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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 942-947 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.9014 Full-Dose Gemcitabine With Concurrent Radiation Therapy in Patients With Nonmetastatic Pancreatic Cancer: A Multicenter Phase II Trial
From the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; Vanderbilt University Medical Center, Nashville, TN; Fox Chase Cancer Center, Philadelphia, PA; Maine Medical Center, Portland, ME; Karmanos Cancer Institute, Detroit, MI; University Hospitals Case Medical Center, Cleveland, OH; and Eli Lilly & Co, Indianapolis, IN Address reprint requests to William Small Jr, MD, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 251 East Huron St, LC-178, Chicago, IL 60611; e-mail: wsmall{at}nmff.org
Purpose Gemcitabine is effective in the treatment of pancreatic cancer and is a potent radiosensitizer. This study assessed safety and efficacy of full-dose gemcitabine administered before and during concurrent three-dimensional conformal radiation (3D-CRT) in patients with nonmetastatic pancreatic cancer. Patients and Methods During cycles 1 and 3, patients received gemcitabine at 1,000 mg/m2 on days 1 and 8 of each 21-day cycle. Cycle 2 included the same dose of gemcitabine on days 1, 8, and 15 of a 28-day cycle with concurrent 3D-CRT at 36 Gy, administered in 15 fractions of 2.4 Gy, over 3 weeks. Resectable patients underwent surgery 4 to 6 weeks after treatment. The primary objective was evaluation of toxicity. Tumor response, CA 19-9, and 1-year survival were also assessed. Results Forty-one patients enrolled at six institutions between April 2002 and October 2003. Among the 39 treated patients, the most common toxicities were grade 3 neutropenia (12.8%), grade 3 nausea (10.3%), and grade 3 vomiting (10.3%). The response rate was 5.1% and disease control rate was 84.6%. Mean post-treatment CA 19-9 levels (228 ± 347 U/mL) were significantly (P = .006) reduced compared with pretreatment levels (1,241 ± 2,124 U/mL). Thirteen (81%) of 16 patients initially judged resectable, three (33%) of nine borderline-resectable patients, and one (7%) of 14 unresectable patients underwent resection after therapy. One-year survival rates were 73% for all patients, 94% for resectable patients, 76% for borderline-resectable patients, and 47% for unresectable patients. Conclusion Full-dose gemcitabine with concurrent radiotherapy was well tolerated and active. Evaluation of this regimen in a larger, randomized trial for patients with resectable or borderline-resectable disease may be warranted.
Effective treatment of pancreatic cancer must address control of both local disease and distant sites of failure. Efforts to better control local disease progression using radiation therapy (RT) have evaluated techniques to safely increase and focus the radiation dose. These efforts have included the use of intraoperative RT,1 brachytherapy,2,3 three-dimensional conformal RT (3D-CRT),4 and intensity-modulated RT.5 Although improved local control has been reported with these techniques, treatment failure is largely attributed to development of distant metastatic disease with no significant impact on survival in several decades. The clinical benefit of gemcitabine as a systemic agent in the treatment of advanced pancreatic cancer has been established.6 Gemcitabine has also been shown to enhance the sensitivity of human pancreatic cancer cells to radiation.7 Early trials designed to assess the combination of gemcitabine and RT in pancreatic cancer used full-dose radiation, but required significant reductions of the gemcitabine dose because of unacceptable toxicities, likely decreasing the effectiveness of systemic gemcitabine on distant metastases.8-10 Despite these initial problems, interest in combining full-dose gemcitabine with reduced-field RT techniques has continued. To assess the effects of full-dose gemcitabine combined with a modified radiation regimen, an early phase I predecessor of the current trial used a standard clinical dose (1,000 mg/m2) of gemcitabine as a systemic agent to control distant metastatic disease.11 To minimize the potential for treatment-related toxicities, an attenuated 3D-CRT regimen directed at the primary tumor was administered by escalating to a smaller total dose of radiation administered over a shorter time period. Results showed this regimen to be active in patients with unresectable pancreatic cancer and established a recommended radiation dose of 36 Gy delivered in 15 2.4-Gy fractions over 3 weeks.11 The objective of the current phase II trial was to evaluate the safety and efficacy of a modified version of this novel chemoradiotherapy regimen delivered in a multi-institutional setting to patients with nonmetastatic pancreatic cancer. A preliminary report from this study focused on the efficacy and surgical outcomes for the cohort of patients initially determined to have potentially resectable tumors.12 The current report reviews the safety and efficacy results for the entire patient population, including patients initially determined to have unresectable or borderline-resectable disease.
Inclusion and Exclusion Criteria Patients with cytologically or histologically confirmed adenocarcinoma of the pancreas were enrolled. Patients with tumors in the head, uncinate process, and body or tail of the pancreas were eligible. Patients with neuroendocrine tumors or with clinical or radiographic evidence of metastatic disease were excluded. Patients with any history of chemotherapy for pancreatic cancer or abdominal RT were ineligible. Enrolled patients had an estimated life expectancy of at least 12 weeks, a Zubrod performance status of no more than 2, and adequate cardiac, hematologic, hepatic, and renal function. All patients provided written informed consent before the initiation of therapy. Institutional review boards at each participating institution approved the trial protocol before patient enrollment.
Pretreatment Evaluation and Treatment Regimen
The treatment regimen is shown in Table 1. Therapy was administered over 10 weeks and consisted of three treatment cycles. During cycles 1 and 3, patients were administered a 30-minute IV infusion of gemcitabine at 1,000 mg/m2 on days 1 and 8 of each 21-day cycle. Cycle 2 included the same dose of gemcitabine on days 1, 8, and 15 of a 28-day cycle concurrent with 2.4 Gy of radiation administered once a day on days 1 through 5, 8 through 12, and 15 through 19. The total dose of RT was 36 Gy. Utilizing the linear-quadratic concept13 (assuming
All patients underwent 3D-CRT utilizing CT simulation with oral and IV contrast unless IV contrast was contraindicated. RT was delivered to the gross tumor volume only, including regional lymphadenopathy. Gross tumor volume was expanded 0.5 cm to obtain a clinical target volume, with an additional 0.5 cm expansion to obtain a planning target volume. Prophylactic irradiation of regional lymph nodes was not performed. Generally, a three-field arrangement was utilized, although any field arrangement fulfilling the RT criteria was accepted. Intensity-modulated RT was not allowed. There was no specification regarding respiratory motion or the use of image-guided RT. Photon energy of at least 10 MV was required. Patients were generally treated supine, with arms up; immobilization was recommended. Treatment planning was performed with the isocenter calculated at 100% and the 95% line encompassing 99.5% of the planning target volume. The prescribed dose was 36 Gy in 2.4 Gy fractions. The spinal cord was not to receive more than 104% of the isocenter dose; no more than 50% of the combined functional renal volume was to receive more than 20 Gy. There were no specific guidelines for liver, small bowel, or colon. All treatment plans were centrally reviewed before initiation of RT. On the days of combined chemoradiotherapy, radiation was administered after gemcitabine infusion. A 1-week rest period was included after each cycle.
Patient Evaluation for Toxicity and Response Tumor resectability was assessed by CT scan. Patients were categorized with either resectable, borderline-resectable, or unresectable tumors using criteria defined in the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for pancreatic cancer.15 All patients underwent repeat staging at 2 to 3 weeks after completion of the final gemcitabine infusion, and before surgery. For patients judged resectable after completing chemoradiotherapy, surgery was performed 4 to 6 weeks after final gemcitabine infusion. Tumor response was determined by comparison of pre- and post-treatment CT scans and assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.16 Response to therapy was also evaluated by comparing the serum levels of CA 19-9 in patients at baseline to levels after completion of chemoradiotherapy. Patients were followed up for at least 12 months after registration.
Statistical Considerations A secondary objective was to determine tumor response rate. A complete response (CR) was the disappearance of the primary tumor. A partial response (PR) was defined as at least a 30% decrease in the longest diameter of the primary tumor. Progressive disease (PD) was defined as at least a 20% increase in the longest diameter of the primary tumor or the appearance of one or more new lesions. Stable disease (SD) was defined as neither a tumor response sufficient to qualify as a PR nor an increase sufficient to qualify as PD. Disease control rate (CR + PR + SD) was included as a post hoc assessment of objective response. As a surrogate measure of response, serum CA 19-9 levels were measured in all patients at baseline and after completion of chemoradiotherapy. Pairwise t test was used to evaluate the change in CA 19-9 levels. An additional secondary objective was 1-year survival. Survival was estimated from the date of treatment initiation to the date of death or last follow-up. Survival rates were determined using product limit estimates method of Kaplan and Meier.18
Patient Characteristics A total of 41 patients were enrolled between April 2002 and October 2003 at six participating sites. However, two patients withdrew consent without receiving treatment. The median follow-up for this trial was 13.8 months (range, 12.9 to 23.2 months). Table 2 summarizes patient demographics.
Before entry, patients were evaluated for surgical resectability. At the time of enrollment, 16 patients had potentially resectable tumors, nine had borderline-resectable tumors, and 14 had tumors considered unresectable (Table 3). This report includes the efficacy and safety results for all patients treated in the study. Results for the patient cohort with potentially resectable tumors have been previously reported.12
Treatment Administration and Toxicity Chemoradiotherapy was initiated for 39 patients enrolled onto the study, and 33 patients completed the treatment regimen. A total of six patients discontinued from study before completion of treatment (Table 2). There was one patient death, assessed as unlikely to be related to therapy. One patient discontinued from study because of unacceptable toxicity. In addition, two patients withdrew themselves from the trial and two patients discontinued because of excessive dose delay or reduction. Table 4 summarizes safety results. A total of 19 patients (48.7%) experienced grade 3 or grade 4 nonhematologic toxicity. However, only 10 patients (25.6%) had grade 3 to 4 nonhematologic toxicities that were related to treatment. One patient experienced a grade 4 gastric outlet obstruction. The most common grade 3 nonhematologic toxicities were nausea (n = 4; 10.3%) and vomiting (n = 4; 10.3%). The most common hematologic toxicity event was grade 3 neutropenia (n = 5; 12.8%). The only grade 4 hematologic toxicity event was thrombocytopenia experienced by one patient, whereas two patients (5.1%) experienced grade 3 thrombocytopenia.
Efficacy Response. Table 5 summarizes radiographic tumor response data. Of the 39 patients treated, one patient experienced a CR and one a PR. The patient with CR enrolled with stage IIA:(T3, N0, M0) disease, and the patient with PR enrolled at stage IB:(T2, N0, M0). The overall response rate was 5.1% (two of 39 patients; 95% CI, 0.01 to 0.17). Two patients (5.1%) experienced PD, and 31 patients (79.5%) had SD. Of the two patients with PD, one patient developed distant metastatic disease, and the other patient had local progression without nodal metastases. Four patients were not evaluated for response. The disease control rate was 84.6% (33 of 39 patients; 95% CI, 0.69 to 0.94).
Response to therapy was also assessed by measuring the serum levels of CA 19-9. For patients with measurable CA 19-9 levels at both baseline and after treatment (n = 32), the mean baseline CA 19-9 level was 1,241 ± 2,124 U/mL (mean ± standard deviation). After chemoradiotherapy, mean CA 19-9 levels showed a statistically significant reduction to 228 ± 347 U/mL (P = .006). The one patient with a radiographic CR had an undetectable level (< 1 U/mL) of CA 19-9 that did not change from baseline. However, the one patient with PR had CA 19-9 reduced by 84.4%. The 29 patients with measurable CA 19-9 and with SD had mean CA 19-9 reduction of 59.4% and the two patients with PD had mean CA 19-9 levels reduced by 38.5%. Table 3 summarizes the pretreatment assessment of resectability with the subsequent post-treatment rates of resection. Thirteen (81%) of 16 patients initially judged with resectable tumors and three (33%) of 9 patients initially judged borderline resectable underwent surgical resection after completion of chemoradiotherapy. In addition, one (7%) of 14 patients initially considered unresectable also underwent surgical resection on restaging after treatment. Survival. One-year survival was another secondary end point for this trial. Table 3 summarizes the survival rates for the entire patient population and for each subgroup (resectable, borderline resectable, or unresectable). The 1-year survival rate was 73% (95% CI, 0.58 to 0.87) for the entire patient group (N = 39), 47% (95% CI, 0.19 to 0.75) for unresectable patients (n = 14), 76% (95% CI, 0.47 to 1.00) for borderline-resectable patients, and 94% (95% CI, 0.82 to 1.00) for resectable patients (n = 16).
There has been significant interest in combination chemoradiotherapy for patients with either resectable or unresectable pancreatic cancer. A regimen providing both localized treatment and systemic control for patients with nonmetastatic but unresectable disease might enhance overall survival and improve the possibility for curative surgical resection. Because it is estimated that approximately 25% of resected patients do not receive adequate postoperative adjuvant therapy as a result of surgical complications,19 a regimen combining the most active chemotherapeutic agent and a biologically effective radiation dosage without undue toxicity would also be desirable for patients with potentially resectable disease. To our knowledge, the current study provides the first complete report of the safety and efficacy of full-dose gemcitabine administered concurrently with 3D-CRT to patients with pancreatic cancer in a multi-institutional setting. This novel approach to chemoradiotherapy was provided to chemotherapy-naïve patients with either resectable, borderline-resectable, or unresectable nonmetastatic pancreatic cancer. The combination of gemcitabine administered concurrently with radiation in pancreatic cancer patients has been previously evaluated with reports of significant toxicity problems.8-10 In an early phase I trial, Blackstock et al8 reported dose-limiting toxicities of nausea/vomiting, neutropenia, and thrombocytopenia in patients who received 50.4 Gy of radiation concurrently with twice-weekly gemcitabine at a dose of 60 mg/m2. Although this dose of gemcitabine is likely to be radiosensitizing, it is unlikely to be effective against systemic disease.7 In another trial, treatment was stopped because of unacceptable toxicities when gemcitabine was administered at 50 to 100 mg/m2 concurrently with 59.4 Gy of radiation and with protracted venous infusion of fluorouracil.9 A subsequent trial by Wolff et al10 also reported substantial toxicities with gemcitabine at doses ranging from 350 to 500 mg/m2 administered concurrently with radiation attenuated to 30 Gy delivered as 10 fractions over 2 weeks. In that study, 44% of treated patients required hospitalization for management of nausea/vomiting and dehydration. These trials all shared the use of large radiation fields that included prophylactic lymph node radiation. A phase I predecessor trial of the current regimen established the safety of a conformal hypofractionated radiation dose (36 Gy in 15 fractions of 2.4 Gy over 3 weeks) administered concurrently with full-dose gemcitabine over a 28-day cycle. In this phase I regimen, a second 3-week cycle with gemcitabine alone was administered after the chemoradiotherapy phase of treatment.11 The current trial utilized a 10-week regimen with the same 28-day chemoradiotherapy phase sandwiched between two 3-week cycles of gemcitabine (administered day 1 and 8) chemotherapy alone. Consistent with the earlier phase I trial, the current treatment regimen was well tolerated with only one patient experiencing grade 4 thrombocytopenia and one patient experiencing a grade 4 gastric outlet obstruction. In total, only 26% of patients experienced grade 3/4 nonhematologic treatment-related adverse events. In the current trial, although only one patient experienced a radiographic CR and one a PR, 31 patients were determined to have SD at 12 to 13 weeks after starting treatment. Only two patients (5.1%) showed PD after completing chemoradiotherapy (Table 5). Thus, the disease control rate in this study was 84.6% (33 of 39 patients). Consistent with this disease control rate, 13 (81%) of 16 patients originally assessed with resectable tumors and three (33%) of 9 patients initially evaluated with borderline-resectable disease went on to surgical resection after completing the full chemoradiotherapy regimen (Table 3). It was previously reported that the surgical resection margins for 16 of 17 specimens from resected patients showed no microscopic evidence of cancer.12 Taken together, these results suggest that the current chemoradiotherapy regimen may provide local disease control for patients with either potentially resectable or borderline-resectable disease. It should also be noted that one patient with SD by CT scan was determined after resection to have a CR by pathologic examination. This suggests that, in some cases, radiographic measurement may not serve as the most sensitive measure of tumor response. A 2005 report by Ko et al20 suggested that CA 19-9 might serve as a unique biomarker for monitoring the course of therapy for patients with pancreatic cancer. The use of CA 19-9 as surrogate for response to chemotherapy is further supported in the literature.21-23 Despite a relatively low radiographic response rate (5.1%) in the current trial, the mean percent decrease in CA 19-9 after chemoradiotherapy was 58.9%. Of note, the one patient with PR had a CA 19-9 reduction of 84.4%, and two patients with PD had an average reduction of only 38.5%. These CA 19-9 results, coupled with a radiography-based disease control rate of 84.6%, suggest that this chemoradiotherapy combination was active. Although the CA 19-9 results reported here suggest a possible correlation with response, the utility of CA 19-9 as a measure of response remains to be validated with an appropriately powered clinical trial. A number of chemoradiotherapy regimens have been evaluated for patients with unresectable locally advanced disease.3,8-10,24,25 In addition, several regimens have been evaluated with patients in the adjuvant,26-35 and the neoadjuvant settings.33-36 Despite these efforts, the potential survival benefit of chemotherapy combined with RT in treatment of pancreatic cancer remains uncertain. The results of this multi-institution study suggest that full-dose gemcitabine chemotherapy in combination with 3D-CRT might provide a 1-year survival advantage for patients with either resectable or borderline-resectable tumors compared with prior chemoradiotherapy studies.31,33,35,37 Murphy et al38 recently reported a retrospective analysis of patients with unresectable, nonmetastatic disease treated with a regimen of full-dose gemcitabine plus RT, similar to the therapy described in the current study. The 1-year survival rate in that report was 46%, which is similar to the rate (47%) we observed for patients with unresectable tumors. Because of the limited enrollment in the current trial and the retrospective nature of the report by Murphy et al, a potential survival benefit of this chemoradiotherapy regimen cannot be reliably determined. In summary, our results show that this chemoradiotherapy regimen was well tolerated and active in patients with locally advanced, nonmetastatic pancreatic cancer. The use of a radiation regimen with reduced field size encompassing only the gross tumor and involved nodes permits the concurrent delivery of full-dose gemcitabine. The manageable toxicity profile and encouraging 1-year survival rates suggest that further study of this regimen in patients with resectable or borderline-resectable tumors may be warranted. Currently, Northwestern University (Chicago, IL) is completing a similar trial using full-dose gemcitabine plus concurrent radiation with the addition of bevacizumab.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: Steven Nicol, Eli Lilly & Co (C); Rong M. Xu, Eli Lilly & Co (C); John F. Gill, Eli Lilly & Co (C) Consultant or Advisory Role: Al B. Benson, Eli Lilly & Co (C) Stock Ownership: Steven Nicol, Eli Lilly & Co; Rong M. Xu, Eli Lilly & Co; John F. Gill, Eli Lilly & Co Honoraria: Cornelius J. McGinn, Eli Lilly & Co Research Funding: William Small Jr, Eli Lilly & Co; Mark S. Talamonti, Eli Lilly & Co; Mary F. Mulcahy, Eli Lilly & Co; Mark M. Zalupski, Eli Lilly & Co; Al B. Benson, Eli Lilly & Co (through Northwestern University); Cornelius J. McGinn, Eli Lilly & Co Expert Testimony: None Other Remuneration: None
Conception and design: William Small Jr, Jordan Berlin, Theodore Lawrence, Mark S. Talamonti, Mary F. Mulcahy, Mark M. Zalupski, Philip A. Philip, Cornelius J. McGinn Administrative support: John F. Gill Provision of study materials or patients: William Small Jr, Jordan Berlin, Gary M. Freedman, Theodore Lawrence, Mark S. Talamonti, Mary F. Mulcahy, A. Bapsi Chakravarthy, Andre A. Konski, Mark M. Zalupski, Philip A. Philip, Timothy J. Kinsella, John P. Hoffman, Al B. Benson, Cornelius J. McGinn Collection and assembly of data: William Small Jr, Gary M. Freedman, Mark S. Talamonti, Mary F. Mulcahy, Mark M. Zalupski, Philip A. Philip, Cornelius J. McGinn Data analysis and interpretation: William Small Jr, Gary M. Freedman, Mark S. Talamonti, Mary F. Mulcahy, A. Bapsi Chakravarthy, Mark M. Zalupski, Philip A. Philip, Nipun B. Merchant, Steven Nicol, Rong M. Xu, John F. Gill, Cornelius J. McGinn Manuscript writing: William Small Jr, Gary M. Freedman, Theodore Lawrence, Mark S. Talamonti, Mary F. Mulcahy, A. Bapsi Chakravarthy, Mark M. Zalupski, Nipun B. Merchant, John P. Hoffman, Steven Nicol, Rong M. Xu, John F. Gill Final approval of manuscript: William Small Jr, Jordan Berlin, Gary M. Freedman, A. Bapsi Chakravarthy, Andre A. Konski, Mark M. Zalupski, Philip A. Philip, Timothy J. Kinsella, Nipun B. Merchant, John P. Hoffman, Al B. Benson, Steven Nicol, Rong M. Xu, John F. Gill, Cornelius J. McGinn
We thank Carol Caillouette, Daniel Normolle, Julie Wietzke, Gayle Woloschak, and Sharon Zou for their support.
Supported by a grant from Eli Lilly & Co, Indianapolis, IN. Presented in part at the 48th Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, November 5-9, 2006, Philadelphia, PA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
/β of 10, 
3 nonhematologic toxicity), then 21 additional patients would receive treatment in the second stage. If six or more of the treated patients in stage 1 or a total of 12 patients in both stage 1 and 2 were to experience unacceptable toxicities, the trial would be stopped. The trial was designed to have a type I error less than 0.05 and type II error less than 0.20. 
