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Phase I Trial of Twice-Weekly Gemcitabine and Concurrent Radiation in Patients With Advanced Pancreatic Cancer

From the Departments of Radiation Oncology, Wake Forest University Baptist Medical Center, Winston-Salem, and University of North Carolina at Chapel Hill, Chapel Hill, NC.

Address reprint requests to A. William Blackstock, MD, Department of Radiation Oncology, Wake Forest University, Medical Center Blvd, Winston-Salem, NC 27516; email ablackst{at}wfubmc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer.

PATIENTS AND METHODS: Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m² by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m² increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed.

RESULTS: The dose-limiting toxicities at 60 mg/m² given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m² dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression.

CONCLUSION: A dose of twice-weekly gemcitabine at 40 mg/m² produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE ANNUAL INCIDENCE and overall number of deaths from pancreatic cancer in developing countries are virtually identical; in 1994 an estimated 81,000 new cases were diagnosed, resulting in 78,000 deaths worldwide.¹ Approximately two thirds of all patients with pancreatic cancer have metastatic disease at the time of diagnosis,² whereas the majority of the remainder have locally advanced unresectable disease.^3,4 A number of studies have shown little benefit with various single-agent and combination chemotherapies for patients with locally advanced disease,^5-7 whereas concurrent fluorouracil and ionizing radiation results in a twofold increase in median survival.^8,9 Despite the limited benefits of concurrent fluorouracil and radiation therapy, many oncologists consider it standard therapy for patients with locally advanced unresectable pancreatic cancer. However, because of the limitations of this combination, further enhancement of the effect of radiation on local disease would be a major asset in obtaining local control and improved relief of symptoms produced by local disease progression.

2'2'-Difluoro-2'-deoxycytidine (gemcitabine) is a fluorine-substituted cytarabine analog. Once the parent drug is converted intracellularly to its active forms, gemcitabine diphosphate and triphosphate, its metabolites reduce the cellular deoxycytidine triphosphate levels. This facilitates both increased gemcitabine phosphorylation and decreased elimination, resulting in continued inhibition of cellular DNA synthesis. Gemcitabine has demonstrated antitumor activity in a number of murine tumor models and in human tumor xenografts.^10-12 Gemcitabine has become the drug of choice for patients with metastatic pancreatic cancer on the basis of randomized studies that demonstrated improved quality of life, although not substantial improvement in survival.¹³

Because gemcitabine decreases intracellular deoxyribonucleotide pools, we and other investigators have postulated the use of gemcitabine as a radiation sensitizer. The initial in vitro work was reported by Lawrence,¹⁴ who showed that 24-hour cell exposures to noncytotoxic concentrations of gemcitabine, when combined with ionizing radiation, resulted in increased cell kill. Additional studies from the University of Michigan demonstrated that equivalent levels of sensitization with a 4-hour exposure of gemcitabine required a threefold increase in drug concentration. These data from Michigan suggest the radiation sensitization is related to altered deoxynucleoside triphosphate pools. Subsequent in vitro and in vivo data from our laboratory in an HT-29 human colon cancer model confirmed gemcitabine as a potent radiation sensitizer. Animal xenografts treated with radiation versus radiation and gemcitabine on a Monday-and-Thursday schedule showed slower tumor growth in patients who received the combined modality therapy.¹⁵

On the basis of these data, a phase I study was undertaken to determine the maximum-tolerated dose (MTD) of twice-weekly gemcitabine that could be delivered concurrently with upper abdominal radiation therapy in the treatment of advanced pancreatic cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Patients with histologically or cytologically confirmed adenocarcinoma of the pancreas were enrolled onto this study from March 1997 to September 1998 at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. Eligible patients were clinically or surgically staged and considered unresectable for cure or medically inoperable. Patients with metastatic disease were eligible if the principal symptom associated with their primary disease was pain and if they had an estimated life expectancy greater than 6 months.

Eligibility criteria also included an Eastern Cooperative Oncology Group performance status of 0 to 2, age 18 years, measurable or assessable disease, adequate hematologic function (granulocyte count > 1,500/µL, hemoglobin level > 10 g/dL, and platelet count > 100,000/µL), adequate renal function (serum creatinine concentration < 2.0/dL), and a life expectancy greater than 2 months. A complete history and physical examination was performed on all patients before treatment. Height, weight, performance status, and tumor stage were recorded at registration. A chest radiographic and abdominal computed tomographic or magnetic resonance imaging study were also performed. All patients gave written informed consent according to federal and institutional guidelines. Data collection and analysis were performed at the Wake Forest University Baptist Medical Center.

Gemcitabine Dosage
Gemcitabine was administered as a 30-minute intravenous infusion each Monday and Thursday for 5 weeks. Gemcitabine was given within 2 hours before radiation treatment. The starting dose of gemcitabine was 20 mg/m² twice weekly (40 mg/m²/wk). Odansetron (Zofran; Cerenex, a division of Glaxo Wellcome Pharmaceuticals, Research Triangle Park, NC) 24 to 32 mg or granisetron (Kytril; SmithKline Beecham, King of Prussia, PA) 2 mg and lorazepam (Ativan; Wyeth-Ayerst Laboratories, Philadelphia, PA) 0.1 to 1 mg were administered 30 minutes before gemcitabine. Patient cohorts had a minimum of three patients at each dose level. If grade 4 toxicity was observed in one or more of the initial three patients or grade 3 toxicity in two or more patients, three additional patients were evaluated at that dose level. If no dose-limiting toxicity was noted, the dosage was escalated in successive cohorts by 20 mg/m². Dose-limiting toxicity was defined as grade 3 or 4 toxicity according to Cancer and Leukemia Group B expanded common toxicity criteria observed at any time during the course of therapy. Grade 4 toxicity in two or more of six patients or grade 3 in four or more of six patients resulted in the preceding dose level being declared the MTD.

Radiation Therapy
An initial 45 Gy in 1.8-Gy daily fractions was delivered to the tumor, peripancreatic nodal regions, and a 1.0- to 2.0-cm margin (to account for set-up variation, patient motion, and tumor volume uncertainty). The celiac axis was treated at the discretion of the radiation oncologist. The boosted volume included the original tumor volume with a 1.0-cm margin and an additional 5.4 Gy in 1.8-Gy daily fractions. The specific design and configuration of the fields were individualized based on the volume and location of the disease. Four field beam arrangements and 10- to 15-mV photon energies were required. In general, a four-field approach used anteroposterior and left and right lateral beams. The spinal cord dose was limited to 45 Gy. To decrease hepatic irradiation, the anteroposterior fields were generally weighted more heavily that the lateral fields.

Criteria for Therapeutic Response
Abdominal imaging studies (either computed tomography or magnetic resonance imaging) were performed every 8 weeks after the completion of therapy. Complete response required the disappearance of all measurable or assessable disease signs, symptoms, and biochemical changes related to the tumor for more than 4 weeks' duration. A partial response required a reduction of greater than 50% in the sum of the products of the perpendicular diameters of the irradiated lesions lasting for longer than 4 weeks, during which no new lesions could appear and no existing lesions could enlarge within the irradiated volume.

Stable disease reflected a less than 50% reduction and a less than 25% increase in the sum of the products of the perpendicular diameters of irradiated lesions and the appearance of no new lesions in the irradiated field for an interval of more than 8 weeks. A greater than 25% increase in the sum of the products of the perpendicular diameters of irradiated lesions was defined as progressive disease.

	RESULTS

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Patient Characteristics
The median age was 61 years (range, 39 to 83 years). Of the 19 patients entered onto the study, two had metastatic disease at the time of enrollment. All patients with localized disease had unresectable tumors determined either at the time of laparotomy or via radiographic imaging studies that demonstrated vascular involvement or regional tumor spread. Patients were treated with radiation and concurrent twice-weekly gemcitabine over three dose levels, as listed in Table 1. Sixteen of 19 patients completed therapy as planned; one patient refused further therapy after the first week of treatment and was not assessable for toxicity or survival. Two other patients were assessable for toxicity but because of patient refusal and noncompliance were removed from the study before completing the planned therapy.

Toxicity
Thrombocytopenia, neutropenia, and nausea/vomiting were the dose-limiting toxicities (Table 2). One patient treated at the 60-mg/m² dose level required a gemcitabine dose reduction. Two of six patients treated at the twice-weekly 20-mg/m² dose level experienced grade 3 toxicity; one patient developed grade 3 diarrhea, and a second suffered grade 3 nausea and vomiting. Three of six assessable patients who received the MTD of 40 mg/m² demonstrated grade 3 toxicity: one patient with thrombocytopenia that resolved after a 1-week break from treatment, a second who suffered grade 3 neutropenia and who also recovered after a 1-week break, and a third who developed grade 3 nausea and vomiting shortly after starting treatment that was successfully managed with aggressive antiemetic therapy. The median nadir counts and total grades 1 to 4 toxicities for the patients in the 40-mg/m² treatment cohort are listed in Table 3. Four of six patients treated at the twice-weekly 60-mg/m² dose level demonstrated grade 3 toxicity: three of six patients developed neutropenia and thrombocytopenia, and one patient developed grade 3 nausea and vomiting despite an aggressive antiemetic regimen. The nausea and vomiting observed varied from patient to patient and did not seem to be cumulative during the course of therapy. No patient died during therapy, although the one patient who refused further therapy after 1 week of treatment died 3 weeks later. Blood transfusions were required in two patients treated at the 60-mg/m² dose level. Otherwise, blood products or granulocyte colony-stimulating factors were not used. In general, therapy was well tolerated in patients treated at the first two dose levels of 20 mg/m² and 40 mg/m² given twice-weekly.

Response
Although this was a phase I study, we did assess tumor response in a limited fashion. Of the 15 patients who were assessable for response, we observed three partial responders. All other patients had stable local disease, and regional or distant disease progression was documented in 10 patients. There was no obvious relationship between the gemcitabine dose and the radiographic response between the three dose levels. Of the eight patients with a minimum follow-up of 12 months, three remained alive: one with stable disease, one with pulmonary disease, and one with an increasing carcinoembryonic antigen level.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The efficacy and acceptable toxicity of gemcitabine in pancreatic cancer has been shown in several clinical trials. Carmichael et al¹⁶ reported modest toxicity in 32 patients with advanced pancreatic cancer; grade 3 World Health Organization toxicity consisted of nausea and vomiting, whereas no grade 4 toxicity was reported. In a multicenter trial reported by Casper et al,¹⁷ 44 patients with pancreatic cancer received gemcitabine at a dose of 800 mg/m² given weekly. Fifteen patients developed grade 3 dose-limiting thrombocytopenia, and all patients suffered mild to moderate flu-like symptoms; an overall response rate of 11% was observed. In a randomized study of 126 patients with advanced pancreatic cancer who received weekly gemcitabine versus fluorouracil-based chemotherapy, a slight median survival advantage was observed in the gemcitabine-treated patients (5.7 months v 4.4 months). The overall survival at 1 year also favored the gemcitabine-treated patients (18% v 2%, respectively).¹³

Although the vast majority of reported phase I/II clinical trials have used gemcitabine as a single agent given weekly, in the present phase I study, we elected to evaluate a twice-weekly gemcitabine schedule. There are intriguing preclinical and clinical data that suggest that gemcitabine possesses equal if not greater cytotoxicity if given at a lower dose over several minutes. Phosphorylation by deoxycytidine kinase (dCK) is required to induce cytotoxicity upon incorporation of the difluorodeoxycytidine triphosphate of gemcitabine (dFdCTP) into DNA.¹⁸ As suggested by Boven et al¹² and supported by Shewach et al,¹⁹ the phosphorylation of gemcitabine in tumor cells is a saturable process. There is evidence that gemcitabine acts as a substrate inhibitor of dCK at high concentrations, which may be the basis for a demonstrable decline in the ability of cells to accumulate dFdCTP at gemcitabine concentrations greater than 20 µmol/L.^20,21 Our preliminary magnetic resonance spectroscopy experiments in a dCK cDNA infected tumor model also indicate that the intratumoral accumulation of dFdCTP is saturable and governed by dCK enzyme levels (Blackstock et al, manuscript submitted for publication).

Data from in vitro experiments suggest an enhanced tumor response with longer exposures to gemcitabine. The incorporation of gemcitabine into DNA is time-dependent, and several researchers have established a clear correlation between cellular DNA incorporation and cytotoxicity; the intracellular accumulation and retention of gemcitabine is relevant.²² In tissue culture data reported by Heineman et al,²³ the dFdCTP metabolite demonstrated a terminal intracellular half-life of 16 hours. Colon carcinoma cell data revealed a greater than 50% retention of the active metabolite dFdCTP at 24 hours after a low-dose incubation. In vitro data from Wayne State showed maximum dFdC activity when the drug was delivered every fourth day (T. Corbett, unpublished data, 1992). Additional data from our laboratory, using fluorine-19 magnetic resonance spectroscopy in a mouse tumor model, suggest that the phosphorylated and presumably DNA-incorporated active metabolite, dFdCTP, remains detectable within a tumor for up to 20 hours after intraperitoneal injection (Blackstock et al, manuscript submitted for publication). Because the information suggests that the active metabolite needs to be present at the time of radiation to obtain radiation enhancement, these data would indicate a biweekly dosing schedule of gemcitabine is more likely than a once-weekly schedule to provide an opportunity for radiation sensitization with each radiation fraction.

Pharmacokinetic studies of mononuclear cells and leukemia cells, both in vitro and from patients during phase I trials,^18,24 have shown that dFdCTP accumulation reaches a plateau when the gemcitabine concentration exceeds 15 to 20 µmol/L. Pilot studies with leukemia patients suggest that a dose rate of 10 mg/m²/min produces plasma gemcitabine concentrations of greater than 20 µmol/L and maximizes the rate of dFdCTP accumulation. Phase I data reported by Grunewald et al²¹ further confirm that the cellular accumulation of the active metabolite, dFdCTP, is maximal at lower doses of gemcitabine, during which plasma steady-state gemcitabine levels of 15 to 20 µmol/L were recorded. A comparison of patients who were infused with 800 mg/m² over 60 minutes with those who received the same dose over 30 minutes demonstrated that the gemcitabine steady-state concentrations were proportional to the dose rate, but that cellular dFdCTP accumulation rates were similar at each dose rate. These studies would suggest that the ability of the cells to convert gemcitabine to its cytotoxic metabolite, dFdCTP, is limited at intravenous doses greater than 350 mg/m² or continuous infusion rates of greater than 10 mg/m²/min.

Additional clinical data support the concept that a lower dose and more frequent dosing schedule may be the optimal way to deliver gemcitabine. In a phase I trial reported by Poplin et al,²⁵ the MTD of twice-weekly gemcitabine (without radiation) was found to be 65 mg/m²/d when the drug was delivered over a 30-minute infusion. Martin et al,²⁶ evaluating a twice-weekly 90-mg/m² schedule, reported equal efficacy compared with a once-weekly 1,000-mg/m² dosing regimen, with response rates of approximately 20% in two cohorts of patients with non–small-cell lung cancer.

The present study of patients with advanced pancreatic cancer was based on the aforementioned previous laboratory investigations. The MTD was determined to be 40 mg/m² administered each Monday and Thursday of the radiation period (80 mg/m²/wk). Although this regimen was well tolerated, neutropenia and thrombocytopenia were not uncommon. Studies that used radiation- and fluorouracil-based regimens have demonstrated a median survival duration of approximately 10 months for patients with locally advanced unresectable pancreatic cancer. The median survival in our small cohort of eight assessable patients eligible for a minimum follow-up of 12 months from registration is an encouraging 11.12 ± 2.3 months. On the basis of these data, a phase II Cancer and Leukemia Group B study is currently accruing patients with locally advanced pancreatic cancer to this regimen of concurrent twice-weekly gemcitabine and radiation.

	ACKNOWLEDGMENTS

 
Supported in part by grant no. CA75949 from the National Cancer Institute, Bethesda, MD, and Eli Lilly Oncology, Indianapolis, IN.

	REFERENCES

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Submitted December 4, 1998; accepted February 24, 1999.

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