This study investigated the maximum-tolerated dose of gemcitabine based on the frequency of dose-limiting toxicities of weekly gemcitabine treatment with concurrent radiotherapy in patients with locally advanced pancreatic cancer. did not demonstrate any sign of dose-limiting toxicity. Of all 15 enrolled patients, six patients (40.0%) showed a partial response. More than 50% reduction of serum carbohydrate antigen 19-9 level was observed in 13 (92.9%) of 14 patients who had pretreatment carbohydrate antigen 19-9 levels of 100?U?ml?1 or greater. The maximum-tolerated dose PD 0332991 HCl small molecule kinase inhibitor of weekly gemcitabine with concurrent radiotherapy was 250?mg?m?2, and this regimen may have substantial antitumour activity for patients with locally advanced pancreatic cancer. A phase II trial of weekly gemcitabine at the dose of 250?mg?m?2 with concurrent radiation in patients with locally advanced pancreatic cancer is now underway. (2002) 86, 1551C1554. DOI: 10.1038/sj/bjc/6600256 www.bjcancer.com ? 2002 Cancer Research UK (1969) and the Gastrointestinal Tumor Study Group (GITSG) (Moertel 4.8%) and survival advantage (median survival, 5.6 4.4 months) weighed against bolus 5-fluorouracil in a phase III trial (Burris also to improve the cytotoxic activity of radiation (Lawrence em et al /em , 1996; Shewach and Lawrence, 1996), even though precise system of radiosensitization continues to be unidentified (van Putten em et al /em , 2001). Some scientific trials of gemcitabine and concurrent radiotherapy have already been reported (Blackstock em et al /em , 1999; Talamonti em et al /em , 2000), however the optimum dosage for a every week gemcitabine schedule hasn’t however been elucidated. Though it provides been reported a twice-weekly plan of gemcitabine is certainly more advanced than a once-weekly routine of gemcitabine for radiosensitization (Blackstock em et al /em , 1999), the dose of gemcitabine was much lower (40?mg?m?2, twice-weekly) than that used for systemic chemotherapy. In patients with locally advanced PC treated with CRT, it is important to enhance the local control and simultaneously reduce the risk of distant metastases. Consequently, this phase I trial was designed to determine the MTD of weekly gemcitabine with concurrent radiation in patients with locally advanced PC. Eligibility criteria of this trial included Karnofsky overall performance status of 50C100 points. However, all enrolled patients experienced the Karnofsky overall performance status of 80 or above, because the patients with poor overall performance status (e.g. Karnofsky overall performance status of less than 70) were considered to be intolerable to CRT for fear of the treatment-related toxicities such as fatigue. We expected that the dose of weekly gemcitabine with concurrent radiotherapy would be close to 1000?mg?m?2, which is the PD 0332991 HCl small molecule kinase inhibitor standard dose for weekly gemcitabine administration for PC. However, DLTs including neutropenia/leukocytopenia and elevated transaminase were observed in three of six patients at the first dose level (350?mg?m?2), and the protocol was therefore revised to include lower dose levels (150 and 250?mg?m?2 per week). All nine patients treated at the dose of 150 or 250?mg?m?2 per week of gemcitabine completed the scheduled course of CRT without DLT. In this CRT, the most common toxicities were leukocyotopenia and/or neutropenia. However, these toxicities were moderate and transient at level ?1 and level 0, and all patients recovered within a week without any specific treatment for these toxicities. Anorexia and/or nausea observed on the day of gemcitabine administration were the major non-haematological toxicities. However, these toxicities were relieved by prophylactic use of granisetron on subsequent administration of gemcitabine. Serum GOT/GPT increase observed at level 0 (250?mg?m?2), PD 0332991 HCl small molecule kinase inhibitor which was another major non-haematological toxicity, was also mild and transient. Therefore, weekly gemcitabine at a dose of 150?mg?m?2 or 250?mg?m?2 was considered well tolerated, and the MTD was determined to be 250?mg?m?2. With regard to antitumour activity of weekly gemcitabine with concurrent radiation, 6 out of 15 patients achieved partial response, giving an overall response rate of 40.0% (95% confidence interval, 15.2C64.8%). Moreover, the serum CA19-9 level was reduced more than 50% after the completion of CRT in 13 (92.9%) of 14 patients with a pretreatment level of 100?U?ml?1 or greater. These results are favourable compared with those of patients treated with CRT at other treatment schedules (Moertel em et al /em , 1969, 1981; Gastrointestinal Tumor Study Group, 1988; Ishii em et al /em , 1997; PRKM8IP Blackstock em et al /em , 1999; Talamonti em et al /em , 2000; Okusaka em et al /em , 2001). Up to now, however, you can find no data on general survival and progression-free survival due to the brief follow-up periods. Stage II trial must clarify the antitumour activity and the result of every week gemcitabine with concurrent radiation on survival. To conclude, the MTD of every week gemcitabine with concurrent radiotherapy was 250?mg?m?2, which regimen may have got substantial antitumour activity for.