Oral Anticancer Agent Research Articles

A phase II study of S-1 for the treatment of cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal cell carcinoma: Updated results.

393 Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 has shown efficacy for cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal-cell carcinoma (mRCC). We report the final results of a phase II study and evaluate 5-FU-related enzymes as a predictor of the response to S-1. Methods: 45 patients received S-1 at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR). The secondary endpoints of progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Formalin-fixed, paraffin-embedded specimens obtained by radical nephrectomy were used for mRNA expression assay, performed by reverse-transcriptase polymerase chain reaction. Results: 45 patients including 6 were progressed after TKI were enrolled from April 2006. 24 patients received more than 5 cycles, and 2 continued to receive S-1 as of October 2011. Two (4.4%) of the 45 patients had complete responses to S-1, 9 (20.0%) had partial responses, and 28 (62.8%) had stable disease. The final PFS and OS were 9.2 and 42.8 months, respectively, and the PFS of TKI refractory patients was approximately two times of final PFS (18.0 months). The most common grade 3-4 adverse events according to CTCAE v.3.0 were similar to the previous report except for hemoglobin decreased and fatigue. On mRNA expression analysis, the expression level of thymidylate synthase correlated with ORR and PFS. On the other hand, OS did not differ significantly between patients with low expression and those with high expression of 5-FU-related enzymes. Conclusions: S-1 is effective and well tolerated in patients with cytokine and/or TKI refractory mRCC. Moreover, long-term treatment with S-1 is safe in mRCC patients enabling long-term disease control, especially in TKI refractory patients. Clinical trial with large number of TKI refractory patients is warranted to determine the efficacy of S-1.

Abstract C4: Inhalational chemotherapy for malignant gliomas

Abstract Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer, based on its mechanism of action as a ras inhibitor and a cell cycle inhibitor. Unfortunately, it had significant gastrointestinal side effects, and was never well received as an oral anticancer agent. Recently, POH has been administered intranasally in a Phase I/II trial for the treatment of recurrent malignant gliomas in Brazil. It is well tolerated when delivered intranasally, with a 50% progression free survival (PFS) of 6 months in patients with recurrent GBM, with radiographic reduction in size in some patients. Similar efficacy compared to bevacizumab (Avastin; Genentech) was obtained in recurrent GBM patients treated with intranasal POH alone. We have recently synthesized a pharmaceutical grade of POH with >98% purity. Synthesized POH inhibits vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and transforming growth factor-beta 2 (TGF-B2). Cytotoxicity, as measured by colony formation assay (CFA), demonstrated a IC50 of 0.5 mM. We have since conjugated POH to a number of different pharmaceutical agents, including temozolomide (TMZ). Data on these conjugates demonstrate increased cytotoxic activity compared to individual drugs alone or in combination. TMZ-POH is much more potent than POH alone (IC50 10–30 uM), and is effective in TMZ resistant glioma cells, inhibits glioma cancer stem cells, and is not toxic to normal astrocytes. Our goal is to use our synthesized POH and TMZ-POH in upcoming Phase I/II trials for recurrent malignant gliomas. Further definition of the perillyl alcohol derivatives will lead to a pipeline of new compounds which will enable further expansion of the intranasal delivery repertoire. Animal models demonstrating efficacy of intranasal delivery of POH and TMZ-POH is currently underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C4.

Clinical Results of Definitive Chemoradiotherapy for Patients With Synchronous Head and Neck Squamous Cell Carcinoma and Esophageal Cancer

To assess the efficacy and toxicity of radical chemoradiotherapy for patients with synchronous head and neck squamous cell carcinoma (HNSCC) and esophageal cancer (EC). Thirty-four patients with synchronous HNSCC and EC were treated mainly with radical chemoradiotherapy at the same time. Median external radiation dose for HNSCC and EC was 70 Gy (range, 60-70.5 Gy), except for 2 patients with tongue cancer, who underwent brachytherapy and 60 Gy (range, 45-70 Gy), respectively. Thirty-one patients were treated with concurrent chemoradiotherapy with cisplatin and/or 5-fluorouracil or TS-1 (oral anticancer agent that combines tegafur, a metabolically activated prodrug of 5-fluorouracil, with 5-chloro-2, 4-dihydoroxypyridine, and potassium oxonate). Thirty-three patients completed the intended treatment. The response rate was 94%, with 26 complete responses (76%) and 6 partial responses (18%). At a median follow-up of 17.3 months, 2-year rates of overall survival, cause-specific survival, and disease-free survival were 44%, 52%, and 33%, respectively. Initial failure patterns were local failure in 14 patients (63%), regional progression in 3 patients (13%), and distant metastasis in 6 patients (27%). The most common acute toxicity was myelosuppression, with 8 patients experiencing grade 3-4 toxicity. Three patients experienced grade 3 mucositis and pharyngitis. No patients experienced late morbidity of grade 3 or higher. Definitive chemoradiotherapy for patients with synchronous HNSCC and EC is feasible with a low mortality rate and acceptable morbidity.

The role of diet on the clinical pharmacology of oral antineoplastic agents

The number of oral anticancer agents has greatly increased in recent years. It is a well-known fact that food intake can induce significant variations in the bioavailability of these drugs. The aim of this review is to describe the interactions between diet and oral anticancer drugs in terms of the possible effects of such interactions on reducing the antineoplastic activity of the drug or increasing its side effects. This was an analytical study of the numerous mechanisms leading to changes in the bioavailability of oral antineoplastic agents due to diet. Food-drug interactions can induce a delay, decrease or increase in the absorption of the oral chemotherapeutic agent. The concomitant intake of food and antineoplastic drugs influence the pharmacokinetic and pharmacodynamic drug processes depending on the composition of the food consumed and the specific interactions of the food with transport mechanisms (p-glycoprotein, multidrug resistance proteins) and intestinal enzymatic systems (cytochrome P450). In prescribing an oral anticancer agent, clinicians must consider the possibility that the consumption of specific food items has the potential to interfere with the pharmacokinetics and pharmacodynamics of the prescribed drug.

A phase II study of oral S‐1 with concurrent radiotherapy followed by chemotherapy with S‐1 alone for locally advanced pancreatic cancer

S-1 is a new oral fluoropyrimidine anticancer agent shown to be effective for pancreatic cancer. In a previous phase I trial, we evaluated the safety of S-1 combined with radiotherapy to determine the maximum tolerated dose and dose-limiting toxicity in patients with unresectable pancreatic cancer. The recommended dose of S-1 for phase II trials of chemoradiotherapy was determined as 80 mg/m(2)/day given on days 1-21 of a 28-day cycle. This phase II study was conducted to further evaluate the efficacy and toxicity of radiotherapy combined with S-1 (UMIN000004794). Eligible patients had locally advanced and unresectable pancreatic cancer without distant metastases, an Eastern Cooperative Oncology Group performance status of 0-1, adequate organ and marrow functions, and no prior anticancer therapy. Patients initially received 4 weeks of chemoradiotherapy. S-1 was given orally at a dose of 80 mg/m(2)/day twice daily on days 1-21. Radiotherapy was delivered in fractions of 1.25 Gy twice daily, 5 days per week for 4 weeks (total dose: 50 Gy in 40 fractions). One month after the completion of chemoradiotherapy, S-1 was administered for 14 days followed by a 14-day rest period. This cycle was repeated as maintenance therapy until disease progression or unacceptable toxicity. Fifty patients were enrolled in this phase II study. Median follow-up was 14.6 months (range 5.4-58.9 months). Forty-three patients (86%) completed the scheduled course of chemoradiotherapy. There was no treatment-related death or grade 4 toxicity. The major toxic effects were leukopenia and nausea. The objective tumor response according to the Response Evaluation Criteria in Solid Tumours criteria was partial response in 15 patients (30%) (95% confidence interval (CI), 18-45%), stable disease in 23 (46%), and progressive disease in 12 (24%). Median progression-free survival and median overall survival were 6.7 months (95% CI, 4.7-11.2 months) and 14.3 months (95% CI, 10.8-20.8 months), respectively. Survival rates at 1 and 2 years were 62 and 27%, respectively. Combination therapy with S-1 and radiation in patients with locally advanced and unresectable pancreatic cancer is considered a promising, well-tolerated regimen that can be recommended as an effective treatment for locally advanced pancreatic cancer.

Phase II trial of concurrent chemoradiotherapy consisting of two courses with S-1 and cisplatin for locally advanced esophageal cancer.

4034 Background: S-1 is a novel oral fluoropyrimidine anticancer agent designed to enhance clinical efficacy, reduce gastrointestinal toxicity, and enhance the effectiveness of radiotherapy. We conducted a phase II study of concurrent chemoradiotherapy with S-1 and cisplatin in patients with locally advanced esophageal cancer. Methods: Chemoradiotherapy consisted of two courses. The first course consisted of 30 Gy of radiotherapy given over 3 weeks plus daily treatment with oral S-1 (80 mg/m2/day) for 2 weeks and a 24-h infusion of cisplatin (70 mg/m2) on day 8. The second course of chemoradiotherapy was administered after 2 weeks. S-1 was administered in powdered form with water. Responders received at least two 4-week courses of chemotherapy with S-1 and cisplatin. Results: A total of 102 patients were enrolled (median age, 66 years; M/F, 88/14; PS 0/1, 77/25). Twelve patients had stage II disease, 61 had stage III disease, and 29 had stage IVa disease. Ninety-seven patients (95%) completed two courses of chemoradiotherapy. The most prominent toxicity was myelosuppression. Grades 3 and 4 leukopenia occurred in 37 (36%) and 14 (14%) patients, respectively. Nonhematological toxicity was moderate: grade 2 nausea, pain, oral mucositis, and renal dysfunction occurred in 31%, 29%, 20%, and 14% of the patients, respectively. These side effects resolved after one course of chemoradiotherapy in all but 7 patients. In patients with stage II disease, complete response (CR) and response rates (RRs) were 92% and 100%, respectively. In patients with stage III disease, CR and RRs were 64% and 85%. In patients with stage IVa disease, CR and RRs were 24% and 66%. All patients with stage II disease survived.Median survival time in patients with stage III disease was 795 days (95% CI: 589-1,038 days), and in patients with stage IVa disease, it was 369 days (95%CI: 194-523 days). Conclusions: Chemoradiotherapy consisting of two courses of S-1 and cisplatin was very effective with mild toxicity. We believe that this regimen can be one baseline treatment for patients with locally advanced esophageal cancer. Further trials in larger cohorts of patients are expected to strengthen the outcomes of this study.

BAYPAN study: A double-blind, phase III randomized trial of gemcitabine plus sorafenib versus gemcitabine plus placebo in patients with advanced pancreatic cancer.

4028 Background: With its inhibitory effects against Raf-1 kinase and vascular endothelial growth factor receptor-2, sorafenib (S) is an oral anticancer agent targeting Ras-dependent signal transdu...

Scarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib

To the Editor: Erlotinib (Tarceva; Genentech, South San Francisco, CA) is an oral anticancer agent that blocks the function of the epidermal growth factor receptor (EGFR) and has been approved by the US Food and Drug Administration for the treatment of non–small cell lung and pancreatic cancers. Therapy is frequently complicated by multiple cutaneous adverse effects ranging from follicular papulopustular (“acneiform”) eruptions, xerosis, nail changes (including paronychia and pyogenic granulomas in the lateral nail folds), and hair texture changes.

A multi-institutional phase II study of combination chemotherapy with S-1 plus cisplatin in patients with advanced non-small cell lung cancer

S-1 is an oral anticancer fluoropyrimidine agent designed to elevate anticancer activity with a decrease in gastrointestinal toxicity. We conducted a phase II study to evaluate the efficacy and safety of combination chemotherapy with S-1 plus cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients were treated with S-1 administered orally at 40 mg/m(2) twice a day for 21 consecutive days, and cisplatin (60 mg/m(2)) infused intravenously on day 8, repeated every 5 weeks. Of the 44 patients enrolled in the study, 40 were assessable for efficacy and safety. The median number of cycles administered was 3 (range 1-9 cycles). Among the 40 assessable patients, 7 partial responses were observed, with an overall response rate (RR) of 17.5% [95% confidence interval (CI), 5.2-29.8]. Patients with squamous cell carcinoma showed a significantly higher RR (55.5%) than those with adenocarcinoma (9.1%) or other types of NSCLC (0%). The median progression-free survival was 4.3 months (95% CI, 3.4-4.9), the median survival time was 17.9 months (95% CI, 15.0-20.8), and the 1- and 2-year survival rates were 63.3 and 27.3%, respectively. Major grade 3-4 hematologic toxicities were leukocytopenia (7.5%), neutropenia (5.0%), anemia (15.0%) and thrombocytopenia (2.5%). No grade 4 non-hematologic toxicity or treatment-related death occurred. These results suggest that combination chemotherapy with S-1 plus cisplatin is a promising therapeutic candidate for patients with advanced NSCLC, particularly squamous cell carcinoma.

An oral fluoropyrimidine agent S-1 induced interstitial lung disease: A case report

A 66-year-old Japanese man with pancreatic cancer received eleven courses of gemcitabine monotherapy. The tumor responded to gemcitabine until metastatic liver tumors progressed. Subsequently, he was treated with S-1, an oral fluoropyrimidine anticancer agent, as salvage chemotherapy. Forty-two days after initiating S-1, he presented with dyspnea and fever. Chest computed tomography showed diffuse interstitial lesions with thickening of the alveolar septa and ground glass opacity. Serum KL-6 level was elevated to 1,230 U/mL and he did not use any other drugs except insulin. Thus, the development of interstitial lung disease (ILD) was considered to be due to S-1. Arterial blood oxygen pressure was 49.6 Torr in spite of oxygen administration (5 L/min). Steroid therapy improved his symptoms and the interstitial shadows on chest radiograph. Although S-1-induced ILD has mostly been reported to be mild, clinicians should be aware that S-1 has the potential to cause fatal ILD.

Interstitial lung disease caused by TS-1: a case of long-term drug retention as a fatal adverse reaction

TS-1 is an oral anti-cancer agent for gastric cancer with a high response rate and low toxicity. We report a case of long-term drug retention of TS-1 causing interstitial lung disease (ILD) as a fatal adverse reaction. A 65-year-old woman underwent a total gastrectomy with pathologic confirmation of gastric adenocarcinoma. She received 6 cycles of TS-1 and low-dose cisplatin for post-operative adjuvant chemotherapy followed by single-agent maintenance therapy with TS-1. After 8 months, the patient complained of a productive cough with sputum and mild dyspnea. A pulmonary evaluation revealed diffuse ILD in the lung fields, bilaterally. In spite of discontinuing chemotherapy and the administration of corticosteroids, the pulmonary symptoms did not improve, and the patient died of pulmonary failure. TS-1-induced ILD can be caused by long-term drug retention that alters the lung parenchyma irreversibly, the outcome of which can be life-threatening. Pulmonary evaluation for early detection of disease is recommended.

Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer

Sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic pathways through inhibitory effects against MAP kinases and vascular endothelial growth factor receptor-2. The objectives of this neoadjuvant phase II-trial in patients with advanced epithelial ovarian cancer were to assess the activity and tolerability of the combination therapy of carboplatin/paclitaxel with multi-target tyrosine kinase inhibitor sorafenib. Patients with histologically proven stage IIIC or IV disease and large volume ascites were eligible. Enrolled patients received 2 of 6 cycles carboplatin (area under the curve 5) and paclitaxel (175 mg/m(2)) preoperatively and concomitant sorafenib 400 mg twice daily. After four cycles of postoperative chemotherapy, a maintenance phase of single agent oral sorafenib through 1 year was planned. This phase II-study was planned with a sample size of 102 patients and progression-free survival as primary study endpoint. Four patients were enrolled. After preoperative treatment and cytoreductive surgery, all patients were excluded from protocol due to severe toxicities. Three patients had life threatening events (cardiac output failure, myocardial infarction, anastomotic leak); two patients had primary progressive disease. The study was terminated on the basis of the recommendation of an independent data safety monitoring board. The addition of sorafenib to carboplatin/paclitaxel chemotherapy was not feasible within this neoadjuvant regimen in primary advanced ovarian cancer. Although the occurrence of serious adverse events might have emerged at random, a detrimental effect of preoperative study medication could not be denied. Further evaluations of sorafenib in ovarian cancer are warranted.

An early phase II trial of S-1 in Japanese patients with cytokine-refractory metastatic renal cell carcinoma

S-1, an oral anticancer agent, contains tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) at a molar ratio of FT:CDHP:Oxo = 1:0.4:1. The aim of this trial was to investigate the efficacy and safety of S-1 in Japanese patients with cytokine-refractory metastatic renal cell carcinoma (RCC). We conducted a non-randomized, open-label trial in Japanese patients with metastatic RCC who had received nephrectomy and had failed cytokine-based immunotherapy. The primary endpoint was response rate. S-1 40-60 mg based on the body surface area was administered twice daily (80-120 mg/day) for 4 consecutive weeks, followed by a 2-week rest period; cycles were repeated every 6 weeks. Patients continued treatment until disease progression, unacceptable toxicity, or withdrawal of consent. A total of 20 eligible patients were enrolled. Among these, 3 patients had partial response, yielding objective response rate of 15%; 13 patients had no change; 4 patients had progressive disease. The median time-to-progression and median overall survival were 12.0 and 25.7 months, respectively. The initial adverse event was generally mild to moderate in severity. The most common grade 3/4 drug-related hematological and non-hematological adverse events were neutropenia (20.0%) and anorexia (20.0%), respectively. S-1 is active and well tolerated for the treatment of cytokine-refractory metastatic RCC.

がん拠点病院における内服抗がん剤Ｓ‐１の院外処方箋―弘前大学医学部附属病院での実態調査―

The oral pyrimidine fluoride-derived anticancer agent S-1 was developed as a three-component combination drug.S1 contains 2 biochemical modulators-5-fluorouracil (5-FU) and tegafur (5-chloro-2,4 dihydroxypyridine)-and potassium oxonate.Tegafur is a metabolically activated prodrug of 5-FU which enhances the pharmacological actions of 5-FU by potently inhibiting its degradation,and potassium oxonate reduces gastrointestinal toxicity.We conducted an investigation of the number or outpatients administered S-1 in combination therapy and number of cases of adaptation disorder at Hirosaki University School of Medicine Hospital,a key cancer hospital,from 2004 to 2008.The use of S-1 increased 4 times in the 5 years with that for head and neck cancer,and gastric cancer both increasing 4 times,and large bowel/rectal cancer 2.3 times.Prescriptions for the 20 mg and 25 mg S1 capsule increased about 15.4 times and 4.6 times,respectively,in this period.The proportions of gastric cancer and pancreatic carcinoma patients receiving injection antineoplastic drugs together with S-1 were 20% and 68%,respectively,in 2008.Between 2004 and 2008 there had been a sharp increase in S-1 prescriptions and therapy had become much more complicated.In view of this,it is important that we regularly provide information to neighboring local dispensing pharmacies on the usage situation of S-1 to help ensure the safety of medical treatment in our hospital.

Feasibility of Bioavailability Testing by Simultaneous Determination of Serum Concentrations of Tegafur and 5-fluorouracil after TS-1 Oral or Tube Administration for Chemotherapy in Oral Cancer Patients

TS-1 is an oral anticancer agent comprising three components: two biochemical modulators of 5-fluorouracil (5-FU) and tegafur (FT), a prodrug of 5-FU. TS-1 displays potent anti-tumor activity by maintaining effective 5-FU concentrations in serum for a prolonged period. FT is gradually converted to 5-FU in vivo via 5'-hydroxylation mediated by cytochrome P450s. As a result, genetic polymorphisms can cause wide individual differences in serum concentration of 5-FU after administration of TS-1, requiring monitoring of serum concentration of 5-FU for each patient. Chemotherapy with TS-1 plays a major role in the treatment of oral cancer. In cases where a patient with oral cancer shows dysphagia, TS-1 may need to be tube-administered. Although tube administration by the simple suspension method has been recommended from a biosafety perspective, particularly for anti-cancer agents, its efficacy remains unclear. We established a simple high-performance liquid chromatography method for simultaneous determination of FT and 5-FU levels at clinical sites by modifying a method reported in the literature.1) Unlike the original method, this simplified method does not require extraction procedures to separate FT and 5-FU, and requires only 250 μl of serum. Using this method, we compared FT concentrations in the sera of oral cancer patients administered TS-1 orally or via a tube-assisted simple suspension method. No significant differences in FT concentrations were apparent between these two modes of administration. TS-1 treatment by tube administration using the simple suspension method thus seems useful for patients with dysphagia as an alternative to oral dosage.

Cost-Utility Analysis of the Oral Fluoropyrimidine S-1 Versus Conventional Intravenous Chemotherapy in Advanced or Recurrent Gastric Cancer

Objective: The aim of this study was to compare the cost-utility of S-1, an oral anticancer agent developed in Japan, and conventional intravenous chemotherapy in patients with advanced or recurrent gastric cancer on the basis of the cost and quality of life (QOL) data we previously reported. Methods: Patients with advanced or recurrent gastric cancer who could ingest food were identified retrospectively from the ordering system database of Showa University Hospital between January 1998 and July 2001. Costs incurred during chemotherapy were calculated on the basis of hospital billing data. The utilities of chemotherapy were assessed by oncology pharmacists and nurses on the basis of the patients' medical records. Cost-utility analysis was conducted from a societal perspective. Results: Of the 23 patients who met the inclusion criteria, 13 received S-1 (S-1 group) and 10 received conventional intravenous chemotherapy (IV chemotherapy group). The average (± SE) monthly cost during chemotherapy was significantly lower in the S-1 group (327,640 ± 47,647 yen) than in the IV chemotherapy group (852,874 ± 62,412 yen). Average (± SE) utilities in the S-1 group (0.84 ± 0.02 - 0.94 ± 0.01) were significantly higher than those in IV chemotherapy group (0.52 ± 0.04 - 0.79 ± 0.02). Conclusion: S-1 is a dominant strategy with lower costs and better health outcomes than conventional intravenous chemotherapy in patients with advanced or recurrent gastric cancer.

Randomized Double-Blind Phase II Trial Comparing Gemcitabine Plus LY293111 Versus Gemcitabine Plus Placebo in Advanced Adenocarcinoma of the Pancreas

LY293111 (LY) is a novel oral anticancer agent with leukotriene B4 receptor antagonist and peroxisome proliferator-activated receptor gamma agonist properties, producing promising results alone and in combination with gemcitabine in pancreatic cancer xenograft models. A phase I study proved that the combination (gemcitabine plus LY) is safe and well tolerated. Chemotherapy-naive patients with histologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas were randomly assigned to gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle and continuously administered LY 600 mg twice daily or gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle and daily oral placebo. Arms were balanced for Eastern Cooperative Oncology Group performance status and disease stage. The primary end point was 6-month survival; secondary objectives include response rate (RR), progression-free survival, and overall survival. Six-month survival was not different between groups (P>0.2, 1-sided); progression-free survival and RR were not different (P>0.05, 2-sided). RR was also not impacted. LY did not increase grades 3-4 hematologic toxicities, but was associated with a trend toward more, grades 3-4 diarrhea. These results do not demonstrate any benefit to adding LY to gemcitabine in unpretreated patients with advanced pancreatic carcinoma.

A phase II trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent external-beam radiotherapy for locally advanced pancreatic cancer

e15570 Background: S-1 is a new oral fluoropyrimidine anticancer agent and has shown a good efficacy for pancreatic cancer. In the phase I trial, we evaluated the safety of S-1 combined with external-beam radiotherapy (EBRT) to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients (H. Shinchi et al,, Br J Ca 2007;96:1353). The phase I trial determined the recommended of S-1 for the phase II chemoradiotherapy trial to be 80mg/m2/day given on days 1–21. This phase II trial was conducted to evaluate the efficacy and toxicity of EBRT combined with S-1 for locally advanced pancreatic cancer. Methods: Eligible patients had locally advanced and unresectable pancreatic cancer without distant metastases, ECOG PS 0–1, adequate organ and marrow function, and no prior anticancer therapy. EBRT was delivered in fractions of 1.25Gy twice daily, totaling 50Gy per 40 fractions for 4 weeks. S-1 was given orally at a dose of 80mg/m2/day twice a day on days 1–21. The primary end-point of this trial was objective tumor response and secondary end-points included toxicity and overall survival. Results: Forty patients were enrolled in this phase II trial. Of the 40 patients, 39 (97%) completed the scheduled course of chemoradiotherapy. The objective tumor responses by RECIST criteria included 13 PR (33%), 20 SD (50%) and 7 PD (17%). The median survival time was 14 months and 1-year survival rate was 67%. Although grade 3 rash and anorexia occurred in one patient each, no grade 4 toxicities were observed. Conclusions: Combination therapy of S-1 and radiation shows favorable efficacy for locally advanced pancreatic cancer and was well tolerated with no severe toxicities. No significant financial relationships to disclose.

A phase II study of S-1 for the treatment of cytokine-refractory metastatic renal cell carcinoma

5100 Background: S-1 is a novel oral anticancer agent, contains tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT: CDHP: Oxo = 1:0.4:1. The purpose of this study was to evaluate the efficacy and safety of S-1 in cytokine-refractory metastatic renal cell carcinoma (mRCC), and to examine the relation between response and mRNA expression levels of 5-FU-related enzymes. Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary type of RCC, measurable lesions, treatment histories with cytokines, an ECOG performance status of 0 or 1 (2 was allowed in patients with bone metastasis), an age of at least 20 years, prior nephrectomy, and adequate organ functions. Any prior treatment for mRCC was discontinued more than 4 weeks before registration. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR) as confirmed by an independent reviewer. The planned sample size was 44 patients. The threshold response rate was defined as 5%, and the expected rate was set at 17.5%. If the lower limit of the 95% CI exceeded the threshold rate (6 of the 44), S-1 was evaluated to be effective. Formalin fixed paraffin embedded specimens, which had been obtained by radical nephrectomy, were used for mRNA expression assay, performed by RT-PCR method. Results: Between April 2006 and May 2007, 45 patients were enrolled, and 31 assay samples were obtained. ORR was 24.4% (11/45, 95% CI: 12.9 - 39.5%). The median PFS was 9.2 months. The median OS could not be calculated, but the survival rate at 1 year was 87.5%. The most common grade 3–4 adverse events assessed according to the CTCAE v.3.0 included anemia (6.7%), neutropenia (8.9%), anorexia (8.9%), hyperglycemia (6.7%), stomatitis (4.4%), diarrhea (4.4%), and fatigue (4.4%). On mRNA expression analysis, the expression level of 5-FU-related enzyme correlated with ORR and PFS. Conclusions: S-1 is effective and well tolerated in patients with cytokine-refractory mRCC. Measurement of the mRNA level of 5-FU-related enzyme in tumors before treatment may facilitate prediction of the response to S-1. No significant financial relationships to disclose.

Phase I evaluation of vandetanib with radiation therapy (RT) ± cisplatin in previously untreated advanced head and neck squamous cell carcinoma (HNSCC)

6016 Background: Vandetanib is a once-daily oral anticancer agent that selectively targets VEGF, EGF and RET receptor tyrosine kinases. We report preliminary results from an ongoing open-label phase I study of vandetanib with RT ± cisplatin in patients (pts) with previously untreated, unresected, locally advanced (stage III-IV) HNSCC. Methods: Eligible pts received once-daily vandetanib for 14 days followed by either 1) concomitant vandetanib + RT (2 Gy/d, 5 d/wk; total 70 Gy) + cisplatin (30 mg/m2, 2 h iv infusion/wk) for 7 wks, or 2) concomitant vandetanib + RT (2.2 Gy/d accelerated fractionation, 5 d/wk; total 66 Gy) for 6 wks. The primary objective was to determine the safety, tolerability and maximum tolerated dose (MTD) of vandetanib in both regimens. The first pt cohort received vandetanib 100 mg/day; escalation to 200 mg and 300 mg in subsequent cohorts was permitted providing <2/6 (33%) pts in the preceding cohort experienced a dose-limiting toxicity (DLT). Cohort expansion at the MTD of vandetanib was also planned. Results: As of Dec 1 2008, 24 pts (median age 53.5 yrs; 19 male; all M0) had received treatment with vandetanib + RT + cisplatin (n=18) or vandetanib + RT (n=6). In the triplet arm, no DLTs occurred in the initial vandetanib 100 mg cohort (n=6); an additional 6 pts were enrolled to receive vandetanib 200 mg but this dose was considered to exceed the MTD since DLTs were reported in 3/5 evaluable pts (Table). Vandetanib 100 mg was therefore declared the MTD with RT + cisplatin and cohort expansion at this dose continues. In regimen 2), 6 pts have received vandetanib 100 mg + RT and evaluation of this initial cohort is ongoing. Conclusions: This study, which continues to recruit, is the first to evaluate dual targeting of VEGFR/EGFR tyrosine kinases with chemoradiation or radiation alone in HNSCC pts. Among the 24 treated pts, 2 have completed the 2-year follow up, 1 death occurred that was causally related to cisplatin, and 21 remain in follow up or continue to receive treatment. [Table: see text] [Table: see text]