Annals of Oncology Advance Access originally published online on October 6, 2006
Annals of Oncology 2007 18(1):93-98; doi:10.1093/annonc/mdl339
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© 2006 European Society for Medical Oncology
gastrointestinal tumors |
Concurrent chemoradiotherapy with twice weekly paclitaxel and cisplatin followed by esophagectomy for locally advanced esophageal cancer
1 Department of Oncology, National Taiwan University Hospital
2 Cancer Research Center, National Taiwan University College of Medicine
3 Department of Emergency Medicine
4 Department of Surgery
5 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
* Correspondence to: Dr A.-L. Cheng, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel: +886-2-23123456, ext 7251; Fax: +886-2-23711174; E-mail: andrew{at}ha.mc.ntu.edu.tw
Correspondence to: Dr Y.-C. Lee, Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel: +886-2-23123456, ext 5070; Fax: +886-2-33933389; E-mail: wuj{at}ha.mc.ntu.edu.tw
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Abstract |
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Background: To test the feasibility of incorporating a twice-weekly paclitaxel (Taxol) and cisplatin regimen into concurrent chemoradiotherapy (CCRT), followed by surgery, for patients with locally advanced esophageal cancer.
Patients and methods: Patients with operable T3N0-1M0 or T1-3N1M0 esophageal cancer were enrolled. The CCRT regimen included paclitaxel (35 mg/m2 1 h on days 1 and 4/week), cisplatin (15 mg/m2 1 h on days 2 and 5/week), and radiotherapy (2 Gy on days 1–5/week). When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated in all patients. In patients for whom esophagectomy was not feasible, CCRT was continued to a dose of 60 Gy.
Results: The majority of 97 patients enrolled had squamous cell carcinoma on histology (95%) and T3N1 disease by endoscopic ultrasonographic staging (90%). All patients received CCRT to 40 Gy. Sixty-one patients underwent surgery, and 26 patients continued definitive CCRT to 60 Gy. The intention-to-treat pathological complete response rate was 25% [24/97, 95% confidence interval (CI) 16–33]. At a median follow-up of 25.3 months, the median progression-free and overall survival was 15.6 and 28.8 months, respectively. The most common grade 3/4 toxic effects were leukopenia (30%), thrombocytopenia (10%), and diarrhea (15%).
Conclusions: CCRT with a twice-weekly paclitaxel and cisplatin regimen followed by esophagectomy is an active treatment of locally advanced esophageal cancer.
Key words: combined modality therapy, drug administration schedule, esophageal neoplasms, paclitaxel
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Patients with esophageal cancer have a poor prognosis. Resection is the best management in terms of local control, although local recurrence and distant metastases remain common after surgery. Postoperative radiotherapy (RT) or chemotherapy does not improve outcomes, and preoperative chemotherapy, RT, or both, have thus become the focus of adjuvant strategies. The rationale for preoperative concurrent chemoradiotherapy (CCRT) in esophageal cancer patients includes eradication of micrometastasis, drug delivery through intact tumor blood vessels, and improvement of primary tumor resectability. Randomized trials demonstrate that CCRT using cisplatin-based regimen followed by surgery decreases local relapse as compared with surgery alone; however, the effect on overall survival (OS) remains uncertain [1–5]. The additional impact of surgery following chemoradiation also remains unclear, with two randomized trials demonstrating an improvement in locoregional control without a benefit in survival [6, 7]. Failure in these studies was attributed to factors such as morbidity and mortality of trimodality therapy and ineffectiveness of their chemotherapy regimens.
Paclitaxel is a very active agent against esophageal cancer, with a single-agent activity of around 30% [8]. Paclitaxel is also classified as a radiosensitizer because it arrests cells at the G2/M phase, the most radiosensitive phase of the cell cycle [9]. This enhancement might be achieved at a non-toxic concentration as low as the nanomolar range [10].
The timing of administration of paclitaxel and irradiation was crucial, with a maximum radiotherapeutic ratio occurring from 6 to 72 h after exposure to paclitaxel [9]. The multiple-dosing, short infusion duration (so-called multi-fractionated) schedule is theoretically advantageous [11, 12]. In a phase I trial of twice-weekly schedule for patients with stage III non-small-cell lung cancer (NSCLC), the maximum tolerated dose of paclitaxel was 35 mg/m2 and dose-limiting toxicity esophagitis [12]. The use of a daily low-dose cisplatin concurrent with radiation is important for the radiosensitizing effect. In a randomized trial for patients with stage IIIb NSCLC, daily low-dose cisplatin plus radiation was superior to weekly cisplatin plus radiation or radiation alone in terms of survival [13]. Preclinical studies indicated that synergism between paclitaxel and cisplatin was sequence dependent [14]. The cytotoxic effect was better when the tumor cells were exposed to paclitaxel first, followed by cisplatin 24 h later.
On the basis of these considerations, we initiated a phase II study to determine the response rate and toxicity of a CCRT regimen consisting of twice-weekly paclitaxel and cisplatin with concurrent RT in patients with locally advanced esophageal cancer (LAEC).
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The Ethics Committee of National Taiwan University Hospital (Taipei, Taiwan) approved this trial. All patients provided written informed consent for participation.
patients
Untreated patients with pathologically proven squamous cell carcinoma or adenocarcinoma of the esophagus were eligible for the study. Before registration, a multidisciplinary team evaluated each patient to determine potential resectability and operability. The extent of the disease should be clinical T3N0-1M0 or T1-3N1M0 (American Joint Committee on Cancer Staging System, 1997) by the findings of computed tomography (CT) scan and endoscopic ultrasound (EUS). Further eligibility criteria were Karnofsky's performance status (KPS) of at least 60%; normal bone marrow, liver, and renal function [white blood cell (WBC) count > 4000/µl or absolute neutrophil count > 2000/µl, platelets > 100 000/µl; transaminases 
1.5 times upper normal limit, bilirubin 2.0 mg/dl; creatinine level 1.5 mg/dl]; and no prior malignancy.
staging
All patients underwent brain, chest, and abdominal CT scan, esophagogram, endoscopy, and EUS examination of the esophagus, bronchoscopy, and pulmonary function test.
treatment
Before and during this protocol treatment, patients' nutritional status should be aggressively improved either by parenteral nutrition or enteral nutrition via jejunostomy. CCRT with twice-weekly paclitaxel (Taxol, Bristol-Myers Squibb Company, New Jersey, USA), cisplatin, and RT was administered over 4 weeks (Figure 1). RT was administered by a high-energy linear accelerator of 6 or 10 mV units. Simulations were carried out to encompass the tumor volume with a 5-cm longitudinal margin and a 2-cm lateral margin, involving the supraclavicular fossa for those with upper and mid thoracic esophageal tumors and celiac trunk for those with lower thoracic esophageal tumors. Radiation was delivered by an anterior–posterior/posterior–anterior technique, with a daily fraction of 2 Gy, 5 days a week. To eliminate radiation exposure of the spinal cord, the treatment portals were designed with two oblique projections when the RT dose was >40 Gy.
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Paclitaxel was given as 35 mg/m2 1-h i.v. infusion before RT on days 1 and 4 of each week. Premedication for the first dose of paclitaxel included dexamethasone 20 mg, diphenhydramine 30 mg, and ranitidine 50 mg, i.v. bolus 1 h before treatment. Dexamethasone was reduced to 8 mg before the second dose of paclitaxel if no hypersensitivity occurs. The premedication was further simplified to diphenhydramine and ranitidine only if no hypersensitivity occurred. Cisplatin was given as 15 mg/m2 1-h i.v. infusion before RT on days 2 and 5 of each week. Appropriate anti-emetics and hydration for cisplatin were given.
When the accumulated RT dose reached 40 Gy, re-staging and risk analysis were carried out to ensure lack of tumor progression and that the patient was in an operable condition. Resection of the esophagus and the proximal stomach was carried out by a separate right thoracic and abdominal approach. Resection included excision of the paraesophageal, paracardial, left gastric, and celiac lymph nodes (two-field lymphadenectomy). The resected esophagus was usually replaced by the stomach using a cervical esophagogastric anastomosis.
For patients with deteriorated overall condition and operable patients who refused esophagectomy, CCRT was continued to a total RT dose of 60 Gy. Patients with progressive disease were removed from the protocol treatment.
dose modification
During CCRT, dose was modified on a weekly basis. If the WBC count was <3000/µl or platelet count was <75 000/µl, paclitaxel on day 4 of the week and cisplatin on day 5 of the week were omitted. If the WBC count was <2000/µl or platelet count was <50 000/µl, all chemotherapy for the week was omitted. If the WBC count was <1000/µl or platelet count was <25 000/µl, CCRT was withheld until WBC and platelet counts recovered to 
1000/µl and 25 000/µl, respectively.
If grade 2 esophagitis or stomatitis occurred, paclitaxel on day 4 of the week and cisplatin on day 5 of the week were omitted. If grade 3 esophagitis or stomatitis occurred, all chemotherapy for the week was omitted. If grade 4 esophagitis or stomatitis occurred, CCRT was withheld until the toxicity resolved.
When grade 3 sensory peripheral neuropathy occurred, paclitaxel on day 4 of the week and cisplatin on day 5 of the week were omitted. If there was progression of the above toxicity after one dose reduction for >1 week, all chemotherapy for the week was omitted. Cisplatin was withheld if the serum creatinine level was higher than 1.8 mg/dl.
evaluation of response and toxicity
During the protocol treatment, the patients were followed-up at least once a week. Assessment at each visit included dysphagia grade, body weight, KPS, and any related symptoms. Hemogram and blood chemistry were checked weekly. Treatment-related toxicities were evaluated according to National Cancer Institute Common Toxicity Criteria, version 2.0.
The protocol demanded locally advanced disease be treated with CCRT, evaluated within 4 weeks after completion of CCRT, followed by surgery essentially at the sixth week after CCRT. Clinical evaluations by CT scan, EUS, esophagogram, and spirometry were designed to ensure the operability of the patients. Clinical response was defined as improvement of dysphagia to grade 2 or less, the near or total disappearance of esophageal tumor by chest CT scan and by endoscopy, and negative endoscopic biopsy finding. All esophagectomy specimens were subjected to pathology evaluation to document the pathologic response. Pathologic complete response (pCR) was defined as no detectable cancer cell in the resected tissue specimens. Microscopic residual disease was defined as microscopic residual carcinoma. A non-responder was defined as a patient who had macroscopic residual carcinoma or pathologic lymph node metastasis.
statistics
The primary end point of this study was the pCR rate. Our previous study on 25 patients with LAEC achieved a 20% pCR rate by combining cisplatin, 5-fluorouracil (5-FU), and irradiation as a preoperative adjunctive [15]. We expected that CCRT with the twice-weekly paclitaxel and cisplatin regimen in this study would achieve a downstage to pCR in 35% of patients. According to the sample size calculation methods of Makuch and Simon [16], the sample size required for this study was 92 to provide 80% power with a two-sided 5% significance level.
Follow-up duration was calculated from the entry date to the end of the study on 31 December 2005. Progression-free survival was defined as the duration between the entry date and the date of documented disease progression, death due to other causes, or last follow-up (censored). OS was defined as the duration between the entry date and the date of patient death or last follow-up (censored). Both the progression-free and the OS were calculated using the Kaplan–Meier method. The differences in objective responses in terms of clinical parameters were evaluated using chi-square or Fisher's exact test. The relationship between survival and clinical parameters was analyzed using the log-rank test.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients
Between March 2000 and June 2005, a total of 97 patients were enrolled in the study. The clinicopathologic features of these patients are summarized in Table 1. Most (95%) patients had squamous cell carcinoma, which is characteristic of the epidemiology of this illness in the Far East [17]. The clinical stage was T3N1 in 90% of patients. Fifty-one percent of patients had recent weight loss of >10%. The KPS was <90% in 70% of patients.
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treatment
The treatment is summarized in Figure 2. Re-evaluation when CCRT reached a total RT dose of 40 Gy revealed 14 patients were inoperable. Three of them had progressive disease (new tracheal involvement in one and new lung metastasis in two). Eleven patients had deteriorated medical condition [a KPS of
70% in six, a forced expiratory volume in 1 s (FEV1) of <1.2 l in five]. Among the 83 operable patients, 20 refused to undergo esophagectomy. Two of the remaining 63 patients died of tumor bleeding at 3 and 24 days, after completion of CCRT of 40 Gy. Esophagectomy was carried out in 61 (63%) of the 97 patients who completed CCRT. Twenty-six patients continued CCRT up to 60 Gy.
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Eighty-seven patients (90%) completed the scheduled preoperative CCRT treatment without any interruption. Eighty-five percent (range 50–100) of the scheduled paclitaxel dose and 83% (range 50–100) of the scheduled cisplatin dose were given. The median time from completion of CCRT to esophagectomy was 45 days (range 15–95). Fifty-five of 61 patients (90%) were operated between the fifth week and the seventh week after CCRT. The median time from esophagectomy to discharge was 30 days (range 14–392).
toxicity
The toxicity profile of CCRT is listed in Table 2. Hematologic toxicity was moderate and manageable. Grade 3 or 4 leukopenia and neutropenia occurred in 30% and 16% of patients, respectively. Infection was noted in 15% of patients. No patient died of neutropenia or infection. Eleven percent and 10% of patients had grade 3 or 4 anemia and thrombocytopenia, respectively. The most common non-hematologic toxicity was diarrhea (15%) followed by stomatitis (11%). Grade 3 or 4 esophagitis occurred in 7% of patients during CCRT. Two patients died of tumor bleeding at 3 and 24 days after completion of CCRT. The CCRT-related mortality rate was 2.1% (2/97).
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The median time from esophagectomy to discharge was 30 days (range 14–392). The most common postoperative complications were anastomotic leak in 13 patients (21%, 13/61) and postoperative pulmonary complication in eight patients (13%, 8/61). Two patients died within 30 days after esophagectomy. One patient died of respiratory failure 14 days after esophagectomy. The other patient, who had alcoholic liver disease, died of hepatic failure 25 days after esophagectomy. The resulting operative mortality (within 30 days of surgery) rate was 3.3% (2/61).
response and survival
Among the 61 patients who underwent surgery, 24 had a pCR, and 12 had microscopic residual disease. The intention-to-treat pCR rate was 25% (24/97, 95% CI 13–33). There was no clear relation between the baseline clinicopathologic factors (such as age or pathology) and pCR. Among the 36 patients who did not undergo esophagectomy, 23 had clinical response. The clinical response rate was 64%.
By 31 December 2005, with a median follow-up of 25.3 months (range 6–70), 33 (34%) of the 97 patients had relapse. Fourteen patients had locoregional recurrence alone (anastomosis site in three, trachea in seven, and supraclavicular or celiac lymphadenopathy in four). Twelve patients had distant metastasis only (lung in five, liver one, bone three, skin one, liver and lung or adrenal gland in two). Six patients had both locoregional recurrence and distant metastasis (anastomosis site and lung or bone in two and celiac lymphadenopathy and liver or bone or adrenal gland in four). One patient had second primary hypopharyngeal cancer. There was a trend towards less locoregional recurrence in patients who underwent esophagectomy (6/61, 9.8%) than that in patients who did not (8/36, 22.2%) (P = 0.09). As of this report, 48 patients were still progression-free. The median progression-free survival was 15.6 months (95% CI 7.2–24.0).
At a median follow-up of 25.3 months, 56 patients were still alive. The OS rate at 2 and 3 years was 53.8% and 49.0%, respectively, with a median survival of 28.8 months (Figure 3). There was no clear relation between the baseline clinicopathologic factors (such as age or pathology) and the OS or progression-free survival duration. There was no difference in OS between the 63 patients who were operable after CCRT to 40 Gy and accepted esophagectomy and the 20 patients who were operable but declined esophagectomy (P = 0.67). Among the 61 patients who underwent esophagectomy, those who were downstaged to pCR had a longer progression-free survival (median not reached versus 15.6 months, P = 0.03) and a trend towards longer OS (median not reached versus 38.4 months, P = 0.16) than patients with microscopic residual disease or no response. Among the 36 patients who did not undergo esophagectomy, the 2-year OS rate was 33.8% and a median survival of 12.8 months. Of note, seven patients had been disease-free for >2 years (range 24–69 months).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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CCRT using a twice-weekly paclitaxel and cisplatin regimen followed by esophagectomy for LAEC appears to be an effective protocol with a moderate toxicity profile. The 25% intention-to-treat pCR rate of this protocol in this study is comparable to that of most taxane- and platinum-containing CCRT regimens. The toxicity profile of CCRT using a twice-weekly paclitaxel and cisplatin regimen was moderate and manageable, which makes it a viable option for esophageal cancer patients who tend to be weak and malnourished.
In this study, the OS rate at 2 and 3 years was 53.8% and 49.0%, respectively, which is in line with other reports using taxane- and platinum-containing CCRT regimen for esophageal cancer (Table 3) [18–24]. The 25% pCR rate of this protocol is comparable to other taxane- and platinum-containing CCRT regimens (19%–36%).
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The most serious grade 3 or 4 hematologic and non-hematologic toxic effects occurred in 30% and 15% of patients, respectively. The toxic effects were the same as or better than those of previous reports summarized in Table 3. Nevertheless, this twice-weekly regimen has relatively more grade 3 or 4 leukopenia (30% versus 3%–12%) and esophagitis (7% versus 2%–4%) than cisplatin and 5-FU-based regimens [1, 3–5]. The reasons why they were manageable are probably attributed to the following. First, CCRT using this twice-weekly (multi-fractionated) chemotherapeutic regimen allows timely adjustment of the treatment according to the condition of the patients. Second, patients' nutritional status has been aggressively improved by either parenteral nutrition or enteral nutrition via jejunostomy before and during this protocol treatment. Although grade 3 or 4 infection occurred in 15% of patients, none of the CCRT-related deaths was associated with infection. Our results indicated that CCRT using this twice-weekly chemotherapy protocol could be safely administered in LAEC patients, either as neo-adjuvant or a definitive treatment.
The final pCR rate (25%) does not meet our defined parameter (35%) partly because a large proportion (37%, 36/97) of patients, as allowed by the protocol, did not receive esophagectomy. Given that the clinical response rate of those 36 patients who did not undergo esophagectomy was 64% and seven of them had been disease-free for >2 years (range 24–69 months), the actual efficacy of this regimen may be higher than expected by the pCR rate. Besides, two patients died within 30 days after esophagectomy in study. All these raise the question of the necessity of surgery in the overall treatment schema. Two recent phase III trials, which compared CCRT alone with CCRT followed by esophagectomy, in patients with esophageal squamous cell carcinoma, failed to demonstrate a survival benefit of adding surgery to CCRT, particularly in patients who responded satisfactorily to CCRT [6, 7].
The current trial supports the feasibility of incorporating twice-weekly paclitaxel and cisplatin into preoperative regimens for patients with LAEC. Nevertheless, whether twice-weekly paclitaxel plus cisplatin regimen is better than conventional cisplatin plus 5-FU regimens or other taxane- and platinum-containing regimens remains to be confirmed by further studies. Moreover, recurrent disease is not uncommon after chemoradiation followed by surgery. Other promising directions include adding effective chemotherapy regimen before CCRT while shrinking the radiation to the involved field [25] and incorporating newer chemotherapeutic or targeted agents into CCRT regimens [26].
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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We thank Dr Yih-Leong Chang, Department of Pathology, for her helpful discussion and comments. We also thank Ching-Fang Bu and Wei-Ling Hsu, Department of Oncology, National Taiwan University Hospital, for their dedicated patient care. Presented in part at the 40th Annual Meeting of American Society of Clinical Oncology, New Orleans, 5–8 June 2004.
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Footnotes |
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These authors contributed equally to this study. 
Received for publication May 26, 2006. Revision received August 3, 2006. Accepted for publication August 14, 2006.
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References |
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