Annals of Oncology Advance Access originally published online on March 9, 2007
Annals of Oncology 2007 18(5):898-902; doi:10.1093/annonc/mdm004
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© 2007 European Society for Medical Oncology
gastrointestinal tumors |
Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer
1 Memorial Sloan-Kettering Cancer Center, New York, NY
2 Veterans Affairs Medical Center, Washington DC
3 Roswell Park Cancer Institute, Buffalo, NY, USA
* Correspondence to: Dr D. H. Ilson, 1275 York Avenue, New York, NY 10021, USA. Tel: +1-212-639-8306; Fax: +1-212-717-3320; E-mail: ilsond{at}mskcc.org
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Abstract |
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Background: The purpose of the study was to evaluate the efficacy of weekly paclitaxel (Taxol) in advanced esophageal cancer.
Patients and methods: One hundred and two patients with advanced esophageal cancer were treated with paclitaxel 80 mg/m2 weekly over a 1-h infusion. One cycle was defined as 4 weeks of therapy. Ninety-five patients were assessable for toxicity and 86 patients who completed at least two cycles of treatment were assessable for response. Sixty-six patients had adenocarcinoma (66%) and 65 patients (68%) had no prior chemotherapy.
Results: A median of three cycles was delivered (range 1–11). Partial responses (PRs) were seen in 11 patients [13%, 95% confidence interval (CI) 6% to 20%]. In patients without prior chemotherapy, PRs were seen in 10 patients (15%, 95% CI 6% to 24%), with comparable response in adenocarcinoma (8/50, 16%) and squamous carcinoma (2/15, 13%). Limited response was seen in patients with prior chemotherapy (1/21, 5%). The median duration of response was 172 days. The median survival was 274 days. Therapy was well tolerated with minimal hematologic or grade 3 or 4 toxicity.
Conclusion: Weekly paclitaxel has limited activity in esophageal cancer. The median survival, modest activity, and tolerance of therapy indicate that weekly paclitaxel may be an option in patients unable to tolerate combination chemotherapy.
Key words: adenocarcinoma, esophageal cancer, squamous cell carcinoma, weekly paclitaxel
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Esophageal cancer is the seventh leading cause of cancer death in men in the United States and will account for 13 770 cancer deaths in the year 2006 [1]. Adenocarcinoma of the distal esophagus, gastroesophageal (GE) junction, and proximal stomach is increasing in incidence and represents an emerging health epidemic in the United States and other Western countries [2]. Overt and incurable metastatic disease is present at diagnosis in 50% of patients, and chemotherapy is the mainstay of palliative treatment. For patients presenting with locally advanced disease treated with primary radiotherapy, systemic chemotherapy is combined with concurrent radiotherapy as the standard of care for radiation-based management. Combined chemoradiotherapy given as preoperative treatment followed by surgery remains a focus of clinical investigation, given the generally poor long-term survival of <20%–30% achieved with surgery alone [3, 4].
Paclitaxel, an antimicrotubule agent isolated from the bark of the Pacific yew, Taxus brevifolia, has undergone phase I and II evaluation in esophageal squamous cell and adenocarcinoma. Trials have evaluated paclitaxel as a single agent and in combination chemotherapy in metastatic disease, and given with concurrent radiotherapy in locally advanced disease. We previously evaluated, in a two-institution trial, paclitaxel given at a dose of 250 mg/m2 by 24-h infusion with granulocyte colony-stimulating factor support. We observed a response rate of 32% in 52 patients [5]. We subsequently undertook phase II trials combining paclitaxel administered once every 3–4 weeks, by either 3-h or 24-h infusion with cisplatin, with and without fluorouracil (5-FU) [6, 7]. Promising antitumor activity ranging from 44% to 48% was observed for paclitaxel combination therapy. Toxicity for combination therapy, however, was significant and included severe myelosuppression, gastrointestinal (GI) and neurologic toxicity, and a significant rate of hospitalization for therapy-related complications. Trials attempting to add concurrent radiotherapy to a once every 3- to 4-week infusion schedule of paclitaxel, in combination with cisplatin, or cisplatin and 5-FU, have also reported substantial and often prohibitive toxicity [8–10].
The identification of the optimal dose and schedule of paclitaxel to use in combination chemotherapy, or in combined modality therapy, is clearly central to the further development of this agent in the treatment of esophageal cancer. Administration of paclitaxel by a once a week, 1-h infusion has proven to have minimal therapy-related toxicity in phase I and II trials in breast and ovarian cancer. Response rates have ranged from 30% in single-institution phase I/II trials in ovarian cancer and non-small-cell lung cancer [11, 12] to 21%–53% in breast cancer [13, 14] with activity seen in both previously treated and untreated patients. On the basis of these promising results, we evaluated the activity of weekly 1-h paclitaxel in patients with advanced esophageal cancer in the current trial.
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patients and methods |
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The study reported in this article was a multicenter, collaborative trial led by the Memorial Sloan-Kettering Cancer Center. Patients were accrued at 23 participating centers. Support for the trial was provided by Bristol-Myers Squibb(Princeton, New Jersey).
Patients were eligible if they had histologic proof of unresectable, metastatic, or locally recurrent squamous cell carcinoma or adenocarcinoma of the esophagus. Patients with tumors of the GE junction were eligible if the bulk of the tumor involved the esophagus or GE junction. Gastric cancers were not eligible. No prior chemotherapy for metastatic disease was allowed. Prior nontaxane-containing chemotherapy given in the adjuvant or neo-adjuvant setting, given alone or in combination with radiation therapy, was permitted. Prior radiotherapy was allowed as long as it encompassed 
30% of the bone marrow. Patients had to have either bidimensionally measurable disease or evaluable disease. Patients were required to be 
18 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of two or less, and have a life expectancy of 3 months. Adequate hematologic function (absolute granulocytes 1500/uL, platelets 100 000/uL), hepatic function (bilirubin 2.0 mg/dl, aspartate aminotransferase less than or equal to two times the institution upper limit of normal), and renal function (serum creatinine less than or equal to two times the institution upper limit of normal) were required. Patients were ineligible if they had brain metastases. Patients were excluded for New York Heart Association Class III/IV heart disease, unstable angina, myocardial infarction within 6 months, congestive heart failure, or significant cardiac arrhythmia or pericardial effusion. Patients with a history of peripheral neuropathy greater than grade 1 were excluded. Patients with a history of prior malignancy within 5 years, with the exception of basal or squamous cell skin cancers or in situ cervix cancer, were also excluded.
The study was approved by the Institutional Review Board of each participating institution, and all patients signed an informed consent document that described the investigational nature of the protocol treatment.
Toxicity was graded by the National Cancer Institute Common Toxicity Criteria. The criteria for response were those reported by Miller et al. [15]. Either measurable or evaluable disease was permitted, but lesions that were treated with prior radiotherapy were not considered to be evaluable for response. Measurable disease was defined as tumor masses that could be evaluated by X-ray, computed tomography (CT), or physical examination in which two perpendicular dimensions could be obtained and followed serially. Mediastinal or hilar lymph nodes had to measure at least 3 cm x 1cm to be considered measurable. A complete response (CR) required disappearance of all evidence of tumor for at least 4 weeks, and for patients with the primary tumor in place or with locally recurrent disease, endoscopic confirmation of a CR with normal endoscopic biopsies or brushings was required. A partial response (PR) was defined as a >50% reduction in the sum of the products of the longest perpendicular diameters of indicator lesions for a period of at least 4 weeks. Evaluable disease was defined as radiographically distinct unidimensional tumor that could be evaluated serially by radiographic studies (i.e. the primary tumor evaluated by double-contrast barium esophagram or CT). Response in evaluable disease was defined as a >50% improvement in unidimensional disease as determined by at least two observers. Duration of response was defined as lasting from documentation of the response to documentation of disease progression.
Pretreatment evaluation included a complete history, physical examination, and a pretreatment 12 lead electrocardiogram. Laboratory evaluation included a complete blood count and chemistry panel with liver function tests. Radiographic evaluation included a chest radiograph, CT of the chest and abdomen, and barium esophagram if the primary tumor was used as the indicator lesion. While on therapy, a complete blood count and platelet count were obtained weekly and blood chemistries were repeated before each 4-week treatment cycle. Repeat radiographic studies were carried out after every two treatment cycles, or at 4 weeks after the observation of a major response, to confirm the response.
treatment plan
Treatment was delivered in the outpatient setting. All patients were premedicated intravenously (i.v.) 30–60 min before therapy with dexamethasone 20 mg, cimetidine 300 mg (or a comparable H2 blocker), and diphenhydramine hydrochloride 50 mg. Paclitaxel (Taxol® Bristol-Myers Squibb, Princeton, NJ) was administered at a starting dose of 80 mg/m2 i.v. over 1 h. One cycle consisted of weekly therapy given over 4 weeks. Dose reductions in increments of 10 mg/m2 were made if thrombocytopenia (platelet count 50 000) or neutropenia (absolute granulocyte count 800) occurred, or if patients developed grade 3 or 4 fatigue, myalgia, or arthralgia. If grade 2 neuropathy developed, a dose reduction by one level was permitted but therapy was allowed to continue as long as neuropathy remained less than or equal to grade 2. A 1-week treatment delay was permitted to allow recovery from toxicity, but delay of therapy of 2 weeks or longer mandated patient removal from the study.
statistical analysis
The primary study end point was treatment response rate. A sample size of 89 patients who were assessable for assessment of response was calculated, to demonstrate an anticipated response rate of 25% with a confidence interval (CI) of between 16%–34%, to contain the actual response rate with an alpha error of 0.05. Allowing for patient dropouts and other reasons that would declare a patient not assessable, a total sample size of 100 patients was estimated to be required.
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results |
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patients
Patient characteristics are outlined in Table 1. One hundred and two patients were accrued at the 23 participating cancer centers from January 1998 through April 2000. Half of the patients accrued were treated at three cancer centers (Memorial Sloan-Kettering Center, Veterans Administration Medical Center of Washington, DC, and the Roswell Park Cancer Institute). Five patients were deemed ineligible (5%) for the following reasons: prior radiotherapy within <4 weeks of starting therapy, prior radiotherapy to the indicator lesion, prior chemotherapy for metastatic disease, and two patients with absence of measurable or evaluable disease. Two additional patients (2%) were inevaluable for toxicity or response due to withdrawal of consent in one patient and delivery of concurrent radiotherapy in one patient. A total of 95 patients were assessable for toxicity (93%). Sixty-three patients had adenocarcinoma (66%) and 32 patients had squamous cell carcinoma (34%). Twenty-one patients had received prior chemotherapy in the adjuvant setting (22%), and 19 of these patients received prior concurrent chemotherapy and radiotherapy (20%). Nineteen patients had undergone prior esophagectomy (20%). The vast majority of patients were male (93%) with a good PS (median ECOG PS of 1). The median age was 59 (range 40–87). More than half of patients (57%) had hepatic metastases. Seventy-eight patients had bidmensionally measurable disease (82%) and 17 patients had evaluable disease (18%).
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Nine patients (9%) were assessable for toxicity only but not for response due to the following reasons: two patients with death after less than one cycle of therapy, due to GI bleeding (after one dose of therapy) and coronary disease (after two doses of therapy); two patients with paclitaxel allergy preventing further treatment (after the first dose); rapid decline in PS or removal for toxicity before response assessment after less than two cycles (four patients); and one death from GI bleeding before response assessment after less than two cycles (one patient). A total of 86 patients (84%) were assessable for response to therapy.
response and survival
Response to therapy is outlined in Table 2. PRs were seen in 11 of 86 assessable patients (13%, 95% CI 6% to 20%). Responses were seen in 10 of 65 patients without prior chemotherapy (15%, 95% CI 6% to 24%) and in one of 21 patients with prior chemotherapy (5%, 95% CI 0% to 14%). No CRs were observed. If the additional nine patients (all previously untreated) who completed less than two cycles of therapy due to death, disease progression, or toxicity are included, the response rate was 12% in all patients (11/95, 95% CI 5% to 19%) and 13% in previously untreated patients (10/74, 95% CI 5% to 21%). Responses were seen in nine of 61 patients with adenocarcinoma (15%), including eight responses in 50 patients without prior chemotherapy (16%, 95% CI 6% to 26%). Two of 25 patients with squamous carcinoma responded to therapy (8%), with both responses seen in the 15 patients without prior chemotherapy (13%, 95% CI 0% to 30%). The median duration of response was 172 days (range 85–578 days). The median time to progression was 93 days. Responses were seen in 10/70 patients (14%) with measurable disease and one of 16 patients (6%) with evaluable disease. Forty-three patients achieved stable disease (SD) (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) as best response (50%), including 52% of patients without prior chemotherapy and 41% of patients with prior chemotherapy. Thirty-two patients had disease progression as best response (37%).
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The median survival was 274 days (21–1178+ days). The 1-year survival was 30% (95% CI 20% to 39%) and the 2-year survival was 6% (95% CI 0% to 11%).
toxicity and therapy delivery
Therapy on study was generally very well tolerated. Toxicity in the 95 assessable patients is outlined in Table 3. Grade 3 or 4 toxicity was uncommon, and the majority of toxic effects were grade 1 or grade 2. Rare grade 3 toxic effects included asthenia (three patients, 3%) and nausea (two patients, 2%). Neurologic toxicity of any grade was seen in 42 patients (44%), but this toxicity was primarily grade 1 (29 patients, 30%) and less commonly grade 2 (10 patients, 11%). Grade 3 neurologic toxicity was uncommon and was seen in only three patients (3%). Two patients developed foot drop grade 1 or 2 (2%). Musculoskeletal toxicity, including myalgias (7%) and arthralgias (10%), was also uncommon and grade 1 in the majority of patients. GI toxicity was uncommon and usually grade 1 or 2, and included nausea in 25% and vomiting in 16% of patients and diarrhea in 20%. Hypersensitivity or allergic reactions to paclitaxel leading to therapy discontinuation occurred in only two patients (2%).
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Hematologic toxicity was relatively mild, with grade 3 or 4 neutropenia seen only in five patients (5%). The median nadir for absolute neutrophils was 2.6 (range 0.1–7.5). Neutropenic sepsis occurred in only one patient (1%) and led to the only treatment-related fatality on study. Thrombocytopenia was also uncommon with only one patient with grade 4 thrombocytopenia (1%). The median nadir for platelets was 228 (range 15–526)
Adverse events related to therapy leading to hospitalization occurred in 12 patients (13%), most commonly due to fever, pneumonia, or sepsis (five patients, 5%) or treatment of severe anemia (two patients, 2%). Other isolated causes of hospitalization included dehydration (two patients), and one patient each with paclitaxel allergy, severe neuropathy, and dyspnea. Seven patients were taken off study for serious adverse events (7%), most commonly for neuropathy (three patients) and paclitaxel allergy (two patients). One patient came off study for diarrheal toxicity and one patient died of neutropenic sepsis.
A total of 1312 doses were delivered to 95 patients. The median number of cycles was three (range 1–11). Only 101 doses (7.7%) were affected by either a delay in therapy delivery (59 doses, 58.4%) or a dose reduction due to toxicity (42 doses, 41.6%). One treatment delay was experienced in 26 patients (27%), five patients had two delays (5%), and 13 patients three or more delays (14%). The most common reason for therapy delay was at the patient's request, for personal reasons, and less commonly for fatigue. A dose reduction for toxicity affected seven patients (7%). The most common reason for dose reduction for toxicity was neurologic toxicity (three patients, 3%) followed by two patients each with diarrhea (2%) or neutropenia (2%).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The administration of paclitaxel by a weekly 1-h infusion has modest but limited activity in metastatic esophageal cancer, with similar response rates seen in squamous cell and adenocarcinoma. Although the anticipated response rate of 25% was not observed, the overall response rate of 15% in patients without prior chemotherapy is comparable to other single agents screened in phase II trials in advanced esophageal and GE junction cancer, including docetaxel [16, 17], irinotecan [18, 19], and vinorelbine [20]. The response rate for the 1-h infusion schedule in this large, multicenter trial is <32% response rate reported for the initial, smaller, two-institution trial evaluating paclitaxel by 24-h infusion. The diminution of response rates observed in larger, multicenter trials in comparison to single-institution trials is not uncommon and probably due to patient selection. A similar observation occurred in breast cancer trials, in which the multicenter evaluation of weekly 1-h paclitaxel yielded a response rate of 21.5% compared with the 53% response rate observed in the initial single-institution trial [13, 14].
Nearly all of the responses in the current trial were seen in chemotherapy naive patients, with only one response seen in patients with prior chemotherapy treatment. In both untreated and previously treated patients, a significant percentage of patients had disease stabilization, with 52% of patients without prior chemotherapy and 41% with prior chemotherapy achieving SD on therapy. The median duration of response and median survival achieved on trial are comparable to reports of other trials of both single agent and combination chemotherapy in advanced esophageal cancer.
The toxicity profile of weekly paclitaxel was favorable in this trial, with the majority of patients experiencing only grade 1 or grade 2 toxicity. Hematologic toxicity was minimal, with only 5% of patients experiencing grade 3 or 4 neutropenia. Neurologic toxicity, a problem observed in trials of paclitaxel administered once very 3–4 weeks using a short infusion schedule [6], was also minimal and mainly grade 1, despite the delivery of a relatively dose dense schedule of paclitaxel.
The minimal toxicity and ease of administration of weekly paclitaxel, and modest antitumor effectiveness, indicate that this therapy may be a treatment alternative in patients unable to tolerate combination chemotherapy. A weekly 1-h infusion schedule of paclitaxel may also be appropriate for development in combination chemotherapy or incorporation into combined modality therapy administered with concurrent radiotherapy. Trials employing a weekly schedule of paclitaxel, administered over a 3-h or 96-h schedule, in combination with cisplatin and radiotherapy have indicated a lessening of myelosuppression and esophagitis [21–25]. Weekly paclitaxel and carboplatin combined with radiotherapy appears to be active and well tolerated as preoperative therapy in esophageal cancer as reported in a recent phase II trial [26], and a recent phase II trial combined the epidermal growth factor receptor-targeted antibody cetuximab to weekly paclitaxel, carboplatin, and radiation therapy in esophageal and gastric cancer [27]. Other centers have combined weekly paclitaxel with continuous infusion 5-FU and radiotherapy in locally advanced disease [28]. The ECOG recently completed a randomized phase II trial comparing weekly 1-h paclitaxel, cisplatin, and concurrent radiotherapy to weekly irinotecan, cisplatin, and radiotherapy as preoperative therapy in esophageal cancer.
Combined modality therapy trials have attempted to combine radiotherapy with a conventional schedule of paclitaxel and cisplatin, using a once every 3- to 4-week dosing of 3-h or 24-h paclitaxel, in combination with cisplatin or carboplatin, either with or without administration of 5-FU [8–10]. Toxicity on these trials has been substantial in some cases prohibitive [8, 9]. The weekly 1-h infusion schedule of paclitaxel may represent the optimal way to develop this agent in combination therapy and combined modality therapy.
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Footnotes |
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Current address: Eisenhower Medical Center, Rancho Mirage, CA, USA 
Received for publication September 26, 2006. Revision received January 8, 2007. Accepted for publication January 9, 2007.
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References |
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