Medical Oncology, vol. 24, no. 2, 239–243, 2007 © Copyright 2007 by Humana Press Inc. All rights of any nature whatsoever reserved. 1357-0560/(Online)1559-131X/07/24:239–243/$30.00
Original Article
Concurrent Gemcitabine and Radiotherapy for Locally Advanced Pancreatic Cancer Mustafa Cengiz, Faruk Zorlu, Suayip Yalcin, Murat Gurkaynak, I. Lale Atahan, and Ibrahim H. Gullu Faculty of Medicine, Hacettepe University, Sihhiye 06100, Ankara, Turkey
Abstract This study is designed to assess the toxicity and therapeutic effectiveness of concurrent gemcitabine and radiotherapy in patients with unresectable pancreatic cancer. Concurrent gemcitabine (400 mg/m2/wk) in six weekly cycles starting on d 1 of radiotherapy (50.4 Gy; 1.8 Gy/fraction/d; 5 d/wk) was prescribed on 22 patients with locally advanced pancreatic cancer. Patients were analyzed with regard to radiological response on computerized tomography, overall survival, and toxicity. Twelve (55%) patients completed the prescription of six gemcitabine cycles and 50.4 Gy radiotherapy; while 10 (45%) received one to five cycles of gemcitabine owing to neutropenia. All patients experienced abdominal discomfort during treatment and three patients required medical intervention. Other toxicities reported were nausea in 13 patients (60%), grade 3 vomiting in 3 (14%). Radiological response evaluations were as follows: complete, 2 (9%); partial, 9 (41%); stable, 7 (32 %); and progressive, 4 (18 %). Median survival was 8.7 mo. Combination of weekly gemcitabine (400 mg/m2) and radiotherapy provided response in 50% of the patients but was associated with severe toxicity resulting in incomplete delivery of the planned chemotherapy. Key Words: Pancreas cancer; radiotherapy; chemotherapy; gemcitabine; concomitant chemoradiotherapy.
approach for locally advanced surgically unresectable disease (2). In addition, GITSG has also compared chemotherapy alone (streptozocin, mitomycin C, and 5-FU; SMF) vs chemoradiation (SMF plus radiotherapy) (3). The addition of radiotherapy to chemotherapy improved median and overall survivals; although this survival increase with combined modality treatment was still not enough and all patients succumbed to their disease. In surgically unresectable carcinoma of the pancreas, the median survival is reported to be approx 6 mo, and combination of radiation and chemotherapy only prolonged median survival to a range of 9–13 mo (1), which led to further research for newer therapeutic approaches. Combination of gemcitabine and radiotherapy has generated much interest because of its clinical benefit
Introduction Pancreatic carcinoma comprises approx 2% of all cancer diagnosis and has the lowest 5-yr survival rate, mainly due to its usual presentation at an advanced stage. Surgery offers the only potential cure, although only 5–25% of cases are resectable (1). The Gastrointestinal Tumor Study Group (GITSG) reported an approx 5 mo survival benefit for patients receiving 5-FU plus radiation over radiation alone; and this regimen became the standard treatment Recieved 08/0106; Accepted 12/0706 Corresponding Author: Mustafa Cengiz, MD, Hacettepe University, Faculty of Medicine, Dept. of Radiation Oncology, Sihhiye 06100, Ankara, Turkey. E-mail: mcengiz@hacettepe. edu.tr
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240 in the setting of metastatic disease and its radiosensitizing properties. Epelbaum et al. (4) reported their early experience with concomitant gemcitabine and radiotherapy stating that 400 mg/m2/wk gemcitabine was well tolerated with concurrent conventional radiotherapy of 50.4 Gy. We have designed this phase II study to assess the toxicity and therapeutic effectiveness of concurrent gemcitabine and radiotherapy in our patients with locally advanced unresectable pancreatic cancer, on the background of current poor treatment outcome in pancreatic cancer and evident independent therapeutic activity of gemcitabine alone with radiosensitizer potential.
Patients and Methods We performed a single-center feasibility study to prospectively assess the toxicity and efficacy of combined gemcitabine–radiotherapy as definitive treatment in advanced unresectable pancreatic cancer. Inclusion criteria were unresectable disease defined as tumor obstructing or invading the celiac axis, superior mesenteric artery, or portal vein, with the following: age >20, baseline Karnofsky performance status of at least 50, adequate bone marrow reserve, defined as white blood cell count (WBC) ≥ 3500/µL, platelet count ≥ 100.000/µL, and hemoglobin ≥ 9.5 gm/dL, adequate baseline hepatic function [total bilirubin ≤ 2 mg/dL, aspartate transaminase (AST) and alanine aminotransferase (ALT) ≥ three times of normal], and adequate renal function (serum creatinine concentration ≤ 1.5 mg/dL). Exclusion criteria were metastatic disease, ascites, or peritoneal implants and previous chemotherapy or radiation. Between January 1999 and March 2002, 28 patients with locally advanced unresectable pancreatic cancer were admitted to Hacettepe University, Department of Radiation Oncology. Twenty-two patients were found eligible while six were excluded from the study due to rejection of enrollment or low performance status. All patients signed the informed consent. Stage distribution according to AJCC 2002 was between IIB and III.
Chemotherapy Gemcitabine (400 mg/m2) was planned to be administered in six weekly cycles starting on d 1 of radiotherapy. A total of six courses of gemcitabine in 150 cm3 0.9% NaCl solution over 30 min of infusion
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Cengiz et al. Table 1 Patient Characteristics Median Age Sex Male Female Tumor size ≤5cm >5cm KPS ≥70 <70 CA 19-9 Stage IIB (T3N1) III T4 N0 T4N1
56 (range, 43–72) 13 9 9 13 18 4 1689 (257–5000) 2 20 13 7
were planned to be delivered during radiotherapy. Intravenous premedication with 8 mg dexamethasone (Decort) and 5 mg metoclorpropamide was given 30 min before gemcitabine administration. Chemotherapy was scheduled to be discontinued in case of patient’s intolerance or decrease of white blood cell count (WBC) under 3500/µL. Sixteen patients received further chemotherapy after the radiotherapy. Six patients received cisplatin and gemcitabine and remaining the 10 patients received 5-FU–based chemotherapy alone or in combination.
Radiotherapy Radiotherapy (50.4 Gy/28 fractions) (RT) was delivered to the primary tumor mass and to the draining lymph nodes over 5 wk. Planning computerized tomography (CT) were taken with IV contrast infusion without any oral contrast with 5 mm slice thickness starting from diaphragm down to pelvis. The clinical target volume was delinated on the planning CT scans slice by slice. Treatment volumes included the pancreatic tumor with 2 cm margin, and porta hepatis, celiac, pancreaticoduodenal, and regional paraaortic nodal bed. The typical volume radiated was between the top of the T11 vertebral body and the bottom of L2. All other margins were defined by a 2 cm distance from all gross residual disease. CT
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Fig. 1. Overall survival.
planning with multiple field technique (3 or 4 field) allowed us to spare more than 50% of the total kidney (both) volume receiving < 50% of the prescribed dose and to limit spinal cord dose below 45 Gy. Treatment was delivered with 6 MV photons.
Toxicity and Response Criteria Pre- and postradiotherapy evaluation at the eighth week after RT was done by computerized tomography. We have used RECIST criteria for radiological response evaluation (5); response was defined as complete for no evidence of tumor, partial for at least 50% reduction in the maximum perpendicular tumor measurements, and progression for >25% increase in tumor size or appearance of ascites or distant metastasis. Toxicity was assessed weekly and scored according to National Cancer Institutes Common Toxicity Criteria version 2.0.
Statistical Analysis Survival curves were calculated according to the Kaplan–Meier method. Survival time and tumor control were calculated from the date of initiation of chemoradiotherapy.
Results Median follow up was 12 mo (range, 2–22 mo). The median age was 56 yr (range, 43–72 yr). Cohort Medical Oncology
included 13 males and 9 females. All patients underwent explorative surgery or biopsy procedure to document pancreatic adenocarcinoma. Tumor size was ≥ 5 cm in 13 (59%) patients; < 5 cm in 9 (41%). Karnofsky performance status was ≥ 70 in 16 patients and < 70 in 6 (Table 1). Twelve (55%) patients could complete the whole planned prescribed chemoradiation with concurrent gemcitabine, while the remaining 10 patients could only receive median three courses of gemcitabine (range 1–5). The most common chemotherapy doselimiting toxicity was grade II neutropenia (10 patients) leading into cessation of the gemcitabine, and severe neutropenia in one patient that even interrupted radiotherapy. Thirteen (60%) patients experienced grade II acute toxicity with moderate nausea and vomiting. We reported severe vomiting (grade III) in two patients (9%) and managed with 5-HT3 receptor blocker antiemetics. All patients experienced nonspecific abdominal discomfort with no further treatment. One patient had acute grade III toxicity with epigastric pain presumed to be from chemoradiation-induced gastritis that was managed by appropriate medical therapy. There was no significant renal or hepatic toxicity as well as no treatment-related deaths. Complete radiological response was documented in two (9 %) patients, partial response in nine (41 %), stable disease in seven (32 %) and progression in four (18 %) patients. Volume 24, 2007
242 At the time of analysis, 20 patients have died with disease while 2 were lost to follow up. Overall median survival for the whole group was 8.7 mo (95% CI 5.9–11.6 mo (Fig. 1). Postmortem examination was not done in deceased patients. Our analysis for potential prognostic factors (age, performance status, tumor size, adjuvant chemotherapy, number of concomitant chemotherapy, and response rate) in this cohort did not reveal any significance for survival, possibly related with the limited small number of patients. Median survival in patients with low performance status was 3.4 mo vs 8.7 mo with good performance status. Correspondingly, patients with response revealed a median survival of 13.1 mo vs 6.7 mo in stable or progressive disease, for which the difference did not reach statistical significance.
Discussion The primary objective of this phase II study was to determine toxicity, tolerability, and therapeutic effectiveness of concurrent gemcitabine and radiotherapy in patients with unresectable pancreatic cancer. We mainly found that concurrent gemcitabine (400 mg/m2/wk) with radiotherapy provided disease control in 50% of the patients despite incomplete delivery of the planned chemotherapy in nearly half of the patients due to its toxicity. Pancreatic cancer is considered to be one of the most difficult cancers to manage, with the standard approach being 5-FU–based chemotherapy and radiotherapy. Combined use of chemoradiotherapy has become the current standard after the GITSG trial following randomization of 194 locally advanced pancreatic cancer to radiation alone to a dose of 60 Gy, 40 Gy plus 5-FU chemotherapy, or 60 Gy plus 5-FU chemotherapy. The interim analysis led to discontinuation of radiation-alone arm as the combined modality arms showed improved survival and time to progression (2). Meanwhile, Southwest Oncology Group (SWOG) randomized 69 patients to MeCCNU and 5-FU with or without testolactone combined with 60 Gy radiotherapy finding no significant difference in overall survival between arms (6). Then GITSG reported another study randomizing 143 patients to radiation with either weekly 5-FU or doxorubicin (7), but median survival was similar in both arms with higher toxicity for doxorubicin.
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Cengiz et al. Therefore, comparison of different regimens against the standard combination of 5-FU and radiation showed no additional advantage but more toxicity. Recently, gemcitabine has become popular in locally advanced pancreatic cancer, being approved as a single agent against metastatic and recurrent pancreatic cancer, as preclinical and clinical studies have demonstrated considerable synergism with ionizing radiation and potent radiosensitization in preclinical studies using human tumor cell lines, including pancreatic cell lines. The integration of gemcitabine in chemoradiation therapy was based on this information, as well as the generally accepted role of chemotherapy with concurrent radiation therapy in the management of pancreatic cancer (8,9). The data gathered from preclinical and clinical studies encouraged the use of gemcitabine instead of 5-FU in conjunction with radiotherapy. Several phase I studies were initiated to determine the maximum tolerated dose (MTD) of gemcitabine when delivered concurrently with radiation in patients with locally advanced unresectable pancreas cancer. Two phase I trials in 1996 commenced to determine maximum tolerated gemcitabine dose with 50.4 Gy radiotherapy in 28 fractions. The starting dose was 300 mg/m2, and maximum tolerated dose was found to be 700 mg/m2 regarding hematological and gastrointestinal toxicity (10). In addition, Wolff et al. at M.D. Anderson Cancer Center (11), demonstrated significant gastrointestinal toxicity with weekly gemcitabine delivered at >400 mg/m2 with concurrent rapid fractionation (30 Gy in 10 fractions); leading to hospitalization for nausea, vomiting, and dehydration in 7 patients out of 12. Epelbaum et al. (4) reported their experience of induction gemcitabine (1000 mg/m2) on 20 patients followed by the same chemoradiotherapy protocol as ours. They noted that 400 mg/m2/wk gemcitabine was well tolerated with concurrent conventional radiotherapy of 50.4 Gy. Although 400 mg/m2 weekly gemcitabine with 50.4 Gy radiation after induction gemcitabine was reported to be safe, we have experienced more toxicity then stated. The main dose-limiting toxicity was hematological leading to the cessation of the intended six courses of concurrent gemcitabine in nearly half of the patients. Despite the similar radiotherapy fields and performance status, our cohort experienced more hematological toxicity.
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Concurrent Gemcitabine and Radiotherapy for Pancreatic Cancer Crane et al. (12) retrospectively evaluated 114 patients with locally advanced disease treated at M.D. Anderson Cancer Center of which 61 received 5-FU (200–300 mg/m2) and 53 received gemcitabine (250–500 mg/m2 weekly) with 30 Gy in 10 fractions. Gemcitabine caused significantly more severe acute toxicity 23% vs 2%, while median survival was similar with a short median follow-up (11 mo vs 9 mo). In our series, 12 (55%) patients completed the treatment as planned and overall survival of the group was 8.7 mo in accordance with the previously reported series. Neutropenia was the most common dose-limiting toxicity in our study, whereas gastrointestinal toxicity was rare and did not change the treatment plan. Noteworthy to mention is that most of our patients did not tolerate the planned concurrent chemotherapy even though not receiving any neoadjuvant chemotherapy that might decrease tolerability. Another report from Turkey by Yavuz et al. (13) demonstrated the maximum tolerated dose of twice-weekly gemcitabine to be 90 mg/m2 in their phase I trial with major dose-limiting toxicity of neutropenia, similar to our series. We conclude that our experience with concurrent gemcitabine depended closely on possible geographic and genetic differences, and, therefore, this regimen should be vigilantly supervised due to the high rate of severe hematological toxicity.
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