouraging response rates, randomized trials compared with surgical resection alone have failed to demonstrate any survival benefit.3-7 Concurrent chemotherapy and radiation schedules, however, have proven superior to radiation therapy alone in several randomized trials8,9 and, when used as a preoperative induction, seem superior to primary surgery alone.10,11 Whether definitive chemoradiotherapy is equivalent or superior to surgery-based treatments, as suggested by some, is unknown.12 The challenge for oncologists has been how best to integrate concurrent chemoradiotherapy into definitive management and to identify which chemotherapeutic agents and doses and what radiation therapy schedules and timing are best. Between August 1991 and August 1995 at the Cleveland Clinic Foundation, a phase II trial of aggressive concurrent chemoradiotherapy was completed in 72 assessable patients with both esophageal adenocarcinoma and squamous cell carcinoma. Fluorouracil (5-FU) and cisplatin were administered concurrently with a split course of accelerated fractionation radiation to a total preoperative dose of 45 Gy.13 Patients underwent careful esophageal ultrasound-based staging both before treatment and after induction. Ninety percent of the patients entered onto this trial proved to have resectable tumors. An overall pathologic complete response rate of 27%, a 3-year Kaplan-Meier overall survival projection of 38%, and a median survival of 18 months were reported in 1998.14 Of particular import in this study was the recognition that no patient completing chemoradiotherapy and surgery experienced a locoregional relapse. As in other similar trials, patients who had achieved a pathologic complete response at the time of surgery had a significantly greater likelihood of survival than patients with less than a complete response. Long-term disease-free survival also proved possible, however, in those patients with residual disease at the time of surgery, suggesting a benefit from surgical resection. Furthermore, aggressive clinical, radiologic, and even ultrasound-based restaging after induction chemoradiotherapy could not accurately identify those patients who had achieved a pathologic complete response at surgical resection.15,16 Thus, the continued importance of surgery was apparent for both responders and nonresponders. Recent work has suggested significant activity for single-agent paclitaxel in the treatment of advanced, unresectable esophageal cancer.17 Response rates of up to 100% have been reported for paclitaxel-based combination chemotherapy regimens.18,19 Paclitaxel, like 5-FU, also seems to be a radiation sensitizer.20-22 In vitro, this drug acts as a mitotic inhibitor and seems to block cells in the more radiosensitive G2 and M phases of the cell cycle. As such, it seemed an ideal chemotherapeutic agent to incorporate into multimodality chemoradiotherapeutic regimens for this disease. We chose to substitute paclitaxel for 5-FU in our previously reported treatment schema. A conventional dose of 175 mg/m2 given over 24 hours every 3 weeks was chosen. Information regarding the tolerance of this paclitaxel dose, with cisplatin and radiation, was not available but constituted one of the objectives of this investigation. Preliminary results from this phase II trial of accelerated fractionation radiation therapy and concurrent cisplatin/paclitaxel chemotherapy followed by surgical resection are presented. Retrospectively, these results are compared, for both toxicity and treatment success, with our previous experience using 5-FU and cisplatin.
Eligibility for this clinical trial required a histologically confirmed diagnosis of esophageal carcinoma (either squamous cell carcinoma, adenocarcinoma, or mixed adenosquamous carcinoma) and locoregionally confined disease. Medical suitability for esophageal resection and an Eastern Cooperative Oncology Group performance status of 0 to 2 were also required. Patients could not be entered onto the study if they had received any previous treatment for their malignancy or if there was any evidence of significant preexisting renal, hepatic, or hematologic dysfunction. Adequate pulmonary function to tolerate an esophagectomy (ie, a forced expiratory volume in 1 second of greater than 50% predicted) was necessary. Patients with tumors anywhere in the esophagus were eligible, including those with gastroesophageal junction cancers. Extension of the malignancy into the stomach did not preclude enrollment. Before entry onto the study, all patients were seen by a thoracic surgeon, gastroenterologist, radiation therapist, and medical oncologist. It should be noted that all patients on these two trials were treated by a single medical oncologist (D.J.A.), and 92% of these patients were treated by a single thoracic surgeon (T.W.R.). This study was approved and reviewed yearly by the Cleveland Clinic Foundation Institutional Review Board, and written informed consent was obtained from all patients before beginning treatment. A full pretreatment staging evaluation was performed for all patients, including a medical history, physical examination, complete blood cell count, urinalysis, and serum chemistry tests, including blood urea nitrogen, creatinine, calcium, phosphorus, alkaline phosphatase, aspartate aminotransferase, lactate dehydrogenase, albumin, total protein, bilirubin, and uric acid. Baseline barium esophagram, chest radiograph, computed tomography scans of the chest and abdomen, and pulmonary function studies were also obtained. Bronchoscopy was performed only when indicated by symptomatology or by the extent or location of the primary lesion. At the time of diagnosis, all patients underwent upper endoscopy with an esophageal biopsy and esophageal ultrasonography. Based on the results of the ultrasound, patients were assigned a preoperative clinical stage according to the 1992 American Joint Committee on Cancer tumor-node-metastasis staging system.23 Patients with hematogenous metastases were ineligible for this trial, but patients with distal esophageal tumors and M1 disease because of celiac lymph node involvement were eligible. These are patients now classified as having M1a disease by the 1997 American Joint Committee on Cancer criteria.24 Only those patients with T3-4 or N1 or M1 (nodal) disease were eligible for this study. Except for this last criterion, these entry eligibility requirements are identical to those previously used in our 5-FU/cisplatin study. In that trial, patients with earlier, ultrasound-based disease stages were also eligible, and five patients with T1-2N0 tumors were entered. Five other patients who could not be staged were also treated on that protocol. In our retrospective comparison of these two clinical trials, these five patients with T1-2N0 disease and the five patients who couldn’t be staged are excluded from analysis of the results of the 5-FU–treated group. All patients are included in toxicity comparisons. These comparisons, however, are made between two consecutive treatment groups, and the data are retrospective and not randomized. Appropriate limitations on interpretation of these comparisons are necessary. Preoperative induction treatment consisted of twice daily radiation therapy and concurrent chemotherapy (Fig 1). A 4-day continuous intravenous infusion of cisplatin (20 mg/m2/d) and a 24-hour infusion of paclitaxel (175 mg/m2) given on day 1 were administered concurrently with external-beam radiation therapy, 1.5 Gy twice daily to a total dose of 24 Gy. Radiation also began on day 1 and required 10 elapsed (8 treatment) days. Three weeks after beginning this treatment, a second course of chemotherapy was given along with another course of accelerated fractionation radiation, to a total preoperative radiation dose of 45 Gy given over 4.5 weeks. No other radiation therapy treatment breaks were permitted. Chemotherapy administration required hospitalization for appropriate hydration and aggressive antiemetic therapy. Chemotherapy courses were administered without dose modification irrespective of the nadir blood counts or the blood counts at the time treatment was due. This treatment schedule is identical to that previously described for our 5-FU–based regimen except that the paclitaxel was substituted for a 4-day continuous infusion of 5-FU given at a dose of 1,000 mg/m2/d on days 1 to 4.
Megavoltage radiation therapy was generated by either a 10-MV or 18-MV linear accelerator. The treatment volume for the preoperative therapy included the area of the primary tumor and potential sites of lymphatic involvement. For treatment of the cervical esophagus, the supraclavicular, cervical, and mediastinal lymph nodes to the carina were included. Fields for midthoracic tumors included the supraclavicular, mediastinal, and celiac lymph nodes. The distal esophageal lesions included a proximal 5- to 10-cm margin of normal esophagus, adjacent mediastinal lymph nodes, half of the left hemidiaphragm, and the celiac lymph node chain. The prescribed dose to these areas was delivered with  5% variation. The dosimetry was generated at the central axis of the field, the center of the target volume, and at planes 1.0 to 1.5 cm inside the superior and inferior margins of the treatment fields. Tissue inhomogeneity corrections were applied in planning. Patients were seen at least weekly during their therapy in an effort to monitor and treat side effects, particularly mucositis and myelosuppression. Hospitalization with antibiotic therapy was required for neutropenia if associated with fever. Hospitalization was also required if mucositis and dysphagia precluded an adequate oral intake. Approximately 3 weeks after completing induction treatment, all patients underwent full restaging. Surgical resection was planned for all patients and was scheduled 1 to 3 weeks after restaging. This restaging evaluation was performed in an attempt to both identify patients who had progressive disease that might preclude surgery and to clinically identify those patients who had achieved a pathologic complete response. Symptomatic, radiographic, endoscopic, or endosonographic normalization (ie, a clinical complete response) could be readily established if present and then compared with the pathologic response. Definition of a clinical partial response proved to be more difficult and of no value. These data are not reported. A near total esophagectomy was planned for all patients. Resection and reconstruction were generally accomplished using simultaneous left thoracoabdominal and left neck incisions. Alternatively, for upper and midthoracic tumors with possible airway or aortic arch involvement, a right thoracotomy was used for resection followed by a midline laparotomy and left neck incision for reconstruction. Transhiatal esophagectomy was not used because it does not allow for adequate lymphadenectomy. The intent of the surgery was to provide disease-free proximal, distal, and soft tissue margins of resection. These margins were sampled at surgery and confirmed to be tumor-free by frozen section analysis. If required for adequate soft tissue margins, a concomitant pharyngolaryngectomy was performed for cervical and upper thoracic malignancies. A continuous two-field lymphadenectomy (from the aortic arch to the celiac axis, with sampling of cervical lymph nodes) was achieved with the left thoracotomy and left neck incisions. When a right thoracotomy was used, the thoracic lymphadenectomy was extended to the apex of the right chest. A cervical lymphadenectomy was performed in patients requiring pharyngolaryngectomy. The organ of reconstruction was generally the stomach, and the anastomosis was constructed, whenever possible, high in the neck to place it outside of the radiation fields. For esophagogastric junction carcinomas with extensive gastric involvement requiring gastrectomy, the esophagojejunal anastomosis was constructed in the left chest above the inferior pulmonary vein but within the radiation fields. The colon was prepared for all patients but not required for reconstruction in any individual. Pathologic examination of the resected esophagus and associated lymph nodes allowed assignment of a pathologic tumor-node-metastasis stage. A pathologic response to chemoradiotherapy was then defined as the pathologic demonstration of any decrease in either the T or N classification with no reciprocal N or T increase when compared with the pretreatment clinical stage. Postoperative chemoradiotherapy was planned to begin for all patients between 4 and 8 weeks after surgery, unless the postoperative pathologic stage was T2N0 or less or unless clinical recovery was significantly delayed. Postoperative treatment included an additional course of the identical chemotherapy and 24 Gy of concurrent accelerated fractionation radiation therapy administered to the tumor bed. Unless there was a positive surgical margin, the esophageal anastomosis was not included in this field. The total planned preoperative and postoperative radiation dose was 69 Gy. The maximum cumulative spinal cord dose was 50 Gy. After the completion of all treatment, patients were evaluated every 3 months for evidence of disease recurrence. Radiographic and endoscopic procedures were repeated as clinically indicated. Disease progression was characterized as either locoregional or metastatic, and sites of disease recurrence were recorded.
Survival times were calculated from the date radiotherapy was initiated, and the results were analyzed as of May 31, 1999. Survival curves were constructed using the Kaplan-Meier method25 and compared using the log-rank test.26 Patient characteristics and responses were compared using the
Between September 1995 and July 1997, all patients seen at the Cleveland Clinic Foundation with T3-4 or N1 or M1 (lymph node) disease were offered participation in this study if other eligibility criteria were met. A total of 40 eligible patients with histologically verified esophageal carcinoma were enrolled. The clinical characteristics of this patient population included a median age of 60 years (range, 39 to 77 years). Race, sex, pathology, and tumor location are listed in Table 1 and are compared with the clinical characteristics of the 5-FU–treated patients. No significant differences were identified between these two cohorts. Twenty-one (84%) of the 25 paclitaxel-treated adenocarcinoma patients were white men, as were 42 (93%) of the 45 5-FU–treated adenocarcinoma patients. In the paclitaxel group, 19 (76%) of the 25 adenocarcinoma patients and one of the 12 squamous cell carcinoma patients had evidence of Barrett’s esophagus. Barrett’s esophagus was found in 27 (60%) of the 45 adenocarcinoma patients in the 5-FU group.
Pretreatment clinical staging, based predominantly on endoscopic ultrasonographic examination, is listed in Table 2. In the paclitaxel group, ultrasound was not possible in the two patients with proximal esophageal tumors. One of these patients could be entered onto this trial based on N1 disease in the neck.23 The second was found to have clinical evidence of disease extension into hypopharynx and was staged as T4NX. The two patients with M1 disease had clinical evidence of celiac nodal involvement. No statistically significant stage differences were identified when the two patient groups were compared. No patients had evidence of hematogenous tumor dissemination.
The toxicity from induction chemoradiotherapy in both treatment groups is listed in Table 3 and was significant. As is apparent, although the paclitaxel-based regimen produced less mucosal inflammation, it was associated with significantly greater neutropenia and febrile neutropenia. Unplanned hospitalization was required in 18 of the 72 patients given the 5-FU–based treatment and 19 of the 40 patients in the paclitaxel group (P = .02). These hospitalizations were required for neutropenic fever, inadequate oral intake, or both. There were no toxic deaths during induction in our paclitaxel patients and only one toxic death among the 5-FU patients, which was caused by an unexplained ascending peripheral polyneuropathy consistent with Guillain-Barré syndrome. Mucositis and dysphagia, although frequent and sometimes severe during induction therapy, were quite transient and did not result in significant weight loss. Enteral and/or parenteral nutritional support was only rarely required. Weight loss, however, was often dramatic after esophagogastrectomy, and jejunostomy feeding tubes were routinely used postoperatively.
Although surgery was planned for all 40 patients entered onto this trial, only 38 (95%) underwent surgery, and 37 (93%) proved resectable for cure. One patient deteriorated medically before surgery, one patient developed metastatic disease before surgery, and one patient was found to have hepatic metastases at the time of esophagectomy. Thirty-seven patients underwent esophagogastrectomy, and one patient underwent laryngopharyngoesophagectomy. Primary anastomosis was possible in all but one patient. There were six postoperative deaths; three caused by the development of adult respiratory distress syndrome, two resulting from catastrophic anastomotic leakage, and one from unanticipated cardiac deterioration. Other nonfatal postoperative complications included chyle leaks in three patients, a contained anastomotic leak in one patient, and a gastric ulcer in one patient. Postoperative recovery was significantly delayed in six other patients because of perioperative pneumonia (three patients), thromboembolic disease (one patient), herpes zoster (one patient), and coincident cardiac disease (one patient). The pathologic response is listed in Table 4. The overall pathologic complete and partial response rate was 60%, with a pathologic complete response achieved in 23% of patients. Significantly more patients with squamous cell carcinoma achieved a pathologic complete response than did those with adenocarcinoma (50% v 8%, respectively; P = .004). Among the 40 patients,18 (45%) experienced a major response, achieving a pathologic stage of T0-2N0 at the time of surgery.
The single postoperative treatment course was given to only 14 of the 40 patients on this trial. In three patients, progressive disease precluded continued chemoradiotherapy, and there were six postoperative deaths. Three patients did not receive postoperative treatment because of a delayed postoperative recovery, one patient refused additional chemoradiotherapy, and 13 pathologically staged T0-2N0 patients were not treated as per the dictates of the clinical protocol. The toxicity of the postoperative treatment course was quite similar to that experienced during induction. One patient died after postoperative chemoradiotherapy from an aspiration pneumonia, which occurred after hematologic recovery. The median follow-up for the patients who are still alive is 33 months (range, 27 to 38 months). The median follow-up for living patients in the 5-FU–treated group is 62 months (range, 46 to 87 months). Kaplan-Meier 3-year projected survivals are presented for the 40 patients in the paclitaxel-treated group and are compared with the actual 3-year survivals achieved by the 62 T3-4 or N1 or M1 patients treated with the 5-FU–based regimen. Thus, the survivals of two sequentially treated, comparably staged cohorts are contrasted in an effort to assess the benefit of substituting paclitaxel for 5-FU. No other treatment alteration was made. The 3-year overall survival is 36% for the 5-FU group and 30% for the paclitaxel group, with median survivals of 17 and 15 months, respectively (Fig 2). These differences are not significant. Similarly, the 41% likelihood of a 3-year recurrence-free interval and the 44% disease-specific survival for the 5-FU group are not significantly different than the 36% chance of a recurrence-free interval and 41% disease-specific survival in the paclitaxel group. Figure 3 portrays the 3-year locoregional control rates of 93% and 81% for the 5-FU and paclitaxel groups, respectively (P = .11), and the distant metastatic disease control rates of 55% and 44% for the 5-FU and paclitaxel patients, respectively (P = .32). No statistically significant survival differences could be identified between patients with adenocarcinoma and patients with squamous cell carcinoma, whether treated with the 5-FU or the paclitaxel regimen.
For patients on either treatment regimen, downstaging to a pathologic stage of T0-2N0 at surgery predicted for a better survival at 3 years than for those patients with a lesser (or no) response; 50% versus 14%, respectively, for the paclitaxel patients (P = .05), and 54% versus 28%, respectively, for the 5-FU patients (P < .01). Importantly, 31% of the paclitaxel patients and 32% of the 5-FU patients who had residual viable tumor at the time of surgery were free from disease recurrence at 3 years, suggesting a clear benefit from surgical resection. At the present time, 11 (28%) of 40 paclitaxel-treated patients are alive and disease-free. Sixteen (40%) of the 40 patients have died as a result of their disease, and seven (18%) have died from treatment-related toxicities. Six additional patients died of unrelated comorbid causes while disease-free. Four patients experienced locoregional failure, but all had simultaneous failure with distant metastases. Disease progression was the cause of death in 12 of the 18 adenocarcinoma patients who died but only two of the eight squamous cell carcinoma patients who died (P = .05). Unrelated causes of death or death caused by treatment toxicity were more likely in the squamous cell cancer patients.
The overall poor prognosis of patients with locoregionally advanced but nonmetastatic esophageal cancer is well recognized.27,28 It is for these patients that multimodality treatment approaches, including chemotherapy, have been tested and for whom some degree of recent success has been achieved.1,2 Paclitaxel represents a promising new agent in the chemotherapeutic armamentarium, with significant antineoplastic activity against many different tumors, including gynecologic, lung, breast, and head and neck cancers.22 Activity in esophageal cancer has also been described.17-19 Coupled with the drug’s radiosensitizing potential, this suggests that paclitaxel would be an ideal agent to consider in concurrent chemoradiotherapy regimens for this disease. Our results, using a cisplatin/paclitaxel regimen in conjunction with this well-tested radiation therapy schedule, have certainly demonstrated the feasibility of the treatment combination. Toxicity, although tolerable, is quite significant, with the almost universal development of grade 3 neutropenia and a resultant need for unplanned hospitalization in almost half of the patients. This toxicity is clearly worse than with our previous, more conventional 5-FU and cisplatin treatment regimen. Such toxicity could be justified, however, if an improved response rate or a survival benefit could be achieved with this treatment regimen. Unfortunately, this proved not to be the case. Indeed, our overall pathologic complete response rate at surgery, a recognized predictor of long-term survival, was only 8% in our adenocarcinoma patients. This is a disappointing result when compared with the 22% complete response rate we observed in adenocarcinoma patients using the 5-FU–based regimen. When we confine our comparison to a similarly staged cohort of T3 or N1 or M1 (nodal) patients treated with the 5-FU–based regimen, there was no suggestion of a superior outcome from the substitution of paclitaxel. Overall survival, relapse-free interval, disease-specific survival, distant metastatic disease control, and locoregional control were equivalent between the two treatment regimens. No differences could be identified by pathologic stage or histology. Clearly, the conclusions that can be drawn from this comparison are limited. Even though the two cohorts are well matched by pretreatment clinical stage and histology, this is a retrospective, nonrandomized analysis. Recently, promising results from several phase II paclitaxel-based chemoradiotherapy trials in esophageal cancer have been reported.29-31 The apparent lack of benefit and increase in toxicity that we observed emphasizes the importance of a careful prospective investigation of these regimens before their incorporation into standard management. Careful clinical staging before treatment will also be critical for an accurate interpretation of these trials. These results also confirm our previous observation that surgical resection is an important component of multimodality treatment regimens for this disease.13 A 31% likelihood of a 3-year recurrence-free interval is projected for those patients found to have residual disease at the time of surgery, suggesting that some benefit is achieved from resection of residual tumor. Unfortunately, our surgical morbidity and mortality are significant after this treatment regimen, irrespective of whether the chemotherapy is 5-FU– or paclitaxel-based. We think this more likely represents the effects of the aggressive, high-dose accelerated fractionation preoperative radiation therapy rather than a reflection of one chemotherapy regimen or another. Clearly, any further improvement in this treatment approach must address this issue. This study demonstrates the feasibility of a paclitaxel-based concurrent chemoradiotherapy and surgery program in esophageal cancer. Toxicity was manageable but worse than our previous 5-FU–based experience. Results with the paclitaxel regimen were also no better than with 5-FU and do not support the substitution of paclitaxel, in this dose or schedule, for 5-FU. At the present time, we have abandoned the use of paclitaxel in our esophageal cancer chemoradiotherapy programs and will continue to further investigate optimal combinations of cisplatin, 5-FU, and radiation.
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Kelsen DP, Ginsberg R, Pajak TF, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979-1984, 1998 8. Herskovic A, Martz K, Al-Sarraf M, et al: Combined chemotherapy and radiotherapy compared to radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326:1593-1598, 1992[Abstract] 9. Smith TJ, Ryan LM, Douglass HO Jr, et al: Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: A study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys 42:269-276, 1998[Medline]
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Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462-467, 1996 11. Urba S, Orringer M, Turrisi A, et al: A randomized trial comparing surgery (S) to preoperative concomitant chemoradiation plus surgery in patients (pts) with resectable esophageal cancer (CA): Updated analysis. Proc Am Soc Clin Oncol 16:277a, 1997 (abstr 983) 12. Algan O, Coia LR, Keller SM, et al: Management of adenocarcinoma of the esophagus with chemoradiation alone or chemoradiation followed by esophagectomy: Results of sequential nonrandomized phase II studies. Int J Radiat Oncol Biol Phys 32:753-761, 1995[Medline] 13. Adelstein DJ, Rice TW, Becker M, et al: Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma. Cancer 80:1011-1020, 1997[Medline] 14. Adelstein DJ, Rice TW, Rybicki LA, et al: Concurrent chemoradiotherapy and surgery for esophageal cancer: Updated results. Can J Gastroenterol 12:15B, 1998 (suppl B, abstr 26) 15. Adelstein DJ, Rice TW, Rybicki LA, et al: Induction therapy for esophageal cancer: Can a pathologic complete response be clinically predicted? Can J Gastroenterol 12:16B, 1998 (suppl B, abstr 28) 16. Zuccaro G Jr, Rice TW, Goldblum J, et al: Endoscopic ultrasound cannot determine suitability for esophagectomy after aggressive chemoradiotherapy for esophageal cancer. Am J Gastroenterol 94:906-912, 1999[Medline]
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Ajani JA, Ilson DH, Daugherty K, et al: Activity of Taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst 86:1086-1091, 1994 18. Ilson DH, Ajani J, Bhalla K, et al: Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients with advanced carcinoma of the esophagus. J Clin Oncol 16:1826-1834, 1998[Abstract] 19. Lokich JJ, Sonneborn H, Anderson NR, et al: Combined paclitaxel, cisplatin and etoposide for patients with previously untreated esophageal and gastroesophageal carcinomas. Cancer 85:2347-2351, 1999[Medline] 20. Geard CR, Jones JM, Schiff PB: Taxol and radiation. Monogr Natl Cancer Inst 15:89-94, 1993 21. Choy H, Rodriguez FF, Koester S, et al: Investigation of Taxol as a potential radiation sensitizer. Cancer 71:3774-3778, 1993[Medline]
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Iizuka T, Isona K, Kakegawa T, et al: Parameters linked to ten-year survival in Japan of resected esophageal carcinoma. Chest 96:1005-1011, 1989 28. Rice TW, Adelstein DJ, Goldblum JR, et al: The therapeutic and prognostic implications of stage in patients with esophageal carcinoma. Can J Gastroenterol 12:15B, 1998 (suppl B, abstr 23) 29. Lynch TJ, Choi N, Wright C, et al: A phase I/II trial of preoperative Taxol (T), cisplatin (P), 5-FU (F) and concurrent boost radiation (XRT) in esophageal cancer. Proc Am Soc Clin Oncol 16:261a, 1997 (abstr 928) 30. Meluch AA, Hainsworth JD, Gray JR, et al: Preoperative combined modality therapy with paclitaxel, carboplatin, prolonged infusion 5-fluorouracil, and radiation therapy in localized esophageal cancer: Preliminary results of a Minnie Pearl Cancer Research Network phase II trial. Cancer J Sci Am 5:84-91, 1999[Medline] 31. Safran H, Akerman P, Cioffi W, et al: Paclitaxel and concurrent radiation therapy for locally advanced adenocarcinomas of the pancreas, stomach, and gastroesophageal junction. Semin Radiat Oncol 9:53-57, 1999 (suppl 1)[Medline] Submitted October 20, 1999; accepted January 26, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, Fisher’s exact test, or the Student’s t test, where appropriate. All statistical tests were two-sided, and P < .05 was used to indicate statistical significance. Recurrence-free interval times of patients who died of unrelated causes were considered censored at the time of patient death. Disease-specific survival times included death caused by cancer and any treatment-related toxicity but not caused by unrelated causes. Overall survival included death as a result of any cause. No patient was lost to follow-up. 
