RADIATION THERAPY WITH ONCE-WEEKLY GEMCITABINE IN PANCREATIC CANCER: CURRENT STATUS OF CLINICAL TRIALS

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1 doi: /s (03) Int. J. Radiation Oncology Biol. Phys., Vol. 56, No. 4, Supplement, pp , 2003 Copyright 2003 Elsevier Inc. Printed in the USA. All rights reserved /03/$ see front matter NEW PARADIGMS IN THE TREATMENT OF PANCREAS CANCER RADIATION THERAPY WITH ONCE-WEEKLY GEMCITABINE IN PANCREATIC CANCER: CURRENT STATUS OF CLINICAL TRIALS CORNELIUS J. MCGINN, M.D.,* AND MARK M. ZALUPSKI, M.D. *Department of Radiation Oncology and Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Health Systems, Ann Arbor, MI Clinical trials investigating a variety of gemcitabine-based chemoradiation therapy regimens were initiated several years ago and remain under active investigation for the treatment of patients with pancreatic cancer. These trials are based, in part, on the activity of gemcitabine as a single agent in pancreatic cancer, preclinical studies that demonstrated radiosensitization, and the need for approaches with greater efficacy than that provided by 5-fluorouracil (5-FU) based chemoradiation therapy. In this review, we describe and compare several Phase I clinical trials investigating dose escalation of once-weekly gemcitabine with concurrent radiation therapy. We also describe a relatively novel approach successfully investigating radiation dose escalation with a standard weekly dose of gemcitabine. Toxicity data from this trial, and the prior trials of gemcitabine dose escalation with more conventional radiation therapy, suggest that the volume of normal tissue radiated in gemcitabine-based chemotherapy regimens may be the most critical consideration for future trial designs. Finally, we highlight the need to fully consider the design of future trials in the context of both local and distant disease control, given the radiosensitizing potential and systemic activity of gemcitabine Elsevier Inc. Pancreatic cancer, Gemcitabine, Radiotherapy, Clinical trials. INTRODUCTION Reprint requests to: Cornelius J. McGinn, M.D., Department of Radiation Oncology, Maine Medical Center, 22 Bramhall Street, Portland, ME Tel: (207) ; Fax: (207) ; mcginn9@spectrummg.com Drugs that affect nucleoside and nucleotide metabolism are among the most effective and widely used agents to sensitize tumor cells to radiation treatment (i.e., radiosensitizers). 5-Fluorouracil (5-FU) remains the predominant agent in clinical use today. The deoxycytidine analog, gemcitabine (2,2 -difluoro-2 -deoxycytidine or dfdcyd; (Gemzar, Eli Lilly, Indianapolis, IN), has recently been shown to be a potent radiosensitizer in preclinical studies using human tumor cell lines, including pancreatic cancer cell lines (1 5). Gemcitabine has been approved for clinical use as a single agent and in combination chemotherapy regimens. The integration of gemcitabine in chemoradiation therapy regimens is based on this information, as well as the generally accepted role of chemotherapy with concurrent radiation therapy (RT) in the management of pancreatic cancer. The treatment strategy of combined-modality therapy in pancreatic cancer is based in large part on data from serial Gastrointestinal Tumor Study Group trials that investigated 5-FU based chemoradiation therapy. A benefit of combined-modality therapy was observed compared with RT alone in patients with unresectable disease and compared with observation in patients who had undergone surgical resection (6, 7). However, the annual mortality from pancreatic cancer continues to nearly equal the incidence, and few significant advances have been made in the nonoperative treatment of these patients (8). A renewed interest in alternative chemoradiation therapy regimens for patients with pancreatic cancer has been stimulated by advances in the technical delivery of RT. The integration of new systemic agents such as gemcitabine with advanced RT techniques in combined modality regimens is promising and requires additional investigation. CLINICAL TRIALS OF GEMCITABINE DOSE ESCALATION Considering the preclinical data indicating substantial radiosensitization and clinical data indicating advantages of gemcitabine relative to 5-FU, the use of gemcitabine with concurrent RT may improve the outcome of pancreatic cancer patients (6, 7). A variety of Phase I studies have now been conducted in patients with pancreatic cancer in an effort to define a tolerable regimen using RT with weekly gemcitabine. RT with twice-weekly gemcitabine has also been investigated in an attempt to maximize radiosensitization and is discussed elsewhere in this Supplement. In 1996, two multicenter Phase I trials were initiated in Received Nov 5, 2002, and in revised form Dec 27, Accepted for publication Jan 24,

2 RT and gemcitabine in pancreas cancer C. J. MCGINN AND M. M. ZALUPSKI 11 Fig. 1. Gemcitabine (G) dose-escalation schema investigated in patients with unresectable and potentially resectable pancreatic cancer. Abbreviation: XRT RT. patients with locally advanced, unresectable disease and potentially resectable disease (9, 10). Both trials attempted to determine the maximal tolerated dose of gemcitabine when delivered once weekly, concurrent with 50.4 Gy in 1.8-Gy fractions (Fig. 1). A margin of 3 cm around the gross target volume was required for the initial field (39.6 Gy). This margin was reduced to 2 cm for the final boost (10.8 Gy). The starting dose of weekly gemcitabine was 300 mg/m 2. Hematologic and GI toxicity were found to be dose limiting at 700 mg/m 2. Late toxicity remains a concern; 2 of 6 patients with unresectable disease treated at 600 mg/m 2 on the trial developed duodenal strictures 3 months after treatment completion, with one requiring a duodenal stent. Objective partial responses were not observed at doses 500 mg/m 2 ; however, 3 of 6 patients treated with 600 mg/m 2 experienced an objective partial response. The final reports of these trials have not yet been published. Significant GI toxicity was encountered with gemcitabine delivered at weekly doses of 400 mg/m 2 with concurrent rapid fractionation (30 Gy in 3-Gy fractions) (11). Seven of 12 patients treated with 400 mg/m 2 required hospitalization for management of nausea/vomiting and dehydration. In that study, gemcitabine was given on the Friday before initiation of RT and was continued weekly during and after the course of RT (Fig. 2). This schedule was based on in vivo data indicating more selective tumor radiosensitization with gemcitabine exposure at least 24 h before radiation (12). The treatment volumes covered the primary tumor with a 3 5-cm margin, as well as the porta hepatis and celiac axis lymph nodes. Field sizes ranged from 10 cm 10 cm to 15 cm 15 cm, and certainly may be implicated in the toxicity encountered. It is unclear whether the schedule of gemcitabine administration influenced toxicity. In a recent Eastern Cooperative Oncology Group Phase I trial, the use of gemcitabine with concurrent protracted venous infusion of 5-FU and RT was investigated. Weekly gemcitabine with doses beginning at 50 mg/m 2 with dose escalation as determined by tolerance was intended (13) (Fig. 3). The RT volume included nodes at risk for occult metastases. Three of 7 patients on the trial experienced GI dose-limiting toxicity at low weekly doses of gemcitabine (50 and 100 mg/m 2 ). In 2 patients, this occurred after RT completion (59.4 Gy in 1.8-Gy fractions). In that trial, the delivery of concurrent protracted venous infusion 5-FU, a relatively high dose of RT, and treatment volumes that included lymph nodes at risk may have contributed to the toxicity observed, despite the low doses of gemcitabine. CLINICAL TRIALS OF RADIATION DOSE ESCALATION In each of the trials discussed above, emphasis was placed on the delivery of RT with gemcitabine dose escalation. An alternative strategy has been investigated at the University of Michigan (Ann Arbor, MI), using standard doses of gemcitabine, considering the clinical benefit associated with its use as a systemic agent (14). The goal of this effort is to maximize the systemic drug effect while providing local control through sensitization of a modest radiation dose. The use of a standard dose of gemcitabine (1000 mg/m 2 /wk) is also consistent with our laboratory data Fig. 2. Gemcitabine (G) dose-escalation schema with concurrent rapid fractionation. Abbreviation: XRT RT.

3 12 I. J. Radiation Oncology Biology Physics Volume 56, Number 4, Supplement, 2003 Fig. 3. Gemcitabine (G) dose-escalation schema investigated in the Eastern Cooperative Oncology Group trial, with concurrent protracted venous infusion (PVI) 5-FU and RT (XRT). that demonstrate maximal radiosensitization when cytotoxic concentrations of drug are used (3). Considering prior clinical experience, it is clear that use of full-dose gemcitabine requires reduction and investigation of the radiation dose and modification of the treatment volumes. Radiation dose escalation, in our initial Phase I trial, was achieved by increasing the fraction size, keeping the duration of RT at 3 weeks (15). The radiation fields were planned with threedimensional RT (3D-CRT) planning, and covered only the gross target volume with a 1-cm margin (i.e., no elective nodal RT). Doses in the range of Gy ( Gy fractions) were investigated. A second cycle of gemcitabine alone was delivered after a 1-week rest (Fig. 4). Thirty-seven patients with unresectable (n 34) or incompletely resected (n 3) pancreatic cancer were treated using this approach (15). Suspected or confirmed metastatic disease was identified at the time of enrollment in 14 patients. Three patients experienced dose-limiting toxicity, two with Grade 4 vomiting (one at the 30-Gy and one at the 42-Gy dose level) and one with gastric/duodenal ulceration at the 42-Gy-dose level. Thus, at the final planned dose level of the trial (42 Gy in 2.8-Gy fractions), dose-limiting toxicity was noted in 2 of 6 assessable patients. Additional escalation could have been considered on the basis of the dose escalation criteria had the trial specified a high dose level. However, the occurrence of dose-limiting GI toxicity in 2 patients at this final dose level suggests that additional dose escalation may result in intolerable toxicity. Two additional patients at this dose level experienced late GI toxicity that required surgical repair. We have elected not to investigate a higher dose on the basis of this observation and the potential for late toxicity. The concern for late toxicity is based on radiobiologic data that indicate an increasing risk of late toxicity as the fraction size increases. Application of the linear quadratic model indicates that 42 Gy in 2.8-Gy fractions is biologically equivalent (with regard to late effects) to 50.4 Gy in 1.8-Gy fractions, a relatively standard dose and fractionation schedule used in the treatment of patients with unresectable pancreatic cancer. With a median potential follow-up of 22 months, local progression was noted in 7, regional progression in 3, and distant progression in 25 of 37 patients. These data represent failure at any site, rather than the first site of failure. Only 1 patient developed local or regional progression in the absence of distant progression. These patterns of failure suggest that the reduction in the radiation dose and field size did not result in excess locoregional failure. The median survival was 11.6 months (95% confidence interval ). The presence of metastatic disease at study entry did not have a significant impact on survival (p 0.69). The relative lack of GI toxicity, in our experience, using a more conformal approach and excluding prophylactic nodal RT, suggests that the RT volume is the most critical variable influencing GI toxicity in gemcitabine-based chemoradiation therapy regimens. This approach of weekly standard-dose gemcitabine combined with conformal RT to Fig. 4. Radiation (XRT) dose-escalation schema with concurrent full-dose gemcitabine (G) investigated at the University of Michigan (Ann Arbor, MI).

4 RT and gemcitabine in pancreas cancer C. J. MCGINN AND M. M. ZALUPSKI 13 Fig. 5. Digitally reconstructed radiographs of (a) anterior and (b) lateral beams for a sample case with radiation field sizes used for target coverage of gross target volume (GTV), which included primary tumor with a 3-cm expansion and additional expansion to cover porta hepatis (PH), celiac axis (CA), and periaortic lymph nodes vs. (c, d) beams that would include the GTV with a 1-cm expansion, without nodal coverage. the gross target volume within 3 weeks is currently being studied in a multi-institutional Phase II trial for patients with resectable or unresectable pancreatic cancer. RT CONSIDERATIONS Traditional RT volumes have included the primary tumor, as defined by CT and/or surgical clips placed at surgery, as well as pancreaticoduodenal, porta hepatis, and celiac nodes that may be at risk (16). A margin of normal tissue around these structures is included as well, given the uncertainties of target definition and variation in daily patient setup. As a result, a substantial volume of small bowel is included within the treatment fields. The use of 3D-CRT planning is now becoming more common and may reduce the toxicity associated with RT (17, 18). This technology

5 14 I. J. Radiation Oncology Biology Physics Volume 56, Number 4, Supplement, 2003 allows more accurate definition of target volumes, as identified on a dedicated RT planning CT scan, thus limiting the amount of adjacent normal tissue irradiated. In addition, nonaxial beam arrangements can be used, which may permit additional reduction in the radiation dose to normal tissue (19). The impact of this technology has not been fully assessed at present. Yet, 3D-CRT planning may become critically important as more effective systemic therapies are developed. In this setting, prophylactic RT of regional nodes may not be required, and accurate targeting of the gross tumor volume, with a minimal margin of normal tissue, may be essential to optimize local control. The issue of RT volume needs to be critically addressed in all chemoradiation studies using gemcitabine, secondary to the potent radiosensitization of normal tissues. A comparison of local toxicity (both acute and late) between trials of gemcitabine dose escalation and full-dose gemcitabine with radiation dose escalation may be informative, because the volumes of normal tissue irradiated (as indicated by the margins of expansion) are dramatically different (Fig. 5). FUTURE CONSIDERATIONS In considering the therapeutic options for patients with pancreatic cancer, both locoregional control and systemic failure must be addressed, particularly in situations in which the radiosensitizer being used also has systemic activity as a cytotoxic agent. This is certainly the case in pancreatic cancer, for which additional improvements in local control are not likely to result in a survival advantage. However, the benefit of local control is obvious and may certainly be augmented by the use of gemcitabine concurrent with RT. The radiation dose-escalation trial described above, in which full-dose gemcitabine was delivered, is an example of such consideration. The approach was also based on preclinical data and may serve as a new paradigm for regimens using gemcitabine with concurrent RT. It is apparent that RT volumes will need to be critically assessed and controlled in subsequent Phase II or Phase III trials. As these trials are designed, the role of gemcitabine-based chemoradiation therapy regimens in the adjuvant setting will need to be considered as well. The sequencing of multimodality therapy in pancreatic cancer also deserves further study. Treatment algorithms generally begin with determination of resectability followed by surgery for patients who appear to have operable disease. Surgical treatment alone uncommonly cures patients with this disease. A substantial fraction of patients are unable to receive postoperative adjuvant therapy or have treatment delayed because of postoperative recovery (after resection or exploration without resection). Preoperative chemoradiation therapy may shorten the course of treatment and increase the fraction of patients receiving all modalities of therapy. Because distant disease is a component of failure in most cases, earlier application of systemic treatment may be a better strategy for control of micrometastasis. This potential would be maximized with the use of chemoradiation therapy regimens that emphasize the systemic component of therapy. Preoperative RT may also be associated with less toxicity as a result of RT volume considerations, because the target remains in situ. Issues of sequencing must also be considered in patients with unresectable disease as determined by imaging, particularly when combined-modality therapy is designed to optimize local control. In this setting, delivery of systemic therapy preceding the measures for local control should be emphasized. The considerations discussed above may, if appropriately applied, provide some incremental benefit to patients with pancreatic cancer. The development of novel agents may improve results as well. As newer agents are integrated into more conventional combined-modality regimens, these considerations become even more critical, such that the novel agents can be incorporated to maximize their therapeutic potential. REFERENCES 1. Shewach DS, Hahn TM, Chang E, et al. Metabolism of 2,2 -difluoro-2 -deoxycytidine and radiation sensitization of human colon carcinoma cells. Cancer Res 1994;54: Lawrence TS, Chang EY, Hahn TM, et al. Delayed radiosensitization of human colon carcinoma cells after a brief exposure to 2,2 -difluoro-2 -deoxycytidine (gemcitabine). Clin Cancer Res 1997;3: Lawrence TS, Chang EY, Hahn TM, et al. Radiosensitization of pancreatic cancer cells by 2,2 -difluoro-2 -deoxycytidine. Int J Radiat Oncol Biol Phys 1996;34: Rosier JF, Beauduin M, Bruniaux M, et al. 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