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Phase I Trial of Combined-Modality Therapy for Localized Esophageal Cancer: Escalating Doses of Continuous-Infusion Paclitaxel With Cisplatin and Concurrent Radiation Therapy

From the Gastrointestinal Oncology Service, Department of Medicine, the Department of Radiation Oncology, the Thoracic Service, Department of Surgery, and the Department of Epidemiology & Biostatistics, Memorial Sloan-Kettering Cancer Center, and the Weill School of Medicine, Cornell University, New York, NY

Address reprint requests to David P. Kelsen, MD, the Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; e-mail: kelsend{at}mskcc.org

	ABSTRACT

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PURPOSE: To define the maximum-tolerated dose (MTD) of paclitaxel when given as a weekly 96-hour infusion with cisplatin and radiotherapy for patients with esophageal cancer.

PATIENTS AND METHODS: Thirty-four patients with locally advanced esophageal cancer and three patients with local recurrence or positive resection margins were treated. Weekly paclitaxel doses of 10, 20, 30, 40, 60, and 80 mg/m², given as a continuous 96-hour infusion, were administered with weekly cisplatin, 30 mg/m² on day 1, weeks 1 to 6, and concurrent radiation (50.4 Gy). Plasma paclitaxel steady-state levels were measured.

RESULTS: Dose-limiting toxicity, defined as a treatment break longer than 2 weeks for toxicity, occurred in one patient in the 80-mg/m²/wk dose level. Major causes for any (including 2 weeks) treatment breaks were mediport complications and neutropenic fever, which occurred mostly at that dose level. At a paclitaxel dose of 60 mg/m²/wk, myelosuppression, mostly neutropenia, was relatively mild and transient; stomatitis, esophagitis, diarrhea. and peripheral neuropathy were uncommon and usually of grade 2 or less. Therefore, the MTD was established at 60 mg/m²/wk. The mean steady-state concentration of paclitaxel at the MTD was 17.2 nmol/L. Complete (R0) resection was possible in 16 (73%) of 22 patients who underwent subsequent surgery, and the pathologic complete response rate was 24%.

CONCLUSION: Weekly, 96-hour infusion of paclitaxel 60 mg/m²/wk, given with concurrent cisplatin and radiotherapy, is a safe and tolerable regimen for patients with localized esophageal cancer. Preliminary efficacy data are encouraging. This regimen is the basis of ongoing Radiation Therapy Oncology Group phase II randomized trials in esophageal and gastric cancers.

	INTRODUCTION

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Esophageal cancer is a highly aggressive neoplasm. In 2003, 13,900 Americans will be diagnosed with esophageal cancer, and more than 90% will die of their disease [1]. Approximately half of these patients present with locally advanced disease [2], with a less than 20% 5-year survival rate after surgical resection or radiation. These results have led to extensive exploration of multimodality treatment approaches. Adjuvant radiation or chemotherapy alone, with surgery, has thus far failed to clearly improve patient outcome [3-5]. In light of the survival advantage of concurrent chemoradiotherapy over radiation alone [6,7], combining chemoradiotherapy with surgery was attempted, with conflicting results in prospective randomized trials [8,9]. Improved chemoradiotherapy programs are required.

The most commonly used chemotherapy regimen for patients with esophageal cancer combines cisplatin and fluorouracil (FU). Nevertheless, cisplatin plus FU–based concurrent chemoradiotherapy programs have limited efficacy and are associated with substantial toxicity [6,7]. This has prompted the investigation of newer chemotherapy regimens for esophageal cancer, such as paclitaxel.

In light of the activity and improved toxicity of the paclitaxel plus cisplatin regimen in advanced disease and the potent radiosensitizing effects of both drugs [10], we evaluated this regimen with concurrent radiation in esophageal cancer. Protracted infusion of paclitaxel was used to exploit several potential benefits of this approach. Paclitaxel has been shown to temporarily arrest cells at the G2-M interface, the most radiosensitive cell cycle phase [11]. Prolonged exposure may increase the proportion of tumor cells in this phase and potentiate radiosensitization. Protracted infusion of paclitaxel may also be associated with higher response rate in several disease models [12-14], with a potentially improved toxicity profile. Therefore, we initiated the current phase I trial, combining bolus cisplatin and escalating doses of a 96-hour intravenous (IV) infusion of paclitaxel, both given weekly, with concurrent radiotherapy for esophageal cancer. The primary objective was to define the maximum-tolerated dose (MTD) of paclitaxel and the recommended dose for phase II trials.

	PATIENTS AND METHODS

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Eligibility
Patients (age 18 years) with histologically confirmed primary or recurrent epidermoid carcinoma or adenocarcinoma of the esophagus (including the gastroesophageal junction) were eligible for the study. Eligible patients included patients with primary disease clinically limited to the esophagus or nodal metastases only (T_1-4, N_0-1, M_0-1A), patients with locoregional failure only, and patients that underwent resection with positive microscopic margins. Patients had to be candidates for curative radiation therapy, with a Karnofsky performance status 60%, and could not have received any prior chemotherapy or radiotherapy. Required laboratory tests included a total WBC count 4,000/µL, a platelet count 150,000/µL, a serum creatinine 1.5 mg/dL and/or creatinine clearance of 65 mL/min/L, and a total serum bilirubin 1.5 mg/dL. Patients were excluded from participation in the study for the presence of any of the following: positive cytology of the pleura, pericardium, or peritoneum; metastases to distant organs; biopsy-proven invasion of the tracheobronchial tree; tracheoesophageal fistula; general medical condition preventing combined-modality treatment (eg, New York Heart Association grade 3 congestive heart failure); or active cancer arising at another primary site other than basal cell carcinoma of skin or in situ cervical carcinoma. The protocol was reviewed and approved by the Institutional Review Board of the Memorial Sloan-Kettering Cancer Center. Written informed consent was obtained from each patient.

Pretreatment Evaluation
Pretreatment evaluation included history, physical examination, electrocardiography, and assessment of bone marrow, renal, and hepatic functions. The extent of disease evaluation included chest radiography, upper endoscopy (with ultrasonography, if technically possible), barium esophagography, and chest and abdominal computed tomography (CT). Positron emission tomography was not used as part of the pretreatment evaluation because it was not a standard staging test for esophageal cancer at the time of the study. Bronchoscopy was performed for cervical or midesophageal tumors. Laparoscopy was recommended for patients with gastroesophageal junction tumors. Bone scan was performed if serum alkaline phosphatase was elevated, and audiography was performed if clinically indicated. The clinical tumor-node-metastasis system stage was defined according to the 1997 (version 5.0) American Joint Committee on Cancer staging system [15].

Treatment Plan
This phase I trial was designed as an open-label, nonrandomized, dose-escalation study. Groups of three to six patients received sequentially increased dosages of paclitaxel, given as a 96-hour continuous IV infusion, combined with a fixed dose of cisplatin and concurrent radiation treatment. Posttreatment surgical resection, usually for patients with residual active cancer, was performed at the discretion of the treating physician.

Radiotherapy
Multifield, external-beam megavoltage radiation was delivered using high-energy linear accelerators (15 MeV). Patients were treated with five daily fractions of 1.8 Gy per week over a 6-week period. The total radiation dose was 50.4 Gy, except for the three patients with prior surgery that involved esophagectomy with a gastric pull up. Because of the presence of the stomach in the target volume, these patients received 45.0 Gy. All fields were treated each day. Treatment was given with a combination of anterior-posterior, oblique, or lateral fields, such that the dose to the target volume did not differ from the dose specified at isocenter by greater than 10%. The administered dose was prescribed to the isodose line covering the volume at risk. Port films were taken of two fields per week or more often if clinically indicated.

The superior and inferior borders of the radiation field were 5 cm beyond the tumor, and the anterior, posterior, and lateral borders were 2 cm beyond the tumor, as defined by barium esophagography, CT, or esophageal ultrasonography (whichever was larger). The locoregional lymph nodes were included.

Chemotherapy
Chemotherapy was administered in the outpatient setting and consisted of weekly treatments of paclitaxel and cisplatin. Cisplatin was given at a fixed dose of 30 mg/m² by a bolus IV injection, and paclitaxel was administered at escalating doses by a 96-hour IV infusion, via an implanted venous access (mediport) and a portable pump, once weekly. Paclitaxel was started at least 3 hours before cisplatin. Before cisplatin administration, patients received IV hydration over 1 to 2 hours. Most patients received six weekly cycles (days 1, 8, 15, 22, 29, and 36 of the radiation treatment). Patients with prior surgery received a lower dose of radiation (45.0 Gy) and shorter course (5 weeks) of chemotherapy. Antiemetic therapy consisted of dexamethasone and 5-hydroxytryptamine-3 receptor antagonists. Given the protracted infusion of paclitaxel, no other premedication (eg, cimetidine or diphenhydramine) was required.

Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) was commercially available. During the 96-hour infusion, pump cassettes were prepared for two 48-hour treatment intervals (ie, with one cassette change on day 3). The total dose was administered through a standard 0.22-µm filter. Cisplatin was commercially available. The drug was infused via peripheral IV at a maximal rate of 500 mL/h.

Evaluation During the Study
During treatment, patients underwent weekly physician evaluation as well as CBC and serum creatinine. Within 4 to 8 weeks from the completion of chemoradiotherapy, upper endoscopy (with biopsy as clinically indicated), barium esophagraphy, and chest and abdominal CT were performed. Treatment responses were then evaluated both clinically, using the standard WHO response criteria, and pathologically. Clinical complete response (cCR) was defined as the disappearance of all residual disease by imaging studies and by endoscopy. Pathologic complete response (pCR) was defined as cCR with no viable tumor found in the endoscopic biopsy and in the resected primary tumor and regional lymph nodes, if operated. For purposes of clarity, surgically proven pCR was defined as surgical pCR.

Dose Escalation and Attenuation
The 96-hour infusion dose of paclitaxel was escalated in cohorts of three to six patients. Paclitaxel initial dose was 10 mg/m²/wk (or 2.5 mg/m²/d for 4 days), representing 17% of the MTD of paclitaxel (60 mg/m²/wk) from the phase I trial combining weekly 3-hour infusion of the drug with thoracic irradiation (60 Gy) for non–small-cell lung cancer [16]. This relatively low dose was chosen based on the significant toxicity observed in that trial, even at the MTD, as well as on several reports suggesting increased gastrointestinal toxicity with prolonged infusions of paclitaxel [13,14]. Paclitaxel doses were escalated using a modified Fibonacci schema.

Toxicities were graded according to the National Cancer Institute common toxicity criteria version 1 and the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria. Although chemotherapy dose attenuation was allowed for toxicity, this was required mainly at the paclitaxel 80 mg/m²/wk dose level. If, according to the dose attenuation schema, chemotherapy had to be held because of toxicity, both drugs, as well as radiation therapy, were held. Dose-limiting toxicity (DLT) was defined as a toxicity-related treatment break greater than 2 weeks. Hospitalization for toxicity, by itself, was not defined as DLT. If DLT occurred, treatment was discontinued, and further therapy was decided by the treating physician. If one of three patients treated at a given paclitaxel dose level experienced a DLT, then three more patients were to be treated at that dose level. If a second patient experienced a DLT, then the MTD was defined. If at a given dose level, six patients were treated and less than two patients had DLT, but substantial toxicities were seen, additional patients may have been added to that level, to clarify its safety and tolerability. A minimum of three patients had to complete the entire chemoradiotherapy program and to be followed for 4 weeks afterwards before the trial could escalate to the next dose. If none of the three patients experienced a DLT, then patients were entered at the next higher dose level.

Pharmacokinetics
Assessments of plasma steady-state paclitaxel concentrations were performed on weeks 1 and 4 of the infusion period. Plasma samples were drawn at time 0 (before treatment initiation) and then twice weekly, on days 2 to 3 and 4 to 5 of these weeks. Paclitaxel concentrations were measured using a standard high-performance liquid chromatography [17]. For each patient, the steady-state paclitaxel concentration was calculated as the mean of the results of all samples drawn while receiving treatment.

Postchemoradiotherapy Management
Patients underwent a repeat extent of disease evaluation on the completion of the combined-modality treatment. Patients may have had surgical resection or expectant observation, at the discretion of the treating physician. Development of systemic metastases or locoregional progression was considered a treatment failure. Patients were evaluated every 3 months for the first 2 years after treatment, every 6 months for the next 3 years, and then annually. Surveillance included interim history, physical examination, and laboratory testing. Upper endoscopy and chest and abdominal CT were performed every 6 months for 2 years and annually thereafter.

Biostatistics
The trial was designed using a conventional dose-escalation schema with the primary objective of defining the MTD of a protracted infusion of paclitaxel in this program. The MTD was defined as one dose level below that at which two or more patients experienced DLT. The described design (see Dose Escalation and Attenuation) provided a 91% chance of dose escalation if the true incidence of DLT at that dose level was 10%, a 31% chance of escalation if the true incidence was 40%, and only a 3% chance of escalation if the true incidence was 70%. Survival was recorded from the onset of treatment to death. Survival probabilities were estimated by the Kaplan-Meier method [18].

	RESULTS

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Patient Characteristics
Between December 1996 and July 1999, 34 patients with previously untreated locally advanced esophageal cancer; two patients with positive surgical margins and one patient with locally recurrent disease were enrolled onto this trial. The patient characteristics are listed in Table 1. All patients received at least one dose of the cisplatin and paclitaxel combination with radiation and were, therefore, considered assessable for toxicity. All 34 patients who received the treatment as primary therapy of their cancer were assessable for treatment efficacy. Twenty-nine patients (78%) were men, and 33 (89%) were white. The median age was 59 years, and the median Karnofsky performance status was 90%. Twenty-five patients (68%) had adenocarcinoma, and 28 (76%) had a tumor of the lower esophagus (nine patients) or the gastroesophageal junction (19 patients, all Siewert type I). Twenty-one patients (57%) had clinical stage III or IVA disease, and all patients who were classified as IIA had T3N0 disease.

Treatment Delivery
Table 4 summarizes treatment delivery according to cohort. At least 89% of the planned dose of chemotherapy was delivered. Three dose reductions for toxicities, all in the last cohort (80 mg/m²/wk), were required. Treatment continuity was interrupted by 12 breaks, nine of which occurred in the last cohort. A treatment break longer than 2 weeks, which was defined as a DLT, occurred in only one patient at the highest paclitaxel dose level. Although only one DLT was observed in that cohort, it was felt that 80 mg/m²/wk was associated with an excessive overall toxicity; eight (47%) of 17 patients in this cohort had grade 3 neutropenia, compared with two (10%) of 20 patients in the others. This cohort had twice as many incidents of grade 3 nonhematologic toxicity (n = 16) than all the other cohorts together (n = 8). As described above, this toxicity has also led to an increased number of treatment breaks. Therefore, a paclitaxel dose of 60 mg/m²/wk was defined as the MTD and the recommended phase II dose for subsequent trials. Five patients did not complete the entire treatment program because of excessive toxicity (three patients), withdrawn consent (one patient), or severe obstruction requiring surgical intervention (one patient).

View larger version (16K): [in this window] [in a new window]   Fig 1. Individual patient mean steady-state serum paclitaxel concentrations according to dose levels (mg/m2/w) (n = 34). In parentheses is the number of patients with available data in each cohort. Acceptable thresholds for neutropenia and radiosensitization are also shown. Min, minimum.

With a median follow-up of 47 months (range, 23 to 64 months), 14 patients (38%) are still alive, and 13 of these (35%) have no evidence of disease recurrence. The 3-year survival rate for the entire patient population was 43% (Fig 2). Eight patients achieved cCR and were not operated on. Of these, three patients are still alive and have been free of disease for over 4 years, one patient died with no evidence of disease recurrence, and four patients died of disease. Notably, in only one of these four patients, the disease recurred within the irradiated area; in three of the patients, it recurred in the liver. Overall, locoregional control was achieved in seven of the eight patients. The failure pattern of these patients may be the most indicative of the impact of the chemoradiotherapy program.

View larger version (10K): [in this window] [in a new window]   Fig 2. Survival for all patients (N = 37).

	DISCUSSION

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Therapy was generally well tolerated. Moderate to severe toxicities (grade 3) were rare and were mostly observed at the highest dose level. The most common toxicities were fatigue and nausea and vomiting, but the most frequent clinically significant toxicities were mediport complications and neutropenia. Although these toxicities required several admissions, a treatment break exceeding 2 weeks, defined as the DLT in our study, occurred only once. The last dose level was associated with substantial toxicity that we considered to have been a DLT. Therefore, the recommended dose of paclitaxel in this regimen was determined to be 60 mg/m²/wk. Significant esophagitis, stomatitis, and diarrhea were rare. Neurologic toxicity was infrequent and mild.

Perhaps the most widely used regimen for chemoradiotherapy therapy for localized esophageal cancer is that used in the RTOG 85-01 trial [6]. In that trial, chemoradiotherapy was associated with 44% and 20% grade 3 and 4 acute toxicities, respectively, mostly esophagitis and neutropenia. Chemotherapy was delivered as planned to only 68% of the patients [6,24]. Other FU and cisplatin–based regimens have been also associated with significant toxicities, primarily gastrointestinal. Heath et al [25] reported grade 3 esophagitis or stomatitis in 24% of patients treated with cisplatin plus FU and radiotherapy; 74% of the patients required enteral nutritional support.

Paclitaxel has been combined with cisplatin and concurrent thoracic irradiation in esophageal and lung cancers mainly as a short infusion. In a trial involving 41 patients with esophageal cancer, a weekly 3-hour infusion of 60 mg/m² of paclitaxel and 25 mg/m² of cisplatin were given. The DLT was neutropenia (grade 3 in 24% of the patients); grade 3 esophagitis was observed in 17% of patients [26]. In two lung cancer trials using similar programs, both neutropenia and esophagitis were common [27,28]. In esophageal cancer, Adelstein et al [29] tried to prolong the paclitaxel infusion; they used a once every 3 weeks regimen of cisplatin and a 24-hour infusion of paclitaxel with concurrent split-course accelerated irradiation. Grade 3 neutropenia and esophagitis were observed in 95% and 13% of the patients, respectively. Using a combination of 96-hour infusion of paclitaxel and cisplatin without concurrent radiotherapy in two lung trials giving paclitaxel 30 mg/m²/d on days 1 to 4 together with cisplatin 80 mg/m² on day 5 every 3 weeks, half of the patients experienced grade 3 neutropenia and approximately 10% experienced grade 3 nausea [30,31].

In the current study, we noted a tolerable toxicity profile at paclitaxel 60 mg/m²/wk. This seems to have less esophagitis and neutropenia than that observed with FU-based programs and, to a lesser extent, those using short infusions of paclitaxel. However, the current treatment was associated with a 24% rate of mediport complications. Other studies using protracted infusion through central venous access devices, including three lung cancer trials using a 96-hour infusion of paclitaxel, did not report similar rates [14,30-32]. It is unclear why a higher rate was seen in our study.

Several pharmacokinetic observations were made. Paclitaxel concentrations were relatively steady over time. Preclinical data suggest that 10 nmol/L represents a threshold for paclitaxel antineoplastic and radiosensitizing effects [11,33-35]. It was also shown that the best pharmacodynamic predictor for toxicity is the duration of exposure to concentrations above a certain level, probably 50 nmol/L [36,37]. In our trial, 82% of the patients around the MTD had mean paclitaxel concentrations within the suggested therapeutic window of 10 to 50 nmol/L. It also seems that patients with significant toxicity had relatively higher concentrations.

The long median follow-up in this trial provides some information as to the potential efficacy of the regimen. We noted a 24% pCR rate, a 73% R0 resection rate in operated patients, and a 43% 3-year survival. These data are encouraging.

In summary, weekly treatment with cisplatin and a 96-hour infusion of paclitaxel, with concurrent irradiation, is feasible and safe. The recommended dose levels in this schedule are cisplatin 30 mg/m², paclitaxel 60 mg/m²/wk, radiation therapy 50.4 Gy. Antitumor efficacy is encouraging. Two RTOG phase II randomized trials in esophageal and gastric cancers are currently using this regimen as one of their investigational arms.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: David Ilson, Sanofi; Bruce Minsky, Sanofi, Roche, Bristol-Myers-Squibb, and Pfizer. Performed contract work within the last 2 years: Bruce Minsky, Sanofi, Roche, Bristol-Myers-Squibb, and Pfizer. Received more than $2,000 a year from a company for either of the last 2 years: David Ilson, Roche and Pfizer; Bruce Minsky, Sanofi, Roche, Bristol-Myers-Squibb, and Pfizer.

	NOTES

 
Supported in part by grant no. U01 CA69913 from the National Cancer Institute, Bethesda, MD.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted May 6, 2003; accepted October 9, 2003.

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