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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 CLINICAL RESEARCH IN PANCREATIC CANCER: THE RADIATION THERAPY ONCOLOGY GROUP TRIALS CHRISTOPHER G. WILLETT, M.D.,* HOWARD SAFRAN, M.D., ROSS A. ABRAMS, M.D., WILLIAM F. REGINE, M.D., TYVIN A. RICH, M.D., AND THE GASTROINTESTINAL COMMITTEE OF THE RADIATION THERAPY ONCOLOGY GROUP *Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA; Department of Medical Oncology, Brown University, Providence, RI; Department of Radiation Oncology, Johns Hopkins Oncology Center, Baltimore, MD; Department of Radiation Oncology, University of Kentucky, Lexington, KY; Department of Radiation Oncology, University of Virginia Health Sciences Center, Charlottesville, VA Purpose: To summarize the clinical research activities of the Radiation Therapy Oncology Group program in the treatment of patients with locally advanced, as well as resected, pancreatic cancer. Methods and Materials: Phase II and III clinical trials are underway, examining novel cytotoxic and targeted agents with irradiation (RT) for patients with locally advanced and resected pancreatic cancer. Results: A Phase II study incorporating concurrent paclitaxel with external beam radiotherapy in the locally advanced setting has been completed and recently analyzed. This experience has served as the foundation of a Phase II study using concurrent paclitaxel and gemcitabine with RT followed by R115777, a farnesyltransferase inhibitor, as maintenance therapy. In the adjuvant treatment of pancreatic cancer, an Intergroup Phase III trial has compared conventional postoperative chemoirradiation (5-fluorouracil before, after, and during RT) and gemcitabine before and after RT (with 5-fluorouracil during RT). This study has recently closed, meeting its accrual goal. The successor study will evaluate the use of gemcitabine given concurrently with RT, as well as in a maintenance schedule. Conclusion: This report summarizes current and future Radiation Therapy Oncology Group clinical trials in the treatment of patients with localized pancreatic cancer Elsevier Inc. Radiation Therapy Oncology Group, Pancreatic cancer, Radiotherapy, Adjuvant treatment. INTRODUCTION One of the major research goals of the Gastrointestinal Cancer Committee of the Radiation Therapy Oncology Group (RTOG) is the evaluation of novel and targeted chemotherapeutic agents with irradiation (RT) in the treatment of patients with localized pancreatic cancer. Pancreatic cancer remains one of the most formidable challenges in oncology. In 2003, the American Cancer Society estimated that 30,700 new cases of pancreatic cancer in the United States will develop and 30,000 deaths from the disease will result (1). Thus, pancreatic cancer is the fourth leading cause of cancer-related death, with 5% survival 5 years after diagnosis. To improve these survival rates, RTOG Phase II and III clinical studies are evaluating a variety of novel treatment strategies for patients with locally advanced and unresectable tumors, as well as resected lesions. This report summarizes these efforts. LOCALLY ADVANCED PANCREATIC CANCER Approximately one-half of all patients with newly diagnosed pancreatic cancer have locally advanced disease at Reprint requests to: Christopher G. Willett, M.D., Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom St., Boston, MA Tel: ; Fax: 617- presentation. Radiotherapeutic approaches are frequently used, because these patients have unresectable tumors by virtue of local invasion of the portal, mesenteric, or celiac vessels in the absence of clinically detectable metastases. The Gastrointestinal Study Group (GITSG) first demonstrated a survival advantage with the combination of 5-fluorouracil (5-FU) and RT compared with RT alone for patients with locally advanced pancreatic cancer (2, 3). The RTOG is investigating new chemoradiation regimens to enhance locoregional control, as well as incorporating molecular-based agents to prevent or delay progression of occult metastatic disease. RTOG 9812 RTOG 9812 has served as the foundation of these studies. This study evaluated paclitaxel and concurrent RT for locally advanced pancreatic cancer. Paclitaxel synchronizes cells at G 2 /M, a relatively radiosensitive phase of the cell cycle (4). In vitro studies suggested that paclitaxel can enhance the cytotoxicity of radiation even in cancer cells that are resistant to paclitaxel as a single agent (5, 6). Also, ; cwillett@partners.org Received Nov 5, 2002, and in revised form Jan 21, Accepted for publication Jan 31,

2 32 I. J. Radiation Oncology Biology Physics Volume 56, Number 4, Supplement, 2003 Fig. 1. Unresectable pancreatic cancer studies: RTOG 9209 and RTOG the stem cells of the GI mucosa are not substantially radiosensitized by paclitaxel (7). Furthermore, the response to paclitaxel/rt was not affected by the presence of p53 mutations (8). Paclitaxel/RT protocols have been piloted by the Brown University Oncology Group (9). An early Phase I study by this group demonstrated the maximal tolerated dose of paclitaxel was 50 mg/m 2 /wk for 6 weeks with 50 Gy abdominal radiation. Abdominal pain within the radiation field, nausea, and anorexia were the dose-limiting toxicities. In a follow-up Phase II Brown study, these investigators reported that the overall response rate was 29% (10). The incidence of Grade 3-4 GI toxicity was 10%. Myelosuppression was uncommon. RTOG 9812 was completed in 15 months, accruing 122 patients with locally advanced, nonsurgically staged, pancreatic cancer (11). RT was delivered to 50.4 Gy in 28 fractions of 1.8 Gy/fraction to the tumor and draining lymph nodes during 5 weeks. Paclitaxel, 50 mg/m 2 /wk, was administered as a 1-h i.v. infusion for 6 weeks on Days 1, 8, 15, 22, 29, and 36. The overall response rate in the RTOG study was 33%, with a 7% complete response and 26% partial response rate. The median survival was 11.3 months, with a 1-year survival rate of 43.1% (8). This median survival time and 1-year survival rate suggested a modest improvement compared with the 7-month median survival and 27% 1-year survival rate of RTOG 9209 with 5-FU based chemoradiation (Fig. 1 and Table 1). Four patients (4%) experienced Grade 4 toxicity, and one (1%) treatmentrelated death from infection occurred. Only 1 patient (1%) experienced Grade 4 late radiation toxicity. All six cycles were delivered in 85% of patients. The full protocol dose of radiation (within 5%) was delivered in 89% of patients. Although surgery was not an end point of this study for unresectable patients, three did have tumor regression after protocol treatment, resulting in complete surgical resection. Table 1. Treatment results of RTOG 9209 and RTOG Patients entered (n) 122 (15 mo) 51 (47 mo) Median survival (mo) month survival (%) Abbreviation: RTOG Radiation Therapy Oncology Group. Fig. 2. Unresectable pancreatic cancer study: RTOG PA RTOG PA-0020 RTOG PA-0020 will build on RTOG 9812 in two ways. Gemcitabine will be combined with paclitaxel during RT and an oral farnesyl transferase inhibitor, R115777, will be administered as maintenance therapy (Fig. 2). Gemcitabine is also an active agent in pancreatic cancer and is a potent radiosensitizer. Preclinical and clinical investigations have also shown that gemcitabine can be combined with other chemotherapy agents, demonstrating promising activity with acceptable toxicity in non smallcell lung cancer, bladder cancer, and breast cancer, and that it is a radiosensitizer. In a Phase I study in pancreatic cancer by the Brown University Oncology Group, paclitaxel, gemcitabine, and RT were combined. Patients received 50.4 Gy of radiation, paclitaxel, 40 mg/m 2 /wk, and escalating doses of gemcitabine (12). The initial dose level of gemcitabine, 75 mg/m 2 /wk for 6 weeks, was the maximal tolerated dose. Gemcitabine dose levels of 150 mg/m 2 and 110 mg/m 2 were also evaluated. Eight patients were treated at the gemcitabine 75 mg/m 2 dose level. Of these 8 patients, only 1 had Grade 3 toxicity consisting of anorexia and dehydration. Four patients responded and three had stable disease, including one who underwent resection after chemoradiation and had a pathologic complete response and a second patient with a near-complete pathologic response. Three patients were treated at the gemcitabine dose level of 150 mg/m 2 /wk; Grade 3 GI toxicity, including diarrhea, nausea, and anorexia, developed in all 3 patients and 1 patient also had Grade 3 myelosuppression. An intermediate dose level of gemcitabine, 110 mg/m 2, was subsequently added. Three of four patients had Grade 3 or 4 toxicities. One of these patients had Grade 4 hypersensitivity pneumonitis that responded to prednisone. On the basis of this Phase I study, the dose level of gemcitabine 75 mg/m 2 /wk, paclitaxel 40 mg/m 2 /wk, and 50.4 Gy concurrent radiation will be investigated in a new Phase II study. This dose level was well tolerated with major activity, including a pathologic complete response. This novel combination of radiosensitizers may have substantially more activity than either agent alone with acceptable toxicity. In addition to the active chemoradiation used to improve

3 RTOG pancreatic cancer studies C. G. WILLETT et al. 33 locoregional control, more effective therapy is necessary for the control of occult metastatic disease. A new RTOG protocol (PA-0020) will evaluate the use of a farnesyl protein transferase (FPTase) inhibitor R after paclitaxel, gemcitabine, and RT (Fig. 2). FPTase inhibitors have been developed to alter the activity of ras oncogenes and the proteins they encode. The ras genes [Harvey (Ha), Kristen (Ki), and N-ras] encode low-molecular-weight proteins called Ras (13). Ras, after several posttranslational modifications, localizes itself to the inner surface of the plasma membrane (14). Ras proteins normally cycle between guanosine diphosphate (GDP)-bound (inactive) and guanosine diphosphate (GTP)-bound (active) states to regulate cellular proliferation and differentiation. Growth factors bind to these cellular receptors causing activation of the GDP- bound Ras protein, which exchanges its bound GDP for GTP. This activated form of the Ras protein subsequently triggers a cascade of events that ultimately lead to cell proliferation. The GTPase activity of ras then turns off the biologic event, Ras returns to its inactive form (GDPbound), and the cycle is thus closed. Ras then remains in an inactive form until a new growth signal arrives (15). A single point mutation changing an amino acid is responsible for altering the wild-type ras gene into an oncogene that efficiently induces neoplastic transformation (13). The mutations in ras genes frequently found in cancer inhibit the GTPase activity of the Ras protein, and thus Ras remains bound to GTP and permanently activated. This results in the active Ras protein constitutively stimulating cell growth and proliferation (16). Mutations of the ras gene are found in 90% of pancreatic tumors (17). Thus, inhibition of ras gene function is a rational target in pancreatic cancer. Recent progress at blocking ras-induced cell transforming activity has centered on inhibiting the enzyme FPTase (18). Membrane localization of Ras is essential for its normal function and the cell-transforming activity of its mutated, oncogenic form. Membrane anchoring of Ras is achieved through a series of posttranslational modifications. The first and most critical modification is farnesylation of its carboxyl-terminal motif, catalyzed by FPTase (13). Inhibition of the farnesylation reaction by synthetic FPTase inhibitors nullifies ras membrane anchorage and therefore inhibits Ras protein function, as well as its cell-transforming capability (16 18). Recent evidence suggests that inhibition of the farnesylation of other proteins may contribute to the antitumor effect of farnesyl transferase inhibitors. R is a potent and selective nonpeptidomimetic inhibitor of FPTase both in vitro and in vivo. It has been shown in several preclinical tests to inhibit H-ras, K-ras, and N-ras activity in transformed tumors. Recent Phase I studies in the United States have determined safe and tolerable oral administration schedules for R In the new RTOG Phase II trial for patients with locally advanced disease, patients on Arm 2 will receive R until disease progression. Because patients will require long-term administration, a relatively nontoxic schedule is preferred. A dosage of 300 mg p.o. b.i.d. for 21 days every 28 days has therefore been selected. In RTOG PA-0020, patients with locally advanced disease will receive gemcitabine, paclitaxel, and RT and will be randomized to receive R until disease progression. ADJUVANT THERAPY FOR PANCREATIC CANCER At present, surgery offers the only therapeutic means of cure for pancreatic cancer. Only 5 25% of patients present with tumors amenable to resection. Patients who undergo resection for localized pancreatic carcinoma have a longterm survival rate of approximately 20% and a median survival of months (19 24). Favorable subsets include patients with resected tumors measuring 3 cm, negative nodal status, and microscopically negative surgical margins. Even in the most favorable patient subsets, the 5-year survival rate is only 36% (20 23, 25, 26). Among patients undergoing resection with curative intent, prospective randomized evaluation of adjunctive chemoradiation has been limited, until recently, to a single trial conducted by the GITSG that showed a statistically significant doubling in median survival and modest improvement in 5-year survival for patients receiving adjuvant splitcourse chemoradiation followed by weekly maintenance 5-FU for a planned 2 years compared with observation. Therapy involved 40 Gy within 6 weeks, with a mid 2-week break, and 3-day infusions of 5-FU at the start of Weeks 1 and 5, followed by weekly infusions of maintenance 5-FU (500 mg/m 2 ). Among the 21 patients randomized to adjuvant split-course chemoradiation, the median survival was 21 months, the 2-year survival rate was 43%, and the 5-year survival rate was 19% compared with 11 months, 18%, and 5%, respectively, for the observation group (p 0.03). No life-threatening complications or deaths attributable to therapy occurred (27, 28). These results were duplicated in an additional cohort of 30 patients treated with the same therapy on a nonrandomized basis (27 29). Of the 51 treated patients in the GITSG study, 2 (4%) developed possible late treatment-related complications. In moving beyond GITSG from the 1970s (when the GITSG trial began) to the 1990s (when the European Organization for Research and Treatment of Cancer and ESPAC trials began), a number of realities have become clear in this evolving clinical arena, even if the role of adjuvant therapy has not. First, surgical morbidity and mortality have dramatically improved. In major centers, the expected mortality of pancreaticoduodenectomy is now about 1% (29, 33). This operation is associated with a median hospital stay of 2 weeks, can be safely performed among properly selected elderly patients (34), and may enhance survival even when performed for overtly palliative (as opposed to curative ) reasons, leaving small amounts of visible tumor behind (35). This dramatic evolution in surgical skill and accomplishment is resulting in increasing numbers of successfully resected, physiologically intact,

4 34 I. J. Radiation Oncology Biology Physics Volume 56, Number 4, Supplement, 2003 good performance status patients, for whom the issues of whether to undergo postoperative adjuvant therapy seem far from academic as they confront the unappealing survival statistics associated with their illness. In addition, it is equally clear that after curative resection, patients are prognostically heterogeneous and that this variation can be characterized by a number of clinicopathologic parameters, including tumor size, presence or absence of nodal involvement, presence or absence of tumor histologically at the resection margins, histologic grade, DNA ploidy, and intraoperative blood loss or transfusion (23, 29, 36 37). Since the 1970s, the role of adjuvant therapy has become well established and continues to evolve in upper aerodigestive tract cancer (38, 39), breast cancer (40), rectal cancer (41), and colon cancer (42). Also, postoperative adjunctive therapy for pancreatic carcinoma and other GI sites has evolved into use of higher dose, non split-course, and potentially more toxic, chemoradiation regimens than that used in the GITSG study (43 45). A Phase III evaluation of such an approach in rectal carcinoma, with the use of RT doses of Gy within 6 weeks combined with continuous infusion 5-FU, has been associated with a significant improvement in survival compared with a less doseintensive chemoradiation regimen (46). A second development with an impact on these considerations is the approval of gemcitabine for use in patients with advanced and metastatic pancreatic cancer. This is the first chemotherapeutic agent since 5-FU to be approved for use in this context in 35 years. Although the objective response rate observed with this drug was low (5%) in patients with locally advanced or metastatic disease (47), the Food and Drug Administration approved gemcitabine on the basis of the results of two trials of patients with symptomatic Stage IV pancreatic cancer (47, 48). These trials introduced the concept of a clinical benefit response; that is, a response determined by performance status, analgesic requirement, pain intensity, and weight gain. In a prospective randomized trial comparing 5-FU and gemcitabine for advanced pancreatic cancer, gemcitabine demonstrated a clinical benefit response of 24% compared with 5% for 5-FU (p ); the corresponding objective response rates were 5% and 0%. The median survival was 5.7 months for gemcitabine and 4.4 months for 5-FU and the 1-year survival rate was 18% and 2%, respectively (p ). The second trial was a single-arm Phase II trial in 63 patients whose tumors had failed 5-FU therapy (48). Treatment was gemcitabine at the same dose and schedule. The clinical benefit response was 27% and the 1-year survival rate was 4%; the median survival was 3.9 months. The toxicity of gemcitabine was mild to moderate. Only 10% of patients discontinued therapy because of toxicity, most commonly myelosuppression. RTOG 9704 RTOG 9704 is a Phase III study of postoperative adjuvant treatment of resected pancreatic adenocarcinoma evaluating postoperative chemoradiation (50.4 Gy in 28 fractions plus Fig. 3. Intergroup adjuvant pancreas cancer trial: RTOG continuous infusion 5-FU at 250 mg/m 2 /d), preceded and followed by systemic chemotherapy with randomization to either 5-FU or gemcitabine (Fig. 3). This study is available as an Intergroup trial in the RTOG, Eastern Cooperative Oncology Group, and Southwest Oncology Group. It is the first American Phase III cooperative group study in nearly a quarter century (GITSG activated February 1974) to evaluate adjuvant chemoradiation in patients with localized and resected adenocarcinoma of the pancreas. The study schema is detailed in Fig. 3. Patient eligibility was as follows: localized adenocarcinoma of the pancreas after gross total resection (i.e., removal of all gross local disease); Stage T1 T3N0-N1, protocol treatment to begin within 3 6 weeks of definitive tumor-related surgery; Karnofsky performance status 60; age 18 years; adequate oral nutrition (e.g., 1500 calories/d); white blood cell count 3000, platelets 100,000; bilirubin and creatinine 1.5 the institutional upper limits of normal; serum glutamic-oxaloacetic transaminase 5 the institutional upper limits of normal; and CA19-9 level should be measured less than 14 days before randomization. The study incorporated modern therapeutic principles of chemoradiation, RT planning, RT quality assurance, and current developments in chemotherapy for pancreatic cancer. The use of a sequence of chemotherapy3 chemoradiotherapy3chemotherapy has been found to produce optimal results and is routinely incorporated in intergroup postoperative adjuvant gastric and rectal trials (39, 41). In addition to the theoretical advantages associated with this approach, systemic chemotherapy can be instituted somewhat sooner in the postoperative period than can RT to the upper abdomen. Because, in the past, it has not been uncommon to have to delay the onset of chemoradiotherapy to the seventh or eighth postoperative week to allow for recovery of nutritional balance and surgical healing, a chemotherapy-first sequence should allow significantly earlier initiation of therapy with only a minimal delay in the timing of RT. For patients starting chemotherapy in postoperative Week 4, it is likely that chemoradiation will begin in postoperative Week 8, resulting in essentially no delay over standard practice and with a significantly earlier onset of postoperative therapy. This sequencing also allows for prospective quality review of RT films, a feature not used in previously reported Phase III adjuvant pancreas trials. This review is a process that has been clearly demonstrated to be helpful given the potential technical complexities associated

5 RTOG pancreatic cancer studies C. G. WILLETT et al. 35 Fig. 4. Pancreatic cancer RTOG efforts: new agent/ebrt Phase II studies or Phase III studies. with RT planing to the upper abdomen, as demonstrated by the recently reported Intergroup adjuvant gastric trial (39, 49). The use of continuous infusion 5-FU at 250 mg/m 2 /d during chemoradiation is based on the Eastern Cooperative Oncology Group reported results of a Phase I trial evaluating the maximal tolerated dose of continuous infusion 5-FU with concurrent RT in patients with unresectable, residual, or recurrent carcinoma of the pancreas or bile duct (50). The use of gemcitabine after chemoradiation is not anticipated to be a problem. In animal studies, gemcitabine- RT sequencing that separates the two treatments by more than a few hours does not appear to enhance the radiation effects (51), and in preliminary data from the Fox Chase Cancer Center, postchemoradiation maintenance gemcitabine has been well tolerated (52). Gemcitabine has intentionally been omitted from the chemoradiation phase because of the concern that adequate experience with concurrent RT and gemcitabine is not yet available to justify its use in a Phase III trial. RTOG/Intergroup Study 9704 was activated in July 1998 with a projected accrual rate of 5 patients monthly and a targeted accrual of 330 patients. Somewhat unexpectedly, the monthly accrual rate was much greater. Through 2001, the study had accrued approximately 450 patients at an average accrual rate of 13 patients monthly. This no doubt reflected a significant patient population for which no national study has been conducted in nearly a quarter century. Thus, in early 2001, it was decided, because of the unexpected rapid accrual to the study, that the sample size should be increased so as to increase the power to find a potential treatment effect. The revised sample size was set at 520 patients. The study has thus far demonstrated the generally expected toxicities, which have been primarily GI in the 5-FU arm and hematologic in the gemcitabine arm. Study accrual was reached in July 2002 (538 patients totally accrued). To increase survival for patients with completely resected pancreatic cancer, improvements are needed in adjuvant systemic therapy. In RTOG 9704, when patients receive 5-FU and RT, patients do not receive gemcitabine for an extended period. Multiple Phase I studies have demonstrated that systemic doses of gemcitabine can be incorporated with RT in pancreatic cancer by reducing the RT field size. McGinn et al. (52) used full-dose gemcitabine, 1000 mg/m 2 /wk, with radiation fields planned with three-dimensional conformal techniques to cover only the gross tumor volume and not elective nodes. Radiation doses in the range of Gy ( Gy fractions) have been investigated. Toxicity has primarily been hematologic and has not limited escalation. The preliminary response and survival data have been encouraging. The relative lack of GI toxicity in this experience, using a more conformal approach and exclusion of prophylactic nodal RT, suggests that the RT volume is perhaps the most critical variable influencing GI toxicity in gemcitabine-based chemoradiotherapy regimens. However, this approach may not be appropriate in the adjuvant setting, because the gross disease has been resected, and the risk of recurrence is equally distributed throughout the region of the primary tumor, regional nodes, and surgical anastomotic sites (hepaticojejunostomy and pancreaticojejunostomy). FUTURE ADJUVANT TRIAL The RTOG will base their next adjuvant pancreatic cancer chemoradiation regimen on the Phase I data of Hoffman et al. (52) for patients with locally advanced pancreatic cancer. Gemcitabine was delivered once weekly, concurrent with 50.4 Gy (1.8-Gy fractions). The radiation field size was limited to the gross tumor volume with a 2 3 cm expansion. In retrospect, this represents a compromise between the conventional field size (which covers the primary tumor with a 3 5-cm margin, as well as porta hepatis and celiac axis lymph nodes) and the restricted field size used with full-dose gemcitabine. The starting dose of gemcitabine in this trial was 300 mg/m 2. Hematologic and GI toxicity limited the dose to 700 mg/m 2, and the recommend dose for additional investigation is 600 mg/m 2. The RTOG will therefore perform a single-arm Phase II study. All patients will receive gemcitabine, followed by concurrent gemcitabine and RT, followed by 3 months of additional gemcitabine. This study will address two specific aims: (1) to determine the 2-year survival rates of patients with resected pancreatic cancer treated with gemcitabine and RT combined with gemcitabine either before or after chemoradiation; (2) to determine the toxicity of postoperative adjuvant gemcitabine and RT.

6 36 I. J. Radiation Oncology Biology Physics Volume 56, Number 4, Supplement, 2003 CONCLUSION Under the auspices of the RTOG, Phase II and III clinical trials are evaluating novel treatment strategies for patients with locally advanced and resected pancreatic cancer (Fig. 4). A Phase II study incorporating concurrent paclitaxel with external beam radiotherapy in the locally advanced setting has been completed and recently analyzed. This experience has served as the foundation for the current Phase II study using concurrent paclitaxel and gemcitabine with RT, followed by R115777, a farnesyl transferase inhibitor, as maintenance therapy. In the adjuvant treatment of pancreatic cancer, the current Intergroup trial compares conventional postoperative chemoirradiation (5-FU before, after, and during RT) vs. gemcitabine before and after RT (with 5-FU during RT). This trial recently met its accrual goals. 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