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Gemcitabine, Cisplatin, and Radiotherapy for Patients With Locally Advanced Pancreatic Adenocarcinoma: Results of the North Central Cancer Treatment Group Phase II Study N9942

Michael G. Haddock, Revathi Swaminathan, Nathan R. Foster, Mark D. Hauge, James A. Martenson, John K. Camoriano, Philip J. Stella, Richard C. Tenglin, Paul L. Schaefer, Dennis F. Moore, Jr, Steven R. Alberts

From the Mayo Clinic, Rochester; CentraCare Clinic, St Cloud, MN; Illinois Oncology Research Association Community Clinical Oncology Program (CCOP), Peoria, IL; Mayo Clinic, Scottsdale, AZ; Michigan Cancer Research Consortium, Ann Arbor, MI; Rapid City Regional Oncology Group, Rapid City, SD; Toledo Community Hospital Oncology Program CCOP, Toledo, OH; and the Wichita Community Clinical Oncology Program, Wichita, KS

Address reprint requests to Michael G. Haddock, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: haddock.michael{at}mayo.edu

	ABSTRACT

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Purpose: A phase II study was conducted to determine the efficacy and toxicity of radiotherapy with concomitant gemcitabine and cisplatin for patients with locally advanced pancreatic adenocarcinoma.

Patients and Methods: Forty-eight patients with locally advanced pancreatic adenocarcinoma received gemcitabine (30 mg/m²) and cisplatin (10 mg/m²) twice weekly during the first 3 weeks of radiotherapy. The radiation dose to the primary tumor and regional nodes was 45 Gy in 25 fractions, and the gross tumor volume received an additional 5.4 Gy in three fractions. Four weeks after radiotherapy, patients received gemcitabine (1,000 mg/m²) once weekly every 3 of 4 weeks for a 12-week period. The primary end point was survival at 12 months. Secondary end points were time to progression, toxicity, and quality of life.

Results: Survival at 1 year was 40% for 47 eligible patients. The median survival was 10.2 months. Confirmed responses were observed for 8.5% (two partial, two complete), and median time to progression was 7.3 months. Grade 4 or higher toxicity was observed for 31% and consisted primarily of hematologic and GI toxicity. There was a trend toward improved overall quality of life, measured by the Symptom Distress Scale (P = .06), with significant improvements in domains of insomnia, pain, and outlook.

Conclusion: The combination of radiotherapy, gemcitabine, and cisplatin was well tolerated. Survival results were similar to those achieved with other treatment regimens for patients with locally advanced pancreatic cancer but did not meet our predefined criteria for additional evaluation of this regimen.

	INTRODUCTION

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Pancreatic cancer is the most dreaded of all malignancies of the GI tract. The number of newly diagnosed cases in the United States (32,180 in 2005) is approximately equal to the number of deaths (31,800 in 2005), and pancreatic cancer is the fourth leading cause of cancer death.¹ Approximately one third of patients present with locally advanced disease and no evidence of distant metastases. Although complete surgical resection is the only therapy associated with a chance of cure, it is possible in less than 10% of patients at initial diagnosis.² Furthermore, less than 20% of patients undergoing resection survive for 5 years.^3,4

More than 30 years ago, Moertel et al⁵ showed that modest doses of radiation combined with fluorouracil prolonged the median survival of patients with unresectable disease to 9 or 10 months. Little progress has been made since that time, and numerous studies that combined radiotherapy with chemotherapy have not resulted in long-term survival without surgical resection.^6,7 Systemic therapy has been largely ineffective; since 1991, more than 30 studies of more than 30 new agents showed a median objective response rate of 0%.

Gemcitabine is the only known systemic agent with greater activity than fluorouracil for the treatment of pancreatic cancer. A phase III clinical trial of patients with advanced pancreatic cancer comparing fluorouracil versus gemcitabine showed a change in median survival (4.41 and 5.65 months, respectively) and a change in 1-year survival (2% and 18%, respectively). Although the prolongation of life was minimal, gemcitabine administration was associated with significant clinical benefits as measured by decreased pain, reduced weight loss, and improved performance status.⁸

Gemcitabine is a nucleoside analog (2',2'-difluorodeoxycytidine) that inhibits DNA synthesis after phosphorylation by competing with difluorodeoxycytidine triphosphate and inhibiting ribonucleotide reductase activity.⁹ Synergistic cytotoxicity is observed in vitro when gemcitabine is combined with radiotherapy. Enhancement of cytotoxicity has been observed for 48 hours after drug administration, which suggests that drug administration more than once per week during radiotherapy may be beneficial.¹⁰ Synergistic cytotoxicity has been observed with gemcitabine and cisplatin in pancreatic cell lines.¹¹

Given that concomitant radiotherapy and chemotherapy in patients with unresectable disease has resulted in meaningful prolongation of survival when compared with either treatment alone,^6,12,13 a strategy to increase survival by enhancing locoregional effectiveness of therapy was explored. A novel combination regimen with twice weekly gemcitabine and cisplatin during radiotherapy was designed to maximize the potential effect on the basis of available in vitro data. A phase I North Central Cancer Treatment Group study showed that gemcitabine 30 mg/m² and cisplatin 10 mg/m² could be delivered intravenously twice weekly (concomitant with radiation therapy) with acceptable toxicity for patients with locally advanced pancreatic cancer.¹⁴ We report findings of a phase II study that was designed to investigate the efficacy, toxicity, and effects on quality of life (QOL) using this approach.

	PATIENTS AND METHODS

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Patients
Adult patients were eligible for the study if they had histologically proven, unresectable, and invasive ductal pancreatic adenocarcinoma or incompletely resected pancreatic cancer with gross residual disease. Measurable disease was not required. Pretreatment evaluation included a history, physical examination, chest radiograph, and computed tomographic scan of the abdomen. Patients were required to have an Eastern Cooperative Oncology Group performance score of 0 or 1, a neutrophil count greater than 1,500 cells/µL, and a platelet count greater than 100,000/µL. Adequate hepatic function (total bilirubin levels 2x the upper normal limit, alkaline phosphatase and AST levels 3x the upper normal limit) and renal function (creatinine levels 1.5x the upper normal limit) were required.

Surgical staging was not required, but patients who underwent laparotomy could not be enrolled onto the study less than 3 weeks after surgery. Pregnant and lactating women were excluded from participation. Patients with distant metastatic disease or disease extension beyond the limits of tolerable radiation ports were excluded, as were patients with considerable nausea, vomiting, infection, or other medical conditions that would preclude protocol therapy. Patients with prior malignancy (other than nonmelanoma skin cancer) within the last 5 years were excluded. No prior chemotherapy or radiation to the upper abdomen was allowed. Patients with histologic findings other than invasive ductal pancreatic adenocarcinoma were excluded. Written informed consent and local institutional review board approval were required before patients enrolled onto the study.

Treatment Protocol
Radiotherapy consisted of an initial 45 Gy in 25 fractions (dose specified at the isocenter) with a minimum photon energy of 6 MV. An additional 5.4 Gy in three fractions was delivered to a boost field. A four-field technique (anteroposterior, posteroanterior, laterals) was mandated. The initial field included the gross tumor volume and regional nodes, including the celiac axis, porta hepatic, and pancreaticoduodenal nodes. A 2- to 3-cm margin to the blocked field edges was required. The boost field consisted of the gross tumor volume and a 2-cm margin to the blocked field edge. The maximum acceptable size of the initial anterior field was 400 cm² (20 x 20 cm or equivalent), and blocking was required to attempt to limit the anteroposterior field to 225 cm² or less. For normal tissues, dose limits included a maximum dose of 45 Gy for the spinal cord, maximum dose of 52 Gy for the small bowel, mean dose less than 37 Gy for the liver, and less than 20 Gy to spare at least two thirds of one functioning kidney.

Gemcitabine 30 mg/m² was delivered intravenously for 30 minutes twice weekly during the first 3 weeks of radiotherapy. Cisplatin 10 mg/m² was delivered for 1 hour immediately after gemcitabine administration. Beginning 4 weeks after completion of radiotherapy, gemcitabine 1,000 mg/m² was delivered intravenously during 30 minutes once weekly for 3 consecutive weeks and was followed by 1 week without treatment. Patients received a total of three cycles over 12 weeks. Patients were evaluated 4 weeks after completion of radiotherapy, every 3 months for 2 years, and every 6 months for 1 year.

Statistical Analysis
The primary end point of this trial was the 12-month survival rate. All eligible patients who initiated study treatment were included in the primary end point evaluation. A two-stage phase II Fleming study design¹² was used to test whether we had sufficient evidence to determine a 12-month survival rate of at least 60% (ie, clinically promising therapy) or no more than 40% (ie, clinically inactive therapy). This study had 91% power to detect a 12-month survival rate of 60% and had a .09 level of significance.

To justify additional evaluation of this regimen in a phase III study, at least 23 of 45 patients had to survive for 12 months or longer. After the first 20 eligible patients had been enrolled onto the study for 12 months, a planned interim analysis was performed. To continue the study, at least seven of 20 patients had to survive for at least 12 months. CIs were calculated using the method of Duffy and Santner,¹³ and any patient enrolled after the 45th patient was included in the second stage of accrual for this calculation.

Secondary end points included adverse event rates, overall survival, time to disease progression, confirmed response rate, duration of response, and QOL. Adverse events were evaluated before each cycle of treatment. The maximum grade for each type of adverse event was recorded for each patient, and frequency tables were used to determine adverse event patterns. Kaplan-Meier methodology¹⁵ was used to estimate the distributions of survival time and time to disease progression. The duration of response was calculated from the date of the patient's first objective partial or complete response to the date of disease progression. The confirmed response rate was estimated by the number of patients who had documented confirmed responses (partial or complete responses that were maintained for a minimum of 4 weeks) divided by the total number of eligible patients who had started treatment.

QOL information was collected at baseline, at completion of radiotherapy, at completion of gemcitabine therapy, and at the first follow-up visit. The symptom distress scale (SDS)¹⁶ and linear analog self-assessment tools were used. A global SDS score was calculated for each patient (the score was an average of the answered individual SDS questions). All QOL scores were translated into percentages (higher percentages reflected better QOL). Simple summary statistics (eg, mean, standard deviation) were used to evaluate changes in QOL from baseline to the last QOL assessment. Normality testing with the Shapiro-Wilk procedure¹⁷ determined whether parametric or nonparametric procedures would form the basis for analysis (t tests, Wilcoxon tests). Values of P < .05 were statistically significant. All analyses were conducted using SAS software, version 8.0 (SAS Institute, Cary, NC). Adjustments to statistical tests were not made for multiple comparisons.

	RESULTS

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Between October 2001 and July 2003, 48 patients were enrolled onto the study. Patient characteristics are summarized in Table 1. One patient was excluded from survival analyses because of adrenal metastases at diagnosis. Forty-five patients (96%) had disease progression, and 44 patients (94%) died by the time of the analysis. The median follow-up was 32.1 months (range, 12.4 to 36.0 months) for the three patients alive at the time of analysis. Nineteen patients (40.4%) survived at least 12 months (95% CI, 28.6% to 57.2%); this did not meet our predefined criteria for proceeding to a phase III trial. The median survival (Fig 1) was 10.2 months (95% CI, 8.2 to 13.0 months), and the median time to progression (Fig 2) was 7.3 months (95% CI, 5.7 to 8.2 months). No difference in survival or time to progression was observed between patients diagnosed by laparotomy and those diagnosed by other means. The confirmed response rate was 8.5% (95% CI, 2.4% to 20.4%), which consisted of two partial and two complete responses. The median duration of response for these four patients was 13.4 months (range, 6.3 to 36.0 months). Treatment results are summarized in Table 2.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival (n = 47): median, 10.2 months; 95% CI, 8.2 to 13.0 months.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Time to progression (n = 47): median, 7.3 months; 95% CI, 5.7 to 8.2 months.

The protocol-specified treatment was completed by 54% of patients. Thirty-five percent of patients did not receive gemcitabine after radiotherapy. The median percentage of the targeted dose administered during radiotherapy was 83% (range, 32% to 101%) and 83% (range, 33% to 102%) for gemcitabine and cisplatin, respectively. One patient had a major treatment violation and received 466% of the targeted gemcitabine dose during radiation. The median percent of the targeted dose administered of gemcitabine after radiotherapy ranged from 58% (during cycle 1) to 21% (during cycle 3). Forty-three patients (90%) received at least 45 Gy as the initial treatment volume, and 41 patients (85%) received the prescribed dose of 50.4 Gy as the boost volume. Two patients (4%) had deviations from the study protocol (non–toxicity-related prolongation of treatment time by more than 20%).

All patients were evaluated for adverse events (National Cancer Institute Common Terminology Criteria, version 2.0; Table 3). Forty-four patients (92%) had at least one adverse event that was grade 3 or higher, and 15 patients (31%) had at least one adverse event that was grade 4 or higher. One patient had grade 5 melena, which possibly was attributable to the study therapy. The most common grade 3 or higher hematologic adverse events were leukopenia (63%), neutropenia (46%), and thrombocytopenia (42%). Commonly occurring nonhematologic adverse events included abdominal pain (27%), nausea (23%), fatigue (23%), vomiting (19%), anorexia (19%), and elevated alkaline phosphatase levels (19%).

	DISCUSSION

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Consistent with the goal of improving the locoregional effectiveness of therapy, a novel regimen of twice weekly chemotherapy during radiotherapy was used. Preclinical data suggested that gemcitabine dosing more than once weekly might improve efficacy.¹⁹ The combination of gemcitabine and cisplatin was attractive, given the radiosensitizing properties, the differing mechanisms of toxicity, and preclinical data that suggested the possibly of synergistic cytotoxicity.²⁰

Gemcitabine dosing is highly dependent on the schedule, and dosage is reduced markedly when it is administered more than once weekly or when combined with radiotherapy. A Dartmouth phase I study of twice weekly gemcitabine and concomitant radiotherapy determined that the maximum-tolerated dose of gemcitabine was 50 mg/m² (severe upper GI tract bleeding was observed at a dose of 60 mg/m²).²¹ On the basis of their phase I study, Blackstock et al²² suggested 40 mg/m² as the maximum-tolerated dose of twice weekly gemcitabine. An Eastern Cooperative Oncology Group phase I study combining radiotherapy, fluorouracil, and gemcitabine was stopped early because of ulceration and bleeding (weekly gemcitabine doses were 50 to 100 mg/m²).¹⁸ The phase I North Central Cancer Treatment Group study combining twice weekly gemcitabine and cisplatin showed that gemcitabine (30 mg/m²) and cisplatin (10 mg/m²) were tolerable, but a gemcitabine dose of 45 mg/m² was associated with unacceptable levels of nausea and vomiting.¹⁴

Despite optimism about promising new regimens for locally advanced pancreatic cancer, median survival times remain in the 9- to 11-month range; 40% to 50% of patients survive for 1 year, and less than 20% survive for 2 years. The results of our study are similar to those reported by other cooperative groups in recent phase II studies that combined radiotherapy and chemotherapy. The Radiation Therapy Oncology Group²³ conducted a phase II study of radiotherapy and weekly paclitaxel 50 mg/m² for 109 patients. They reported a median survival of 11 months; the 1-year survival rate was 43%, and the 2-year survival rate was 13%. The Cancer and Leukemia Group B 89805 study used gemcitabine 40 mg/m², twice weekly in combination with radiotherapy 50.4 Gy in 28 fractions); afterward, patients received five cycles of weekly gemcitabine 1,000 mg/m² for 3 of 4 weeks. Median survival was 8 months, and 33% survived for 1 year. These findings are comparable to the median survival of 10 months and the 40% 1-year survival rate observed in our study.

In contrast to the Cancer and Leukemia Group B trial, surgical staging to exclude clinically occult peritoneal spread of disease was not required before enrollment onto the current study. In addition, patients were eligible if the local extent of disease could be encompassed within an acceptable radiotherapy treatment volume. Therefore, patients with mesenteric, peripancreatic, and celiac axis nodal involvement were eligible, and more than 40% of patients had clinically apparent lymph node metastases.

The treatment regimen reported in our study was associated with acceptable tolerance. Rates of grade 3 or 4 hematologic and GI toxicity were similar to those reported for other gemcitabine-based chemotherapy and radiation regimens.²⁴ Most patients completed the combined-modality portion of the protocol; 54% completed all therapy described in the protocol, which was similar to the 51% rate reported in the Cancer and Leukemia Group B 89805 study.²⁴ Marked reductions in gemcitabine dosage were required after combined-modality therapy. Of interest, QOL evaluation findings suggested that the therapy did not have a negative impact; rather, a trend toward improved QOL was noted. Improved pain control was also a beneficial effect of therapy.

The observation that nearly half the patients initially had locoregional progression emphasizes the need for more effective local therapy. Enthusiasm about the effectiveness of new targeted agents notwithstanding, improved local control likely will require novel combinations of systemically active therapies and radiotherapy. Currently available systemic therapies are minimally effective for controlling disease. The addition of erlotinib to gemcitabine for patients with advanced pancreatic cancer has been shown to prolong median survival by 2 weeks and progression-free survival by 6 days, a statistically significant but clinically meaningless advance.²⁵ Progress in the treatment of pancreatic cancer likely will require a move away from empirically derived tolerable combinations and toward treatments that are based on a greater understanding of pancreatic cancer biology.

In conclusion, for patients with locally advanced pancreatic cancer, this novel treatment regimen (based on sound preclinical data) was associated with acceptable tolerance, improved QOL, and survival results similar to those obtained with other regimens. Survival results did not achieve the predetermined target that would warrant additional evaluation in a phase III study. Future efforts will continue to focus on combinations of novel systemic therapies with targeted radiotherapy.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Consultant: N/A Stock: N/A Honoraria: Paul L. Schaefer, Eli Lilly & Co Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Michael G. Haddock, James A. Martenson, Steven R. Alberts

Provision of study materials or patients: Michael G. Haddock, Revathi Swaminathan, Mark D. Hauge, James A. Martenson, John K. Camoriano, Philip J. Stella, Richard C. Tenglin, Paul L. Schaefer, Dennis F. Moore Jr, Steven R. Alberts

Collection and assembly of data: Revathi Swaminathan, Nathan R. Foster, Mark D. Hauge

Data analysis and interpretation: Michael G. Haddock, Nathan R. Foster, James A. Martenson, Steven R. Alberts

Manuscript writing: Michael G. Haddock, Nathan R. Foster, James A. Martenson, Steven R. Alberts

Final approval of manuscript: Michael G. Haddock, Nathan R. Foster, Mark D. Hauge, James A. Martenson, John K. Camoriano, Philip J. Stella, Steven R. Alberts

	Appendix

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The following additional institutions participated in the study: Cedar Rapids, IA (Martin Wiesenfeld, MD); Duluth Community Clinical Oncology Program (CCOP), Duluth, MN (Daniel A. Nikcevich, MD); Siouxland Hematology-Oncology Associates, Sioux City, IA (Donald B. Wender, MD); Iowa Oncology Research Association, Des Moines, IA (Roscoe C. Morton, MD); Geisinger Clinic & Medical Center CCOP, Danville, PA (Albert M. Bernath Jr, MD); Mayo Clinic, Jacksonville, FL (Edith A. Perez, MD); Meritcare Hospital CCOP, Fargo, ND (Preston D. Steen, MD); Sioux Community Cancer Consortium, Sioux Falls, SD (Loren K. Tschetter, MD); Carle Cancer Center CCOP, Urbana, IL (Kendrith M. Rowland, Jr, MD).

	ACKNOWLEDGMENTS

 
Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic.

	NOTES

 
Supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-63848, CA-35195, CA-52352, CA-35101, CA-35269, CA-37417, CA-35448, CA-35113, CA-60276, CA-35103, CA-35415, and CA-35431 from the National Cancer Institute Department of Health and Human Services, and was conducted as a trial of the North Central Cancer Treatment Group and Mayo Clinic.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted December 1, 2006; accepted March 28, 2007.

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