Abstract
Purpose
To evaluate neoadjuvant therapy with weekly paclitaxel/carboplatin plus 5-fluorouracil (5-FU) with conformal radiotherapy in a phase II trial in resectable esophageal carcinoma.
Methods
Twenty-four patients with T2-4N0-1M0-1a esophageal carcinoma were treated with paclitaxel 45 mg/m2 intravenously over 1 hour and carboplatin at an area under the concentration-time curve (AUC) of 2 intravenously over 30 minutes on days 1, 8, 15, 22, and 29. 5-Fluorouracil 225 mg/m2 was delivered as a continuous infusion on days 1–33. Concurrent conformal radiation was delivered to a dose of 45 Gy. Responders underwent surgical resection within 8 weeks of completing chemoradiotherapy. Kaplan-Meier survival analysis and log-rank test of survival dependent on pathologic response were performed.
Results
Progressive disease was discovered at surgery in three patients. Of the remaining 21 patients, pathologic complete response (pCR) was demonstrated in 12 (pCR rate of 57%) and partial response (PR) occurred in 9, including 4 with near complete response. Median follow-up in all patients was 23 months. Overall survival among all 24 patients was 48% at 3 years, with a median of 31 months. Disease-free survival was 57% at 3 years, with a median of 38 months. Differences in survival time based on pCR vs. PR showed a trend favoring pCR for disease-free survival (P = .12) but not overall survival (P > .20). Grade 3/4 toxicities included esophagitis in 33% of patients, hypotension in 29%, stomatitis in 25%, neutropenia in 13%, and anemia in 8%.
Conclusion
This study demonstrates the activity of neoadjuvant paclitaxel, carboplatin, 5-FU, and conformal radiotherapy in the treatment of localized esophageal cancer. Evaluation with a larger number of patients and longer follow-up will be required to definitively assess the long-term efficacy of this regimen.
Despite advances in surgical techniques, the availability of novel systemic agents, and recent improvements in radiation delivery, primary cancer of the esophagus remains a lethal disease for most patients. American Cancer Society estimates for 2006 included 14,550 new cases of esophageal cancer, with 13,770 esophageal cancer deaths expected.1 Treatment options include surgery alone, chemoradiotherapy, and neoadjuvant chemoradiotherapy. Surgical resection without adjuvant therapy has been associated with 5-year survival rates of 5% to 20% and median survival of approximately 1 to 2 years.2–6 In the Radiation Therapy Oncology Group (RTOG) 85-01 trial, concurrent chemoradiotherapy was shown to be superior to primary radiotherapy in terms of local control and overall survival (median survival, 14 vs. 9 months; 5-year survival, 27% vs. 0%; 8-year survival, 22% vs. 0%).7,8
Neoadjuvant chemoradiotherapy has gained popularity as a treatment option, especially in North America. Several phase II trials have suggested improved local control and survival rates with acceptable toxicity using this approach.9–12 However, randomized trials comparing neoadjuvant chemoradiotherapy to surgery alone have yielded conflicting results, with most trials failing to demonstrate a significant difference in overall survival.13–19 These trials have been criticized for having inadequate statistical power, wide variation in chemoradiotherapy protocols, and short follow-up durations. Three meta-analyses have shown an improvement in survival with preoperative treatment;20–22 however, the benefit of trimodality therapy remains questionable, because the statistical significance of the survival benefit in these studies is lost if one trial13 is excluded from the analyses and because surgical morbidity and mortality is increased with this approach.
Since most neoadjuvant chemoradiotherapy trials have used 5-fluorouracil (5-FU) and cisplatin, investigators have begun to examine the use of novel chemotherapy combinations in an effort to improve durable response rates after surgical resection. This approach is attractive because pathologic complete response (pCR) rates have been shown to correlate with local control and overall survival.23–27
Based on the documented radiosensitizing effects of the taxanes,28–31 investigators at the Minnie Pearl Cancer Center conducted a phase II trial of neoadjuvant chemoradiotherapy including paclitaxel and carboplatin (days 1 and 22) with continuous infusion 5-FU in patients with resectable disease.32,33 Results were encouraging, with 1- and 2-year actuarial survival rates of 71% and 47%, respectively, and a pCR rate of 38% being reported. Grade 3/4 toxicity was significant, however, including leukopenia in 73% of patients and esophagitis in 43%. The toxicity associated with this combination might be reduced with a weekly schedule for paclitaxel and carboplatin. In patients with non–small-cell lung cancer, weekly concurrent paclitaxel and carboplatin with thoracic radiation has resulted in acceptable toxicity and response rates over 70%.34,35 Investigators at our institution thus initiated a prospective phase II protocol employing a neoadjuvant regimen of weekly paclitaxel and carboplatin with infusional 5-FU and concurrent conformal radiotherapy in patients with resectable esophageal cancer.
PATIENTS AND METHODS
Twenty-four patients with biopsy-proven primary nonrecurrent adenocarcinoma or squamous cell carcinoma of the esophagus were prospectively enrolled in this study between July 2001 and June 2006. Disease had to be confined entirely to the esophagus and periesophageal soft tissue. The tumor could not appear to be arising from the stomach in the opinion of the endoscopist upon direct visualization.
Eligible patients included persons with clinical stage T2-4N0-1M0-1a disease with no evidence of metastasis or tracheoesophageal fistula. Patients with enlarged (≥ 1.5 cm) retroperitoneal or celiac lymph nodes with a primary lesion in the distal third of the esophagus were eligible; two such patients are included in the analysis. Patients had to be 18 years of age or older, have a maximum Eastern Cooperative Oncology Group performance status of 1, and be identified as a surgical candidate. Patients were required to have pretreatment white blood cell counts ≥ 3.0 × 106/L, platelets ≥ 100 × 109/L, hemoglobin ≥ 10.0 g/dL, and creatinine clearance ≥ 50 mL/min. All patients determined to be eligible for this study were evaluated by a medical oncologist, radiation oncologist, gastroenterologist, and surgical oncologist before protocol entry.
Exclusion criteria included any history of another malignancy within the past 5 years, with the exception of nonmelanoma skin cancer and in situ cervical carcinoma. Patients who had received prior thoracic radiotherapy or chemotherapy were ineligible. Witnessed informed consent was obtained for all patients using a studyspecific informed consent form approved by the local Institutional Review Board.
Pretreatment staging evaluation with contrast-enhanced computed tomography (CT) of the chest and abdomen was required. Irregular liver findings, other than simple cysts, required evaluation with magnetic resonance imaging (MRI) and/or biopsy to exclude metastatic disease before study entry. Esophageal ultrasound (EUS) with direct visualization and measurement of the tumor was also performed before study entry. Chest x-ray, pulmonary function tests (spirometry and diffusing capacity), and an electrocardiogram were performed as part of the preoperative evaluation. Bronchoscopy was performed if the primary lesion was classified as T3 or T4 or if it was located less than 20 cm from the incisors. Positron emission tomography (PET) became available in 2002–2003, and its use was optional. Repeat CT and EUS were performed 4 to 6 weeks after chemoradiotherapy as part of presurgical evaluation and at 4-month intervals for the first year and 6-month intervals thereafter.
External beam radiation was initiated with concurrent chemotherapy on the first day of treatment. Three-dimensional conformal technique (with lung heterogeneity corrections) was used in all patients in order to limit the dose to surrounding organs with the following constraints: no portion of the spinal cord received a dose of ≥ 45 Gy, ≤ 50% of the stomach received 45 Gy, ≤ 50% of the aggregate kidney volume received ≤ 18 Gy, the aggregate lung dose was limited to ≤ 20 Gy to 37% of lung volume, and the heart dose was limited to 30 Gy to the whole heart and 40 Gy to ≤ 50% of the heart.
A typical plan used anterior and posterior fields initially, followed by a conformal three-field boost (anterior and two posterior oblique fields). Longitudinal margins extended 5 cm beyond the primary lesion as defined on diagnostic CT or EUS (whichever was larger). Radial margins extended 2 cm beyond the primary lesion or regional adenopathy (≥ 1 cm), if indicated. The inferior border could be less than 5 cm (but ≥ 2 cm) from the primary lesion for tumors located at the gastroesophageal junction if necessary to conform to normal tissue dose limits (described above). These margins included the planning target volume and margin for setup error. Paraclavicular and celiac lymph node regions were included for primary lesions located proximal to the carina and in the distal third of the esophagus, respectively. All patients underwent CT-based simulation with esophogram for radiation treatment planning.
Systemic treatment consisted of paclitaxel, carboplatin, and infusional 5-FU given concurrently with radiation as described above. Paclitaxel and carboplatin were administered on days 1, 8, 15, 22, and 29 with paclitaxel given at a dose of 45 mg/m2 over 1 hour and the carboplatin dose adjusted for renal function to achieve a calculated area under the concentration-time curve (AUC) of 2.0 using the Calvert formula.36 The carboplatin dose was recalculated if serum creatinine changed by ≥ 25%. Infusional 5-FU was administered through a central line or indwelling central venous access catheter at a dose of 225 mg/m2/day during days 1–33.
Patients were evaluated with CT and EUS 4 to 6 weeks after the completion of chemoradiotherapy. Surgery was performed within 8 weeks of the completion of neoadjuvant treatment in all patients with documented disease response. A transhiatal approach was used for tumors distal to the carina; a transthoracic resection was performed in more proximal lesions. The resected esophagus was replaced by the stomach with a thoracic esophagogastric anastomosis. Periesophageal, left gastric, and celiac nodal sampling were also performed, and all patients had an R0 resection. The resected specimen was evaluated by the surgical pathology department, using a standard protocol, with respect to presence of residual disease, depth of invasion, lymph node involvement, and margin status. A partial response (PR) was defined as at least a 50% reduction in the maximal dimension of the tumor and a pCR was defined as no evidence of vital tumor cells, with complete tumor regression in the resected specimen.
Patient survival and disease control rates were determined by the Kaplan-Meier method.37 Survival differences based on pathologic response were determined by the log-rank test.38 Survival time was calculated as the duration from initiation of chemoradiotherapy to time of death or last follow-up. Disease-free interval was calculated from the date of surgery to the time of diagnosis of recurrence. The survival analysis was performed on an intent-to-treat basis and included any patients found to have progressive disease (PD) at surgery; data from one patient, who died of a myocardial infarction 7 months after chemoradiotherapy, was censored at the time of death. All calculations were performed using SPSS (version 11.0) software.
RESULTS
Patient Characteristics
Patient characteristics are shown in Table 1. Twenty-four patients were enrolled, consisting of 21 men and 3 women with a median age of 61 years. Most patients had a performance status of 0, adenocarcinoma, disease located in the distal third of the esophagus, and stage T3 disease. Nine patients (38%) had no evidence of regional nodal involvement at diagnosis and two patients (8%) had celiac node involvement. Twenty patients (83%) had a pretreatment weight loss of less than 10%.
Table 1.
Patient characteristics. (N = 24)
| Characteristic | |
|---|---|
| Median age (range), years | 61 (33–74) |
| Men, n (%) | 21 (88) |
| Women, n (%) | 3 (13) |
| ECOG performance status, n (%) | |
| 0 | 16 (67) |
| 1 | 8 (33) |
| Histology, n (%) | |
| Adenocarcinoma | 20 (83) |
| Squamous cell carcinoma | 4 (17) |
| EUS stage, n (%) | |
| T2N0 | 2 (8) |
| T3N0 | 5 (21) |
| T2N1 | 5 (21) |
| T3N1 | 9 (38) |
| T4N0 | 1 (4) |
| T3N0M1a | 1 (4) |
| T3N1M1a | 1 (4) |
| Location, n (%) | |
| Thoracic esophagus | 3 (13) |
| Distal esophagus/GE junction | 21 (88) |
Abbreviations: ECOG = Eastern Cooperative Oncology Group; EUS = esophageal ultrasound; GE = gastroesophageal.
Treatment Results
Median follow-up for the first 24 patients enrolled in this ongoing study was 23 months, with a range of 6 to 60 months. All patients completed neoadjuvant treatment and underwent surgical resection. Progressive disease was discovered at surgery in three patients (13%), manifesting as peritoneal spread in two patients and liver metastases in the other. All other patients had R0 resection with no evidence of viable tumor within 2 mm of the surgical margins.
There was no pathologic evidence of residual disease in the resected esophagus or regional lymph nodes in 12 of the 21 patients without progressive disease, for a pCR rate of 57%. An additional four patients had only “scattered isolated tumor cells” in the resection specimen. Nine patients had a reduction in the maximal tumor size of ≥ 50% for a PR rate of 43%. The pathologic stages of these specimens were as follows: pT2N0M0 in two, pT3N0M0 in two, pT2N1M0 in one, and pT3N1M0 in four. Three of the four patients without nodal disease at resection and one of the five patients with nodal disease at resection had only scattered tumor cells in the resected esophagus. One patient died of a myocardial infarction 7 months after surgical resection. He had a pCR at the time of surgery and was censored at the time of death. He did not have significant (≥ grade 3) treatment-related toxicity; therefore his death was not considered related to treatment.
All 24 patients were included in the survival analysis. Three-year overall survival was 48% and median overall survival was 31 months (Figure 1). Disease-free survival at 3 years was 57%, with a median of 38 months (Figure 2). Analysis according to pCR vs. PR showed that median overall survival and median disease-free survival had not been reached for patients with a pCR; median disease-free survival and overall survival rates for patients with PR were 38 and 22 months, respectively (Figures 3A and 3B). The difference between pCR and PR for overall survival was not significant (P > .2); there was a trend for longer disease-free survival (P = .12) for patients with pCR by the log-rank test. The median survival for patients with PD was 9 months. Median distant disease-free survival was 40 months (56% at 3 years). Four patients (19%) developed biopsy-proven local recurrence at 6, 9, 22, and 25 months after resection. All four patients with local recurrence had PR; at resection, three had a pathologic stage of pT3N1M0 and the fourth had pT3N0M0 residual disease.
Figure 1.
Kaplan-Meier overall survival curve for all patients (N = 24).
Figure 2.
Kaplan-Meier disease-free survival curve for all patients (N = 24).
Figure 3.
Kaplan-Meier overall (A) and disease-free (B) survival for patients with pathologic complete response (n = 12, solid line) vs. partial response (n = 9, dashed line).
Toxicity
There were no deaths related to neoadjuvant treatment. Twenty-one patients (88%) received all 5 weeks of chemotherapy, with two (8%) receiving four cycles and one (4%) receiving three cycles. Fifteen patients (63%) required a reduction in the dose of chemotherapy, with stomatitis, neutropenia, and esophagitis being the most common reasons. Grade 2 hematologic toxicities consisted of neutropenia in 46%, anemia in 29%, and thrombocytopenia in 13%. Three patients (13%) developed grade 3 neutropenia and two patients (8%) developed grade 3 anemia. No grade 3 thrombocytopenia or grade 4 hematologic toxicities were observed.
Esophagitis was the most common severe nonhematologic toxicity, with 8 patients (33%) developing grade 3 esophagitis. Other grade 3 toxicities included stomatitis in six patients (25%) and hypotension in seven patients (29%); no grade 4 nonhematologic toxicities were observed. Placement of a percutaneous feeding tube was necessary in 2 patients (8%) because of odynophagia and dysphagia during chemoradiotherapy. Grade 2 toxicities included esophagitis in 88%, stomatitis in 21%, and hypotension requiring outpatient hydration in 58%.
Two patients died within the postoperative period, for an in-house 30-day mortality of 8%. Both patients developed pulmonary complications; the cause of death in each was determined to be acute respiratory distress syndrome. Other major complications included one thoracic duct injury, one recurrent laryngeal nerve injury, one case of wound dehiscence, and one case of tracheobronchial fistula. Anastomotic leakage was detected postoperatively in two patients (8%) and was conservatively managed in both. Nine patients (38%) developed stricture at the anastomotic site that required dilatation at a median of 7 months (range, 2–29 months). All patients were eventually able to resume eating solid food after completion of treatment.
DISCUSSION
Despite controversy in the literature, neoadjuvant chemoradiotherapy remains a popular treatment strategy for the management of locally advanced esophageal cancer. Only one of three randomized trials evaluating neoadjuvant chemoradiotherapy in patients with adenocarcinoma of the esophagus has demonstrated a survival benefit in patients receiving trimodality therapy in comparison to surgery alone.13,14,39 The study by Walsh et al13 showed a survival advantage in patients receiving 40 Gy of radiation with concurrent cisplatin and 5-FU in comparison to esophagectomy without adjuvant treatment (3-year survival, 32% vs. 6%; median, 16 vs. 11 months). However, this trial has been criticized because of the low survival rate in the surgery-alone arm, inconsistent pretreatment staging, and high surgical morbidity and mortality.
Meta-analyses of randomized trials20–22 have not clarified this issue. For example, in an analysis including six trials reported by Fiorica et al,22 neoadjuvant chemoradiotherapy was associated with improved 3- year survival (odds ratio, 0.53; P = .03); however, surgical morbidity and mortality were increased with neoadjuvant chemoradiotherapy, four of the six trials enrolled only patients with squamous cell carcinoma, and there was considerable variation in preoperative regimens among the trials. Nevertheless, the survival effect appeared greater for patients with adenocarcinoma and the odds ratios favored patients receiving preoperative therapy in all six trials.
A consistent finding in the literature is an improvement in overall and diseasefree survival in patients achieving a complete or near complete response to neoadjuvant therapy.5,13,40,41 In a study reported by Donnington et al,26 use of chemoradiotherapy in 108 of 366 patients undergoing esophagectomy for esophageal adenocarcinoma was associated with improved 3-year overall survival (64% vs. 34%) and disease-free survival (57% vs. 30%) in patients who had a pCR at the time of surgical resection compared with those who did not. Other data have shown an improvement in locoregional and distant failure rates in patients achieving a pCR as well.24 Pathologic complete response rates reported in the randomized trials are approximately 20% to 30% with mostly cisplatin-based regimens.42
Based on the good response rate and survival observed in a phase II trial with trimodality therapy including paclitaxel/carboplatin every 3 weeks in esophageal cancer32,33 and the success with weekly paclitaxel/carboplatin in neoadjuvant chemoradiotherapy in non–small-cell lung cancer,34,35 we designed the current study regimen with the hope of improving tolerability and obtaining a high pCR rate. Carboplatin may be favored over cisplatin in such a combination due to its relatively favorable comparative toxicity profile.43,44 Its use permits a higher dose of concurrent paclitaxel and may allow more patients to complete the prescribed chemotherapy regimen, which has been shown to correlate with overall survival in the treatment of esophageal cancer.45 Such factors may partially explain (apart from the small sample size in the current study) the better response rate observed with the carboplatin-containing regimen in our study compared with the use of cisplatin with a concurrent taxane.46 The RTOG 0113 trial is currently evaluating two paclitaxel-based regimens for the definitive treatment of esophageal cancer; the results may help to identify optimal concurrent regimens.
The results of our study are consistent with others showing an improved pCR rate with the use of taxane-based regimens. We observed an impressive 57% pCR rate, with 76% of patients achieving either a near complete or complete response. Although a trend toward an improvement in diseasefree survival was seen in patients achieving pCR compared with PR, no significant difference emerged in overall survival. The absence of differences in survival for pCR vs. PR may in part be related to the 8% perioperative mortality, but any potential differences in outcome based on pathologic response rates would also be unlikely to be statistically significant due to the small number of patients and the limited statistical power of the study. Nevertheless, the 3-year overall survival rate of 48% (median 31 months) is favorable in comparison with other reports in this setting.
We also observed an impressive local control rate of 81%, with local control observed in all patients with a pCR. These remarkable results in terms of response were not without cost. Sixty-three percent of patients (15/24) required at least one chemotherapy dose reduction, and perioperative mortality and morbidity were significant, though consistent with other published studies. In addition, the outcomes must be considered in the context of the possible bias inherent in single-institution phase II trials (physician bias, performance status selection, ability to be treated at a particular institution).
The potential benefit of neoadjuvant treatment would likely be less obscured by the toxicity of the neoadjuvant regimen and perioperative mortality if patients who would benefit from surgery could be identified on the basis of their response to neoadjuvant treatment. In a French multicenter trial47 in 259 patients with at least PR after 46 Gy of radiation and two cycles of cisplatin and 5-FU, there was no difference in 2-year survival (34% vs. 40%) or median survival (18 vs. 19 months) between patients treated with surgery vs. three additional cycles of chemoradiotherapy. Global quality of life measured with the Spitzer index was significantly decreased for the first 6 postoperative months in patients receiving surgery.18 Such results suggest that response to chemoradiotherapy may correlate with good prognosis, even in the absence of surgical resection. Unfortunately, current methods of evaluating the response to chemoradiotherapy without surgical resection (EUS and CT) are unreliable,48 though some promising results with the use of PET have been reported.49,50
Other data support the benefit of surgical resection in patients not responding to neoadjuvant treatment. In a German Esophageal Cancer Study Group trial,19 patients receiving neoadjuvant cisplatin, 5-FU, leucovorin, and etoposide, followed by cisplatin and etoposide with radiation were randomized to surgery or chemoradiotherapy alone (with a higher radiation dose). There was no significant difference in 3-year survival between the groups (31% vs. 24%); however, it was noted that 3-year survival was 32% in patients not responding to neoadjuvant treatment when surgery was performed with negative margins. The RTOG 0246 trial is evaluating the use of salvage surgical resection in patients with residual disease after neoadjuvant treatment, and results are pending at this time.
In conclusion, we found that a neoadjuvant chemoradiotherapy regimen including weekly paclitaxel and carboplatin with 5-FU resulted in high pCR and local control rates and an encouraging 3-year survival rate of 48% in patients with esophageal cancer. Toxicity was substantial, but manageable. Further, the distant failure rate was relatively high, which may suggest the need for more active systemic agents. Further study with longer follow-up and larger patient numbers is required to confirm the long-term safety and efficacy of this regimen.
Footnotes
Disclosures of Potential Conflicts of Interest
Dr. Gannett has no potential conflicts of interest to disclose.
REFERENCES
- 1.Jemal A, Siegel R, Ward E, et al. Cancer statistics 2006. CA Cancer J Clin. 2006;56:106–130. doi: 10.3322/canjclin.56.2.106. [DOI] [PubMed] [Google Scholar]
- 2.Swisher SG, Hunt KK, Holmes EC, et al. Changes in the surgical management of esophageal cancer from 1970 to 1993. Am J Surg. 1995;69:609–614. doi: 10.1016/s0002-9610(99)80231-1. [DOI] [PubMed] [Google Scholar]
- 3.Hulscher JF, van Sandick JW, de Boer AM, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347:1662–1669. doi: 10.1056/NEJMoa022343. [DOI] [PubMed] [Google Scholar]
- 4.Nygaard K, Hagen S, Hansen HS, et al. Preoperative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy—the second Scandinavian trial in esophageal cancer. World J Surg. 1992;16:1104–1110. doi: 10.1007/BF02067069. [DOI] [PubMed] [Google Scholar]
- 5.Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med. 1998;339:1979–1984. doi: 10.1056/NEJM199812313392704. [DOI] [PubMed] [Google Scholar]
- 6.Law DE, Fok M, Chow S, et al. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg. 1997;114:210–217. doi: 10.1016/S0022-5223(97)70147-8. [DOI] [PubMed] [Google Scholar]
- 7.Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992;326:1593–1598. doi: 10.1056/NEJM199206113262403. [DOI] [PubMed] [Google Scholar]
- 8.Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer. Long-term follow-up of a prospective randomized trial (RTOG 85-01) JAMA. 1999;281:1623–1627. doi: 10.1001/jama.281.17.1623. [DOI] [PubMed] [Google Scholar]
- 9.Vogel SB, Mendelhall WM, Sombeek MD, et al. Downstaging esophageal cancer after preoperative radiation and chemotherapy. Ann Surg. 1995;221:685–695. doi: 10.1097/00000658-199506000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Forastiere AA, Orringer MB, Perez-Tamayo C, et al. Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: final report. J Clin Oncol. 1993;11:1118–1123. doi: 10.1200/JCO.1993.11.6.1118. [DOI] [PubMed] [Google Scholar]
- 11.Brucher BL, Stein HJ, Zimmermann F, et al. Responders benefit from neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma: results of a prospective phase II trial. Eur J Surg Oncol. 2004;30:963–971. doi: 10.1016/j.ejso.2004.06.008. [DOI] [PubMed] [Google Scholar]
- 12.van Meerten E, Muller K, Tilanus HW, et al. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer. 2006;94:1389–1394. doi: 10.1038/sj.bjc.6603134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Walsh T, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335:462–467. doi: 10.1056/NEJM199608153350702. [DOI] [PubMed] [Google Scholar]
- 14.Urba S, Orringer M, Turrisi A, et al. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19:305–313. doi: 10.1200/JCO.2001.19.2.305. [DOI] [PubMed] [Google Scholar]
- 15.Bosset J, Gignoux M, Triboulet J, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997;337:161–167. doi: 10.1056/NEJM199707173370304. [DOI] [PubMed] [Google Scholar]
- 16.Law S, Kwong DLW, Tung HM, et al. Preoperative chemoradiation for squamous cell esophageal cancer: a prospective randomized trial. Can J Gastroenterol. 1998;12(suppl B):56B. (abstr) [Google Scholar]
- 17.Le Prise E, Etienne PL, Meunier B, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer. 1994;73:1779–1784. doi: 10.1002/1097-0142(19940401)73:7<1779::aid-cncr2820730702>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
- 18.Bonnetain F, Bedenne L, Michel P, et al. Definitive results of a comparative longitudinal quality of life study using the Spitzer index in the randomized multicentric phase III trial FFCD 9102 (surgery vs. radiochemotherapy in patients with locally advanced esophageal cancer) Proc Am Soc Clin Oncol. 2003;22:250. (abstr 1002) [Google Scholar]
- 19.Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23:2310–2317. doi: 10.1200/JCO.2005.00.034. [DOI] [PubMed] [Google Scholar]
- 20.Kaklamanos IG, Walker GR, Ferry K, et al. Neoadjuvant treatment for resectable cancer of the esophagus and the gastroesophageal junction: a meta-analysis of randomized clinical trials. Ann Surg Oncol. 2003;10:754–761. doi: 10.1245/aso.2003.03.078. [DOI] [PubMed] [Google Scholar]
- 21.Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg. 2003;185:538–543. doi: 10.1016/s0002-9610(03)00066-7. [DOI] [PubMed] [Google Scholar]
- 22.Fiorica F, Di Bona D, Schepis F, et al. Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut. 2004;53:925–930. doi: 10.1136/gut.2003.025080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Chirieac LR, Swisher SG, Ajani JA, et al. Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer. 2005;103:1347–1355. doi: 10.1002/cncr.20916. [DOI] [PubMed] [Google Scholar]
- 24.Rohatgi PR, Swisher SG, Correa AM, et al. Failure patterns correlate with the proportion of residual carcinoma after preoperative chemoradiotherapy for carcinoma of the esophagus. Cancer. 2005;104:1349–1355. doi: 10.1002/cncr.21346. [DOI] [PubMed] [Google Scholar]
- 25.Rohatgi P, Swisher SG, Correa AM, et al. Characterization of pathologic complete response after preoperative chemoradiotherapy in carcinoma of the esophagus and outcome after pathologic complete response. Cancer. 2005;104:2365–2372. doi: 10.1002/cncr.21439. [DOI] [PubMed] [Google Scholar]
- 26.Donnington JS, Miller DL, Allen MS, et al. Tumor response to induction chemoradiation: influence on survival after esophagectomy. Eur J Cardiothorac Surg. 2003;24:631–636. doi: 10.1016/s1010-7940(03)00397-x. [DOI] [PubMed] [Google Scholar]
- 27.Kesler KA, Helft PR, Werner EA, et al. A retrospective analysis of locally advanced esophageal cancer patients treated with neoadjuvant chemoradiation therapy followed by surgery or surgery alone. Ann Thorac Surg. 2005;79:1116–1121. doi: 10.1016/j.athoracsur.2004.08.042. [DOI] [PubMed] [Google Scholar]
- 28.Choy H, Rodriguez FF, Koester S, et al. Investigation of taxol as a potential radiation sensitizer. Cancer. 1993;71:3774–3778. doi: 10.1002/1097-0142(19930601)71:11<3774::aid-cncr2820711147>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
- 29.Ajani J, Ilson D, Daugherty K, et al. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst. 1994;86:1086–1091. doi: 10.1093/jnci/86.14.1086. [DOI] [PubMed] [Google Scholar]
- 30.Liebermann J, Cook JA, Fisher J, et al. Changes in radiation survival curve parameters in human tumor and rodent cells exposed to paclitaxel (taxol) Int J Radiat Oncol Biol Phys. 1994;29:559–564. doi: 10.1016/0360-3016(94)90456-1. [DOI] [PubMed] [Google Scholar]
- 31.Liebermann J, Cook JA, Fisher J, et al. In vitro studies of taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst. 1994;86:441–446. doi: 10.1093/jnci/86.6.441. [DOI] [PubMed] [Google Scholar]
- 32.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. 1999;5:84–91. [PubMed] [Google Scholar]
- 33.Meluch AA, Greco FA, Gray JR, et al. Preoperative therapy with concurrent paclitaxel/carboplatin/infusional 5-FU and radiation therapy in locoregional esophageal cancer: final results of a Minnie Pearl Cancer Research Network phase II trial. Cancer J. 2003;9:251–260. doi: 10.1097/00130404-200307000-00007. [DOI] [PubMed] [Google Scholar]
- 34.Choy H, Akerly W, Safran H, et al. Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer. J Clin Oncol. 1998;16:3316–3322. doi: 10.1200/JCO.1998.16.10.3316. [DOI] [PubMed] [Google Scholar]
- 35.Kaplan B, Altynbas M, Eroglu C, et al. Preliminary results of a phase II study of weekly paclitaxel (PTX) and carboplatin (CBDCA) administered concurrently with thoracic radiation therapy (TRT) followed by consolidation chemotherapy with PTX/CBDCA for stage III unresectable non-small-cell lung cancer (NSCLC) Am J Clin Oncol. 2004;27:603–610. doi: 10.1097/01.coc.0000135739.37072.ff. [DOI] [PubMed] [Google Scholar]
- 36.Calvert AH, Newell DR, Grumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989;7:1748–1756. doi: 10.1200/JCO.1989.7.11.1748. [DOI] [PubMed] [Google Scholar]
- 37.Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481. [Google Scholar]
- 38.Wellek S. A log-rank test for equivalence of two survivor functions. Biometrics. 1993;49:877–881. [PubMed] [Google Scholar]
- 39.Burmeister BH, Smithers BM, Gebski V, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the esophagus: a randomized controlled phase III trial. Lancet Oncol. 2005;6:635–637. doi: 10.1016/S1470-2045(05)70288-6. [DOI] [PubMed] [Google Scholar]
- 40.Roth JA, Pass HI, Flanagan MM, et al. Randomized clinical trial of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg. 1988;96:242–248. [PubMed] [Google Scholar]
- 41.Swisher SG, Holmes EC, Hunt KK et al. The role of neoadjuvant therapy in surgically resectable esophageal cancer. Arch Surg. 1996;131:819–825. doi: 10.1001/archsurg.1996.01430200029005. [DOI] [PubMed] [Google Scholar]
- 42.Geh JI, Crellin M, Glynne-Jones R, et al. Preoperative (neoadjuvant) chemoradiotherapy in esophageal cancer. Br J Surg. 2001;88:338–356. doi: 10.1046/j.1365-2168.2001.01670.x. [DOI] [PubMed] [Google Scholar]
- 43.Alberts DS, Green S, Hannigan EV, et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol. 1992;10:706–717. doi: 10.1200/JCO.1992.10.5.706. [DOI] [PubMed] [Google Scholar]
- 44.Kosmidis PA, Samantas E, Pountzilas G, et al. Cisplatin/etoposide versus carboplatin/etoposide chemotherapy and irradiation in small cell lung cancer: a randomized phase II study. Semin Oncol. 1994;21(suppl 3):23–30. [PubMed] [Google Scholar]
- 45.Roof KS, Coen J, Lynch TJ, et al. Concurrent cisplatin, 5-FU, paclitaxel, and radiation therapy in patients with locally advanced esophageal cancer. Int J Radiat Oncol Biol Phys. 2006;65:1120–1128. doi: 10.1016/j.ijrobp.2006.02.013. [DOI] [PubMed] [Google Scholar]
- 46.Urba S, Hayman J, Ianettonni M, et al. Preoperative chemoradiation with cisplatin (CDDP), 5-fluorouracil (5FU), and paclitaxel (Tax), followed by surgery and adjuvant chemotherapy, for loco-regional esophageal carcinoma. Proc Am Soc Clin Oncol. 2004;22:4029. (abstr) [Google Scholar]
- 47.Bedenne L, Michel P, Bouche O, et al. Randomized phase III trial in locally advanced esophageal cancer: radiochemotherapy followed by surgery versus radiochemotherapy alone (FFCD 9102) Proc Am Soc Clin Oncol. 2002;21:130a. (abstr) [Google Scholar]
- 48.Kalha I, Kaw M, Fukami N, et al. The accuracy of endoscopic ultrasound for restaging esophageal carcinoma after chemoradiation therapy. Cancer. 2004;101:940–947. doi: 10.1002/cncr.20429. [DOI] [PubMed] [Google Scholar]
- 49.Song SY, Kim JH, Ryu JS, et al. FDG-PET in the prediction of pathologic response after neoadjuvant chemoradiotherapy in locally advanced, resectable esophageal cancer. Int J Radiat Oncol Biol Phys. 2005;63:1053–1059. doi: 10.1016/j.ijrobp.2005.03.033. [DOI] [PubMed] [Google Scholar]
- 50.Erasmus JJ, Munden RF. The role of integrated computed tomography positron-emission tomography in esophageal cancer: staging and assessment of therapeutic response. Semin Radiat Oncol. 2006;17:29–37. doi: 10.1016/j.semradonc.2006.09.005. [DOI] [PubMed] [Google Scholar]