Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer

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Gemcitabine has been reported to be a potent radiosensitiser in human pancreatic cell lines. This study was conducted to evaluate the efficacy and toxicity of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. In all, 42 patients with pancreatic cancer that was unresectable but confined to the pancreatic region were treated with external-beam radiation (50.4 Gy in 28 fractions over 5.5 weeks) and weekly gemcitabine (250 mg m−2, 30-min infusion). Maintenance gemcitabine (1000 mg m−2 weekly × 3 every 4 weeks) was initiated 1 month after the completion of the chemoradiotherapy and continued until disease progression or unacceptable toxicity. Of the 42 patients, 38 (90%) completed the scheduled course of chemoradiotherapy. The major toxicity was leucopenia and anorexia. There was one death attributed to duodenal bleeding and sepsis. The median survival time was 9.5 months and the 1-year survival rate was 28%. The median progression-free survival time was 4.4 months. In 35 patients with documented disease progression at the time of analysis, 34 (97%) showed distant metastasis as the cause of the initial disease progression. The chemoradiotherapy used in this study has a moderate activity against locally advanced pancreatic cancer and an acceptable toxicity profile. Future investigations for treatment with more systemic effects are warranted.


Pancreatic cancer is the fourth leading cause of cancer death in the United States and the fifth leading cause in Japan. The statistics indicate a rapid increase in the number of deaths and the death rate due to pancreatic cancer in Japan, but the precise reasons are not clear, except for smoking. Pancreatic cancer in most patients is surgically unresectable at the time of diagnosis because of the difficulty of early detection of this disease. For patients with locally advanced pancreatic cancer, chemoradiotherapy has been accepted as standard treatment because the results of previous randomised trials have indicated that concurrent external-beam radiation therapy and 5-fluorouracil (5-FU) therapy results in a significantly longer survival time than radiotherapy (Moertel et al, 1969; Gastrointestinal Tumor Study Group, 1981) or chemotherapy alone (Gastrointestinal Tumor Study Group, 1988). In attempts to improve the efficacy of the treatment, numerous trials using modified approaches of chemoradiotherapy have been conducted (Chakravarthy and Abrams, 1997; Okada, 1999). However, there has not yet been a regimen that has demonstrated superiority over conventional chemoradiotherapy performed in randomised controlled trials.

Gemcitabine is a novel deoxycytidine analog, which has demonstrated significant clinical benefit and survival improvement compared with 5-FU in patients with advanced pancreatic cancer (Burris et al, 1997). Gemcitabine has also been shown to be a potent radiosensitiser in human pancreatic and other solid tumour cell lines (Lawrence et al, 1996; Shewach and Lawrence, 1996; van Putten et al, 2001), suggesting that the combination of radiotherapy and gemcitabine may improve survival in patients with locally advanced disease. A phase I trial that was conducted in our hospital determined the recommended dose of weekly gemcitabine for the phase II chemoradiotherapy trial to be 250 mg m−2 (Ikeda et al, 2002). We report our results of the phase II study that was conducted to clarify the efficacy and toxicity of concomitant chemoradiotherapy with gemcitabine in patients with locally advanced pancreatic cancer.

Patients and methods

Patients eligible for this study had locally advanced pancreatic cancer for which they had not received any anticancer treatment. Each patient was required to meet the following eligibility criteria: pathological proof of adenocarcinoma of the pancreas; an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; adequate bone marrow reserve (white blood cell count 4000 mm3, platelet count 100 000 mm3, haemoglobin level 10 g dl−1); adequate renal function (normal serum creatinine and blood urea nitrogen levels, and a creatinine clearance level 60 mg min−1); a serum aspartate aminotransferase (AST) level <2.5 times upper normal limit (UNL); a serum alanine aminotransferase (ALT) level <2.5 times UNL; and written informed consent. Patients with obstructive jaundice were required to have a serum total bilirubin level of less than 2.0 mg dl−1 after biliary drainage. Pretreatment staging included ultrasonography and dynamic computed tomography (CT) scans of both the abdomen and the chest. The possibility for resection of the local tumour was assessed by dynamic CT and/or angiography. Obstruction or bilateral invasion of the portal vein and/or tumour encasement of the celiac or superior mesenteric arteries was considered to be unresectable. Patients were excluded if they met the following criteria: concomitant malignancy, pleural and/or peritoneal effusion, active ulcer of the gastrointestinal tract, active infection, severe heart disease, pregnant or lactating females, or other serious medical conditions. The goal was set at 40 eligible patients. This number of patients was planned using a design based on the assumptions that the median survival time in conventional chemoradiotherapy was 10 months, expected median survival time was 14 months, type I error was 5% (one-tailed) and statistical power was 70%.

Radiotherapy was delivered via a racetrack microtron (MM50, Scanditronix, Upsala, Sweden) with a 25 MV X-rays. A total dose of 50.4 Gy was delivered in 28 fractions over 5.5 weeks. All patients had treatment planning, CT scans (X-vision, Toshiba, Tokyo) and FOCUS (version 3.2.1, CMS, St Louis, MO, USA) was used as a radiotherapy treatment planning system. Clinical target volume (CTV) included the primary tumour, nodal involvement detected by CT scan and regional draining and paraaortic lymph nodes, which included the peripancreatic nodes, celiac and superior mesenteric axes. Planning target volume was defined as CTV plus a 10-mm margin. Four field techniques (anterior, posterior and opposed lateral fields) were used. Spinal cord dose was maintained below 45 Gy and 50% of liver was limited to 30 Gy, 50% of both kidneys were limited to 20 Gy.

Gemcitabine at a dose of 250 mg m−2 was given intravenously over 30 min starting 2 h before radiotherapy weekly for 6 weeks. This schedule was based on an in vitro study which revealed that gemcitabine induced its radiosensitising effect in cells within 2 h (Lawrence et al, 1997). Toxicity was assessed according to the National Cancer Institute – Common Toxicity Criteria version 2.0. When grade 3 haematological toxicity, serum creatinine of 1.5–2.0 times UNL, total bilirubin level of 3.0–5.0 times UNL, serum AST/APT of 5.0–10 times UNL and/or grade 2 nonhaematological toxicity (excluding nausea, vomiting, anorexia, fatigue, constipation, alopecia and dehydration) were observed, gemcitabine administration was omitted and postponed to the next scheduled treatment day. The radiotherapy was also suspended, and then resumed when the toxicities recovered. In patients who experienced the above adverse effects, dose reduction of gemcitabine to 200 mg m−2 was allowed in subsequent administrations. The combined treatment was discontinued when grade 3 leucopenia and/or neutropenia with high fever, grade 4 haematological toxicities after dose reduction of gemcitabine, serum creatinine of >2.0 times UNL, total bilirubin level of >5.0 times UNL, serum AST/APT of >10 times UNL, grade 3 or 4 nonhaematological toxicities (excluding nausea, vomiting, anorexia, fatigue, constipation, alopecia and dehydration), grade 4 vomiting, a total of 2 weeks of delay due to toxicity for any reason or tumour progression were observed. At 1 month after the completion of chemoradiotherapy, maintenance chemotherapy of gemcitabine at a dose of 1000 mg m−2 was administered as a 30-min intravenous infusion weekly for 3 weeks with 1-week rest until disease progression or unacceptable toxicity. Follow-up CT was performed within 1 week after the completion of chemoradiotherapy, and thereafter every 2 months to evaluate tumour response according to the WHO criteria (World Health Organization, 1979).

Progression-free and overall survival times were calculated from the first day of treatment using the Kaplan–Meier method (Kaplan and Meier, 1958). Serum CA 19-9 levels were measured monthly by a radioimmunometric assay using the Centocor radioimmunoassay kit (Centocor, Inc., Malvern, PA, USA).


Patients and treatments

In all, 42 patients were enrolled in the study between July 2001 and July 2002. Patient characteristics are listed in Table 1. A total of 38 patients (90%) received the full regimen of chemoradiotherapy, and the remaining four patients (10%) discontinued the treatment after 18.0–45.0 Gy. The reasons for the treatment discontinuation were elevated serum ALT of >10 times UNL (two patients), duodenal bleeding (one), and patient's refusal of treatment due to general fatigue (one). After discontinuation of the chemoradiotherapy, the two patients who showed the ALT elevation suspected as gemcitabine-related toxicity received chemoradiotherapy using 5-FU, and the other two patients underwent only supportive care. Of 241, 30 (12%) planned gemcitabine injections (0.7 injections per patient) were omitted owing to adverse events including grade 3 or more leucopenia and/or neutropenia, grade 2 fever, grade 2 skin rash and patient's refusal due to nausea, vomiting or fatigue. In three patients who showed grade 4 leucopenia and/or neutropenia, the dose of gemcitabine was modified in subsequent injections. Maintenance chemotherapy was initiated in 23 of the 38 patients who completed the full regimen of chemoradiotherapy. Of the remaining 15 patients, seven showed deterioration of general condition due to disease progression before initiating the chemotherapy, seven refused the treatment due to appetite loss (4) or general fatigue (3) and one transferred to another hospital (1).

Table 1 Patient characteristics

Response and survival

Tumour response was determined in 40 patients. Two patients were excluded from the protocol efficacy analysis because their treatment was switched over to chemoradiotherapy using 5-FU before the response evaluation due to the ALT elevation. Nine patients (21%) achieved a partial response, 26 (62%) remained stable and five (12%) showed progressive disease demonstrated by the development of distant metastases. No patients could undergo tumour resection even after the completion of chemoradiotherapy because of infiltration of the adjacent large vessels. In 22 (76%) of the 29 patients with a pretreatment serum CA19-9 (carbohydrate antigen 19-9) level of 100 U ml−1 or greater, the level was reduced more than 50% within 14 weeks after initiation of treatment.

A total of 35 patients documented disease progression at the time of analysis. The initial sites of disease progression are listed in Table 2. The pattern of failure was distant metastases in 33 patients (94%), local–regional recurrence in one patient (3%) and both in one patient (3%). The median progression-free interval and the median survival time were 4.4 and 9.5 months, respectively. The overall 1- and 2-year survival rates were 28 and 23%, respectively (Figure 1).

Table 2 Patterns of initial disease progression
Figure 1

Progression-free survival and overall survival curves of patients with locally advanced pancreatic cancer receiving radiotherapy with gemcitabine.


The acute toxicity is summarised in Table 3. The haematological toxicity was relatively brief and reversible in most patients. Grade 3–4 leucopenia and neutropenia occurred in 22 (52%) and 14 (33%) of the patients, respectively. Grade 3 thrombocytopenia occurred in one patient (2%) on the day after the chemoradiotherapy completion. The patient, who showed grade 4 anaemia, suffered catastrophic duodenal bleeding requiring embolisation under angiography. She exhibited cholangitis and sepsis subsequently and died on day 63.

Table 3 Acute toxicity

The most common nonhaematological toxicity was anorexia, which was observed in 38 patients (90%). In total, 14 patients (33%) required intravenous hyperalimentation. In all, 33 patients (79%) complained of fatigue and one of them refused continuation of the chemoradiotherapy. Nine patients (21%) experienced grade 3 nausea. Liver function abnormality was another major adverse effect. Four patients (10%) showed grade 3 elevation of serum transaminase levels. Two of them discontinued the treatments after 19.8 and 21.6 Gy, respectively, due to serum ALT elevation of 10 times UNL according to the protocol criteria (maximum level: 452 and 435 IU l−1), although the serum ALT levels of both recovered to the grade 1 levels 4 days after discontinuation of the treatment. We suspected that the ALT elevation in these two patients was gemcitabine-related toxicity because it was never reproduced after their treatment was switched over to chemoradiotherapy using 5-FU. One patient suffered unexpected acute abdominal pain requiring morphine 2 months after the completion of the chemoradiotherapy and was diagnosed with perforation of pancreatic pseudocyst into the duodenum. This pain disappeared completely by only medical management within 1 week. No patients experienced any symptoms considered to be late toxicity as of the time of analysis.


Based on previous randomised trials (Moertel et al, 1969; Gastrointestinal Tumor Study Group, 1981; Gastrointestinal Tumor Study Group, 1988), concurrent external-beam radiotherapy and 5-FU have been generally accepted as the standard treatment for locally advanced carcinomas. To intensify the treatment efficacy, various anticancer agents and radiation schedules are being investigated in clinical trials of chemoradiotherapy (Roldan et al, 1988; Seydel et al, 1990; Wagener et al, 1996; Thomas et al, 1997; Prott et al, 1997; Okusaka et al, 2001). However, marked improvement in their survival has not been observed. In an attempt to optimise radiosensitisation, radiotherapy with protracted 5-FU infusion has been examined recently, but the median survival times were similar to those observed in previous studies (Ishii et al, 1997).

Gemcitabine has been expected to be an agent that improves the outcome of chemoradiotherapy for locally advanced pancreatic cancer because it is a chemotherapeutic drug having meaningful palliative and prognostic impact against advanced pancreatic cancer, and it is also a potent radiosensitiser. Several experimental studies have shown that more than one mechanism leads to the potentiation of radiation-induced cell killing by gemcitabine (Lawrence et al, 1996; Shewach and Lawrence, 1996; van Putten et al, 2001). In clinics, various phase I studies for radiotherapy with gemcitabine have been conducted (McGinn et al, 2001; Pipas et al, 2001; Wolff et al, 2001; Ikeda et al, 2002; Poggi et al, 2002), although the efficacy and safety of this combination have not been fully elucidated in phase II trials. A phase I trial that was conducted in our hospital determined the recommended dose of weekly gemcitabine in the phase II chemoradiotherapy trial to be 250 mg m−2, because three of the six patients give a dose of 350 mg m−2 of gemcitabine demonstrated dose-limiting toxicities involving neutropenia/leucopenia and elevated transaminase (Ikeda et al, 2002).

The toxicity associated with radiotherapy with gemcitabine was relatively severe in this phase II study. Grade 3–4 leucopenia and neutropenia were observed in 52 and 33% of the patients, respectively, although none of the patients showed neutropenic fever. Nausea and anorexia were the most serious non-haematological toxicities in this treatment; 73% of the patients experienced various degrees of nausea and 33% required intravenous hyperalimentation. In all, 78% of the patients complained of general fatigue and one patient (2%) refused continuation of the treatment because of this adverse effect. These troublesome toxicities observed in this study seem to be more frequent and more severe compared with those in 5-FU-based chemoradiotherapy (Ishii et al, 1997). There was one death attributed to duodenal bleeding, which was arrested by transcatheter arterial embolisation, but deterioration of the general condition and lethal sepsis were induced subsequently.

The present study, in which 42 patients with locally advanced pancreatic cancer were treated with radiotherapy and weekly gemcitabine, documented a marginal impact on patient survival; the median survival time of 9.5 months is comparable to that in patients receiving conventional chemotherapy using 5-FU. However, the incidence rate of distant metastasis at the time of disease progression was remarkably higher with this treatment (97%) as compared to that with 5-FU-based chemoradiotherapy, which was reported to be 50% in our previous study (Ishii et al, 1997). This suggests that gemcitabine at a dose of 250 mg m−2 is a potent radiosensitiser for controlling local disease, but its ability as a chemotherapeutic agent is insufficient to counteract systemic tumour spread. To improve prognosis for these patients, future investigations for treatment with more systemic effects are warranted.

In an effort to increase capacity for systemic therapy, reduction of the radiation field has been attempted. Investigators at the University of Michigan elected to radiate the primary tumour alone, without the inclusion of regional lymph nodes, and administer full-dose gemcitabine concurrently, because the use of full-dose gemcitabine requires reduction of the radiation dose, based on their prior clinical experience (McGinn et al, 2001; Muler et al, 2004). Reduction of the radiation field may be one of the strategies not only for intense systemic therapy but also for decreasing the troublesome gastrointestinal toxicity often observed in our study; our recent retrospective study showed that a larger planning target volume for irradiation was only a significant predictor of severe acute intestinal toxicity in patients treated with chemoradiotherapy using gemcitabine (Ito et al, 2003).

Crane et al (2002) retrospectively compared the toxicity and efficacy of concurrent gemcitabine-based chemoradiation with those of concurrent 5-FU-based chemoradiation in patients with unresectable pancreatic cancer treated in the University of Texas MD Anderson Cancer Center. In the study, there was a significantly higher severe toxicity rate in patients treated with gemcitabine than in those with 5-FU, although the median survival times were similar between the two arms (gemcitabine vs 5-FU: 11 vs 9 months). They concluded that concurrent gemcitabine and radiotherapy could be an extremely difficult combination to administer safely, with a very narrow therapeutic index. Recently, investigators in Taiwan reported favourable results for radiotherapy with concurrent gemcitabine administration (600 mg m2 week−1 for 6 weeks) in a small randomised study (Li et al, 2003). The gemcitabine-based chemoradiotherapy showed a significantly better median survival time (14.5 months) and a comparable toxicity profile in comparison with the 5-FU-based chemoradiotherapy (7.1 months). However, the number of enrolled patients in this study was only 16–18 in each arm. The results need further confirmation by larger multi-institutional clinical trials.

In summary, the chemoradiotherapy used in this study has a moderate activity against locally advanced pancreatic cancer and an acceptable toxicity profile, but appears to have more frequent acute toxicities compared with conventional chemoradiotherapy using 5-FU. Most patients who underwent this therapy demonstrated rapid appearance of distant metastasis. To explore innovative approaches for locally advanced pancreatic cancer, future investigations for treatment with more systemic effects and less toxicity are needed.


  1. Burris III HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15: 2403–2413

  2. Chakravarthy A, Abrams RA (1997) Radiation therapy and 5-fluorouracil in pancreatic cancer. Semin Radiat Oncol 7: 291–299

  3. Crane CH, Abbruzzese JL, Evans DB, Wolff RA, Ballo MT, Delclos M, Milas L, Mason K, Charnsangavej C, Pisters PW, Lee JE, Lenzi R, Vauthey JN, Wong AB, Phan T, Nguyen Q, Janjan NA (2002) Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer? Int J Radiat Oncol Biol Phys 52: 1293–1302

  4. Gastrointestinal Tumor Study Group (1981) Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads+5-fluorouracil), and high dose radiation+5-fluorouracil. Cancer 48: 1705–1710

  5. Gastrointestinal Tumor Study Group (1988) Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 80: 751–755

  6. Ikeda M, Okada S, Tokuuye K, Ueno H, Okusaka T (2002) A phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with locally advanced pancreatic cancer. Br J Cancer 20(86): 1551–1554

  7. Ishii H, Okada S, Tokuuye K, Nose H, Okusaka T, Yoshimori M, Nagahama H, Sumi M, Kagami Y, Ikeda H (1997) Protracted 5-fluorouracil infusion with concurrent radiotherapy as a treatment for locally advanced pancreatic carcinoma. Cancer 79: 1516–1520

  8. Ito Y, Okusaka T, Kagami Y, Ueno H, Ikeda M, Sumi M, Imai A, Ikeda H (2003) Evaluation of acute intestinal toxicity in relation to the volume of irradiated small bowel in patients treated with concurrent weekly gemcitabine and radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 57: S383–4

  9. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 63: 457–481

  10. Lawrence TS, Chang EY, Hahn TM, Hertel LW, Shewach DS (1996) Radiosensitization of pancreatic cancer cells by 2′,2′-difluoro-2′-deoxycytidine. Int J Radiat Oncol Bio Phys 34: 867–872

  11. Lawrence TS, Chang EY, Hahn TM, Shewach DS (1997) Delayed radiosensitization of human colon carcinoma cells after a brief exposure to 2′,2′-difluoro-2′-deoxycytidine (Gemcitabine). Clin Cancer Res 3: 777–782

  12. Li CP, Chao Y, Chi KH, Chan WK, Teng HC, Lee RC, Chang FY, Lee SD, Yen SH (2003) Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study. Int J Radiat Oncol Biol Phys 57: 98–104

  13. McGinn CJ, Zalupski MM, Shureiqi I, Robertson JM, Eckhauser FE, Smith DC, Brown D, Hejna G, Strawderman M, Normolle D, Lawrence TS (2001) Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 19: 4202–4208

  14. Moertel CG, Childs Jr DS, Reitemeier RJ, Colby Jr MY, Holbrook MA (1969) Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2: 865–867

  15. Muler JH, McGinn CJ, Normolle D, Lawrence T, Brown D, Hejna G, Zalupski MM (2004) Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer. J Clin Oncol 22: 238–243

  16. Okada S (1999) Non-surgical treatments of pancreatic cancer. Int J Clin Oncol 4: 257–266

  17. Okusaka T, Okada S, Tokuuye K, Wakasugi H, Saisho H, Ishikawa O, Matsuno S, Sato T, Sato K (2001) Lack of effectiveness of radiotherapy combined with cisplatin in patients with locally advanced pancreatic carcinoma. Cancer 91: 1384–1389

  18. Pipas JM, Mitchell SE, Barth Jr RJ, Vera-Gimon R, Rathmann J, Meyer LP, Wagman RS, Lewis LD, McDonnell C, Colacchio TA, Perez RP (2001) Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 50: 1317–1322

  19. Poggi MM, Kroog GS, Russo A, Muir C, Cook J, Smith J, Mitchell JB, Herscher LL (2002) Phase I study of weekly gemcitabine as a radiation sensitizer for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 54: 670–676

  20. Prott FJ, Schonekaes K, Preusser P, Ostkamp K, Wagner W, Micke O, Potter R, Sulkowski U, Rube C, Berns T, Willich N (1997) Combined modality treatment with accelerated radiotherapy and chemotherapy in patients with locally advanced inoperable carcinoma of the pancreas: results of a feasibility study. Br J Cancer 75: 597–601

  21. Roldan GE, Gunderson LL, Nagorney DM, Martin JK, Ilstrup DM, Holbrook MA, Kvols LK, McIlrath DC (1988) External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer 61: 1110–1116

  22. Seydel HG, Stablein DM, Leichman LP, Kinzie JJ, Thomas PR (1990) Hyperfractionated radiation and chemotherapy for unresectable localized adenocarcinoma of the pancreas. The Gastrointestinal Tumor Study Group experience. Cancer 65: 1478–1482

  23. Shewach DS, Lawrence TS (1996) Gemcitabine and radiosensitization in human tumor cells. Invest New Drugs 14: 257–263

  24. Thomas Jr CR, Weiden PL, Traverso LW, Thompson T (1997) Concomitant intraarterial cisplatin, intravenous 5-flourouracil, and split-course radiation therapy for locally advanced unresectable pancreatic adenocarcinoma: a phase II Study of 16th Puget Sound Oncology Consortium (PSOC-703). Am J Clin Oncol 20: 161–165

  25. van Putten JWG, Groen HJM, Smid K, Peters GJ, Kampinga HH (2001) End-joining deficiency and radiosensitization induced by gemcitabine. Cancer Res 61: 1585–1591

  26. Wagener DJ, Hoogenraad WJ, Rougier P, Lusinchi A, Taal BG, Veenhof CH, de Graeff A, Conroy T, Curran D, Sahmoud T, Wils J (1996) Results of a phase II trial of epirubicin and cisplatin (EP) before and after irradiation and 5-fluorouracil in locally advanced pancreatic cancer: an EORTC GITCCG study. Eur J Cancer 32A: 1310–1313

  27. Wolff RA, Evans DB, Gravel DM, Lenzi R, Pisters PW, Lee JE, Janjan NA, Charnsangavej C, Abbruzzese JL (2001) Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res 7: 2246–2253

  28. World Health Organization (1979) WHO Handbook for Reporting Results of Cancer Treatment, Offset Publication 48 Geneva: World Health Organization

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This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan. We thank Ms K Kondo for her help with the manuscript preparation.

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Correspondence to T Okusaka.

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  • pancreatic cancer
  • chemoradiotherapy
  • gemcitabine
  • radiosentitiser

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