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In this randomized phase II study, we evaluated the efficacy and safety of sorafenib in combination with capecitabine and cisplatin (XP) as first-line chemotherapy in advanced gastric cancer.Patients with metastatic gastric or gastroesophageal junction adenocarcinoma were randomized (1:1) to receive either sorafenib plus XP (S + XP) or XP alone. In cases of disease progression in the XP arm, crossover to sorafenib alone was allowed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), response rates, safety profiles, and biomarkers, and the response rates and PFS with secondline sorafenib alone after progression in the XP arm.Between Jan 2011 and Feb 2013, a total of 195 patients were accrued (97 in the S + XP arm and 98 in the XP alone arm). The overall response rate was 54% with S + XP, and 52% with XP alone (p = 0.83). With a median follow-up of 12.6 months (range, 0.1-29.2), the median PFS assessed by independent review was 5.6 months in the S + XP arm and 5.3 months in the XP arm (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.67-1.27, p = 0.61). Overall survival was not different between the two arms (median 11.7 vs. 10.8 months; HR 0.93, 95% CI 0.65-1.31, p = 0.66). Frequencies of grade 3/4 toxicities were similar between the S + XP and XP alone arms, except for neutropenia (21% vs. 37%), anorexia (0% vs. 5%), and hand-foot skin reaction (7% vs. 1%). Among 51 patients who crossed over to sorafenib alone after disease progression in the XP arm, there was no objective response and their median PFS was 1.3 months (95% CI, 1.2-1.7).The addition of sorafenib to XP chemotherapy was safe but not more effective than XP alone for first-line treatment of metastatic gastric cancer.

In this post hoc analysis of the PRODIGY study, we aimed to investigate factors associated with survival outcomes and provide evidence for designing optimal perioperative treatment strategies for gastric cancer patients receiving neoadjuvant chemotherapy.A total of 212 patients in the neoadjuvant chemotherapy group of the PRODIGY study were included as the study population. The prognostic impact of clinicopathologic factors, including the initial radiological clinical stage (cStage) and post-neoadjuvant chemotherapy pathological stage (ypStage), was analyzed.The median age was 58 years. The majority of patients (77.4%) had cStage III disease, and about 10% and 25% had ypStage 0 and I disease, respectively. According to the initial cStage, progression-free survival (PFS) and overall survival (OS) were significantly different (P 0.01). PFS and OS were also different according to the ypStage (P 0.01). In multivariate analyses, cStage IIIC disease (vs. cStage II) and ypStage II and III disease (vs. ypStage 0/I) were independent factors for poor survival outcomes. Based on the patterns of PFS and OS according to both cStage and ypStage, three patient groups were defined. These groups showed distinct PFS and OS (P 0.01) with 5-year PFS rates of 95.7%, 77.9%, and 31.3% and 5-year OS rates of 95.7%, 82.4%, and 42.5%, respectively.Both initial cStage and ypStage were independent factors for survival outcomes of gastric cancer patients treated with neoadjuvant chemotherapy. Efforts should be made to develop optimal peri-operative treatment strategies for patients at different risks according to cStage and ypStage.

In East Asia, S-1 plus cisplatin (SP) is one of the standard first-line chemotherapy regimens for metastatic or recurrent gastric cancer (MRGC). Oxaliplatin is generally less toxic and more convenient to administer than cisplatin. This was a multicenter, phase III study assessing whether S-1/oxaliplatin (SOX) was non-inferior/superior to SP in terms of progression-free survival (PFS). Patients with MRGC were randomized 1:1 to receive either SOX (S-1 80 mg/m2/day on days 1–14; oxaliplatin 130 mg/m2 on day 1; every 3 weeks) or SP (S-1 80 mg/m2/day on days 1–14; cisplatin 60 mg/m2 on day 1; every 3 weeks [SP3]). Between October 2012 and October 2014, 338 patients were randomized. The median age was 56 years, and 51% of patients had measurable lesions. SOX was significantly non-inferior but not superior to SP3 in terms of PFS [median 5.6 versus 5.7 months; hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.67–1.07]. In patients with measurable disease, objective response rates were similar between SOX and SP3 (58% versus 60%). Overall, the survival in both groups did not differ (median 12.9 versus 11.4 months; HR 0.86; 95% CI 0.66–1.11). Treatment was well tolerated in both arms. Anemia, leucopenia, neutropenia, febrile neutropenia, and oral mucositis were more common with SP3. In contrast, thrombocytopenia, nausea, vomiting, and peripheral neuropathy were more common with SOX. SOX was non-inferior to SP3. The two regimens were well tolerated with different toxicity profiles. The SOX regimen can be recommended as a first-line treatment for MRGC. ClinicalTrials.gov: NCT01671449

Countries differ in their treatment expertise and research results regarding gastric cancer; hence, treatment guidelines are diverse based on evidence and medical situations. A comprehensive and comparative review of each country's guidelines is imperative to understand the similarities and differences among countries. We reviewed and compared five gastric cancer treatment guidelines in terms of endoscopic, surgical, perioperative, and palliative systemic treatment based on evidence levels and recommendation grades, as well as the postoperative follow-up strategies for each guideline. The Korean, Chinese, and European guidelines provided evidence and grading of the recommendations. The United States guidelines suggested categories for evidence and consensus. The Japanese guidelines suggested evidence and recommendations only for systemic treatment. The Korean and Japanese guidelines described endoscopic treatment, surgery, and lymphadenectomy in detail. The Chinese, United States, and European guidelines more intensively considered perioperative chemotherapy. In particular, the indications for chemotherapy and the regimens recommended by each guideline differed slightly. Considering their medical situations, each guideline had some diversity in terms of adopting evidence, which resulted in heterogeneous recommendations. This review will help medical personnel to comprehensively understand the diversity in gastric cancer treatment guidelines for each country in terms of evidence and recommendations.

Background Poziotinib (HM781-36B) is an irreversible pan-HER tyrosine kinase inhibitor which targets EGFR, HER2, and HER4. This prospective, multicenter, open-label, phase I/II study determined the maximum tolerated dose (MTD) and evaluated the safety and efficacy of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer (GC). Methods Patients with HER2-positive GC previously treated with one line of chemotherapy received oral poziotinib (8 mg or 12 mg) once daily for 14 days, followed by 7 days off. Paclitaxel (175 mg/m2 infusion) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg infusion) were administered concomitantly with poziotinib on day 1 every 3 weeks. Results In the phase I part, 12 patients were enrolled (7 at dose level 1, 5 at dose level 2). One patient receiving poziotinib 8 mg and 2 receiving poziotinib 12 mg had dose-limiting toxicities (DLTs); all DLTs were grade 4 neutropenia, one with fever. The most common poziotinib-related adverse events were diarrhea, rash, stomatitis, pruritus and loss of appetite. The MTD of poziotinib was determined to be 8 mg/day and this was used in the phase II part which enrolled 32 patients. Two patients (6.3%) had complete responses and 5 (15.6%) had partial responses (objective response rate 21.9%). Median progression-free survival and overall survival were 13.0 weeks (95% CI 9.8-21.9) and 29.5 weeks (95% CI 17.9-59.2), respectively. Conclusions The MTD of poziotinib combined with paclitaxel and trastuzumab was 8 mg/day. This combination yielded promising anti-tumor efficacy with manageable toxicity in previously treated patients with HER2-positive GC.

This study investigated the efficacy and safety of S-1 versus capecitabine in elderly patients with metastatic gastric cancer (MGC), and examined the association between cytochrome P450 2A6 (CYP2A6) polymorphisms and treatment outcomes.MGC patients 70-85 years old with Eastern Cooperative Oncology Group (ECOG) performance status 0-2 or 65-70 years old with ECOG PS 2 were randomized to receive S-1 40 mg/m, twice daily, or capecitabine 1250 mg/m, twice daily, on days 1-14 every 3 weeks.From May 2007 up to July 2010, 107 patients were enrolled. G3/4 neutropenia developed in 3.8% of each arm, and the most common G3/4 nonhematological toxicities were anorexia and fatigue. Vomiting and tearing were more frequent with S-1 and hand-foot syndrome with capecitabine. The primary endpoint, the overall response rate, was 26.4% (14/53, 95% confidence interval: 14.5-38.3%) in S-1 and 24.1% (13/54, 95% confidence interval: 12.7-35.5%) in capecitabine, both of which exceeded the null hypothesis response rate of 10%. The median time to progression (TTP; 3.2 vs. 3.4 months, P=0.813) and overall survival (OS; 8.5 vs. 10.3 months, P=0.691) were similar in both arms. CYP2A6 polymorphisms were associated with S-1 efficacy. In the S-1 arm only, patients with CYP2A6 variant/variant alleles had worse TTP and OS than those with wild/wild or wild/variant alleles, and in multivariate analysis, the CYP2A6 genotype was predictive for TTP and OS.Both S-1 and capecitabine were active and tolerable for elderly MGC patients. The CYP2A6 genotyping might guide treatment selection.

Some clinicopathological variables are known to influence the survival of patients with advanced gastric cancer. A comprehensive model based on these factors is needed for prediction of an individual’s survival and appropriate patient counseling. A nomogram for predicting 1-year survival in patients with advanced gastric cancer in the palliative chemotherapy setting was developed using clinicopathological data from 949 patients with unresectable or metastatic gastric cancer who had received first-line doublet cytotoxic chemotherapy from 2001 to 2006 at the National Cancer Center, Korea (Baseline Nomogram). For 836 patients whose initial response to chemotherapy is known, another nomogram (ChemoResponse-based Nomogram) was constructed using the response to chemotherapy as additional variable. Nomogram performance in terms of discrimination and calibration ability was evaluated using the C statistic and Hosmer–Lemeshow-type χ 2 statistics. Two different nomograms were developed and subjected to internal validation. The baseline nomogram incorporated 13 baseline clinicopathological variables, whereas the chemoresponse-based nomogram was composed of 11 variables including initial response to chemotherapy. Internal validation revealed good performance of the two nomograms in discrimination: C statistics = 0.656 (95% confidence interval, 0.628–0.673) for the baseline and 0.718 (95% confidence interval, 0.694–0.741) for the chemoresponse-based nomogram, which showed significantly better discrimination performance than the baseline nomogram (Z statistics = 3.74, p

BACKGROUND Irinotecan-based chemotherapy is a standard backbone of therapy in patients with metastatic colorectal cancer (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimens in elderly patients. PATIENTS AND METHODS Using the patient cohort (n = 1,545) from the UGT1A1 genotype study, we compared the efficacy and safety between elderly and nonelderly patients with metastatic CRC (n = 934) or GC (n = 611) who received first- or second-line FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy. RESULTS Despite lower relative dose intensity in elderly patients, progression-free survival and overall survival were similar between elderly (age ≥70 years) and nonelderly (

Purpose This study evaluated the re-challenge of S-1 or cisplatin in combination with docetaxel in metastatic gastric cancer (MGC) that had progressed on a cisplatin plus either S-1 or capecitabine regimen. Materials and Methods Patients with progressive disease after first-line cisplatin plus S-1 or capecitabine were randomized to receive 3-week cycles of docetaxel 75 mg/m2 intravenously (IV) on D1 (D), docetaxel 60 mg/m2 IV plus cisplatin 60 mg/m² IV on D1 (DC), or docetaxel 60 mg/m2 IV D1 plus oral S-1 30 mg/m2 twice a day on D1-14 (DS). Results Seventy-two patients were randomized to the D (n=23), DC (n=24), or DS (n=25) group. The confirmed response rate was 4.3% (95% confidence interval [CI], 0% to 12.6%), 4.3% (95% CI, 0% to 12.6%), and 8.7% (95% CI, 0% to 20.2%) for the D, DC, and DS groups, respectively. Compared to the D arm, the DS arm had a better progression-free survival (2.7 months vs. 1.3 months, p=0.034) without any deterioration in safety or quality of life, whereas the DC arm had a similar progression-free survival (1.8 months vs. 1.3 months, p=0.804) and poorer overall survival (5.6 months vs. 10.0 months, p=0.035). Conclusion A re-challenge with S-1, but not cisplatin, in combination with docetaxel has potential anticancer benefits over docetaxel alone in MGC with progression after prior cisplatin plus S-1 or capecitabine.

e16586 Background: Approximately 75% of GC cases occur in Asian persons. Pembrolizumab has shown antitumor activity in global studies of GC. KEYNOTE-063 (NCT03019588) is a randomized, open-label, phase 3 trial in Asian patients with advanced PD-L1–positive (combined positive score [CPS] ≥1) GC that progressed after platinum + fluoropyrimidine chemotherapy. After the KEYNOTE-063 study began, results of the global KEYNOTE-061 study (NCT02370498) showed that pembrolizumab did not prolong overall survival (OS) vs paclitaxel in patients previously treated for advanced GC (median OS, 9.1 months vs 8.3 months; hazard ratio [HR], 0.82; 95% CI, 0.66-1.03; 1-sided P= 0.0421 [significance threshold for OS was 1-sided P= 0.0135]). Methods: Eligible patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg Q3W for up to 35 cycles (~2 years) or standard-dose paclitaxel. The primary efficacy end points were OS and progression-free survival (PFS). Planned enrollment was ~360 patients. Results: Because pembrolizumab did not significantly prolong OS in KEYNOTE-061, enrollment in KEYNOTE-063 was discontinued after 94 patients were enrolled (47 patients in each treatment group). In these Asian patients, median OS was 8.4 months in the pembrolizumab group and 7.7 months in the paclitaxel group; median PFS was 1.9 months and 4.0 months, respectively (Table). Objective response rate (ORR) and median duration of response (DOR) are shown in the Table. Drug-related adverse events (AEs) occurred in 59.6% of patients receiving pembrolizumab and in 95.5% of patients receiving paclitaxel (Table). Conclusions: In this small sample of Asian patients with PD-L1–positive advanced GC, definitive conclusions are limited; however, second-line pembrolizumab monotherapy seems to be well tolerated in this patient population. Because this study was terminated early, there was insufficient power for comparisons between groups; therefore, these data should be viewed with caution. Clinical trial information: NCT03019588 . [Table: see text]

Purpose It has been reported that the survival of patients with locally advanced gastric cancer (LAGC) is better in East Asia countries than in developed western countries; however, the prognosis of LAGC remains poor. This study aimed to evaluate the effects of perioperative chemotherapy on the long-term survival of East Asia patients with LAGC. Materials and methods From October 2006 through August 2008, 43 patients with LAGC received perioperative S-1 combined with weekly docetaxel in a phase II study (neoadjuvant group). These patients were matched using propensity scores to patients who underwent surgery without neoadjuvant chemotherapy during the same period (surgery group). The surgical outcomes and long-term survivals were compared between the 2 groups. Results After matching, 43 and 86 patients were included in the neoadjuvant and surgery groups, respectively, and there was no significant difference in their baseline characteristics. Although the operating time was longer in the neoadjuvant group, there was no significant difference in postoperative complications between the 2 groups. The neoadjuvant group had a significantly higher 5-year overall survival (OS) rate (73.3% vs. 51.1%, P=0.005) and a trend towards higher 5-year progression-free survival (PFS) (62.8% vs. 49.9%, P=0.145). In the multivariate analysis, perioperative chemotherapy was an independent factor for OS, with a hazard ratio of 0.4 (P=0.005) and a marginal effect on the PFS (P=0.054). Conclusions Perioperative chemotherapy was associated with better long-term survival without increasing postoperative complications in the setting of D2 surgery for patients with LAGC, suggesting that perioperative chemotherapy can be a therapeutic option in East Asia countries.

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.

Objectives We compared continuous versus stop-and-go chemotherapy after disease stabilisation with induction chemotherapy in the first-line treatment of metastatic gastric cancer (MGC). Methods MGC patients who achieved disease control after 6 cycles of S-1/oxaliplatin (SOX) were randomised to receive either continuous SOX until progression (continuous arm) or to have a chemotherapy-free interval followed by SOX reintroduction at progression (stop-and-go arm). The primary end-point was overall survival (OS). Results Of the 250 patients enrolled, 247 participated in the induction phase. Of these, 121 patients were randomised to the continuous arm (n = 59) or the stop-and-go arm (n = 62). Progression-free survival (PFS) was significantly longer in the continuous arm than in the stop-and-go arm (10.5 versus 7.2 months; hazard ratio [HR] 0.55, 95% CI, 0.37–0.81; P = 0.002). Duration of disease control (DDC) and OS, however, were comparable between the two arms: median DDC, 10.5 versus 11.3 months, HR 0.92 (95% CI, 0.62–1.36; P = 0.674); median OS, 22.6 versus 22.7 months, HR 0.78 (95% CI, 0.50–1.23; P = 0.284). Adverse events including grade ≥3 fatigue (28.8% versus 8.1%; P = 0.003) and sensory neuropathy (25.4% versus 9.7%; P = 0.022) occurred more frequently in the continuous arm than in the stop-and-go arm. Quality of life (QOL) including global health status, physical/role functioning and other symptom scores significantly favoured the stop-and-go arm. Conclusion Compared with the stop-and-go strategy, maintenance chemotherapy improved PFS but not DDC and OS and had a negative impact on QOL, suggesting the stop-and-go strategy may be an appropriate option in MGC patients following induction chemotherapy.

Tissue matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS)may identify lipids differentially expressed between cancer and adjacent normal tissue. To identify lipidomic profiles for gastric cancer, 24 gastric cancerswere profiled for lipid by the histology-directed, tissue MALDI MS technology. Lipid profiles differed between gastric cancer and adjacent normal tissue samples. At P

Background and Aim Gastric cancer bleeding is not rare complication in patients with advanced gastric cancer (AGC). The aim of this study was to evaluate the efficacy and clinical outcomes of endoscopic therapy (ET) for upper gastrointestinal bleeding (UGIB) from unresectable AGC. Methods Data from 113 patients with UGIB from unresectable AGC who underwent ET at the National Cancer Center, Korea were analyzed retrospectively. Success rates of endoscopic hemostasis, rebleeding rates, mortality at 30 days, and overall survival (OS) rate after initial hemostasis were investigated. Results The initial hemostasis rate was 92.9% (105/113). Electrocoagulation was the most common method used (92.0%, 104/113), and combination ET was required in 34 patients (30.1%). Rebleeding occurred in 43 patients (41.0%); 3-day and 30-day rebleeding rates were 18.1% and 29.5%, respectively. Multivariate logistic regression analysis showed that transfusion of packed red blood cells (> 5 units) was associated with early rebleeding (≤ 3 days after initial hemostasis) (odd ratio, 4.75; 95% confidential interval, 1.45–15.57; P = 0.010). ET was attempted in 18 patients with rebleeding; hemostasis was achieved in 88.9%. The 30-day mortality rate after initial bleeding event was 15.9%. Median OS after initial hemostasis was 3.2 months. OS was lower for patients with early rebleeding than for those with late rebleeding (> 3 days after initial hemostasis) or without rebleeding (1.0, 3.1, and 4.3 months, respectively; P = 0.004). Conclusions ET, primarily endoscopic electrocoagulation, achieved a high initial hemostasis rate for UGIB in patients with unresectable AGC. However, rebleeding frequently occurred, and early rebleeding was associated with poor survival.

PURPOSE To evaluate the efficacy and toxicity of oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer who previously treated with 5-FU-based chemotherapy. MATERIALS AND METHODS Between April 1999 and January 2001, thirty-two patients were enrolled in this study. Oxaliplatin 130 mg/m2 was given intravenously (IV) on day 1 as was 5-FU 500 mg/m2 IV followed by continuous infusion of 5-FU 3,000 mg/m2 and LV 100 mg/m2 for 48 hours administered every 3 weeks. Six patients had received 5-FU as an adjuvant setting and 26 patients as a palliative regimen. RESULTS The median age of the patients was 50 years (range; 19-69) and the dominant sites of metastasis were the liver, lung or both in 9, 5 and 2 patients respectively. In 30 evaluable patients, the overall response rate was 27% including 1 complete response and 7 partial responses. The median response duration was 28 weeks (95% confidence interval; 22~34 weeks) and the median progression free survival of all patients was 24 weeks (95% confidence interval; 15~33 weeks). A median 5 cycles (range; 2~9) and total 155 cycles were performed in 32 patients. 150 cycles were evaluable for toxicity. The most common hematologic toxicity was grade 1~2 anemia in 78 cycles (52%). Leukopenia (39%) and thrombocytopenia (23%) were fully reversible. The most common non-hematologic toxicity was nausea/vomiting (43/30%) followed by diarrhea (23%), hepatotoxicity (21%) and neurotoxicity (21%). One patient ceased therapy due to grade 4 diarrhea. No other severe toxicity interrupted this treatment. CONCLUSION Oxaliplatin, 5-FU and LV in combination showed significant activity in previously treated metastatic colorectal cancer with favorable toxicity.

Although gastric cancer with isolated para-aortic lymph node (PAN) involvement is considered an advanced disease, the clinical characteristics of it have not been comprehensively elucidated.We reviewed the medical records of 1,277 patients received palliative chemotherapy with advanced gastric cancer according to metastatic sites: PAN-only metastasis, single organ metastasis other than PAN, and multiple organ metastasis. Time to other organ metastasis (TTOM) was determined only in PAN-only metastasis group as the time interval between initial diagnosis of recurrence or de novo metastasis and confirming distant metastasis beyond PAN area.The median overall survival (OS) of patients with PAN-only metastasis was significantly longer than that of patients with single organ metastasis other than PAN or multiple organ metastasis (13.8 months vs. 11.4 months vs. 8.4 months; P0.001). In the PAN-only metastasis group, patients with recurrent diseases showed longer TTOM beyond the PAN area (10.7 vs. 7.7 months; P = 0.037) and OS (23.8 vs. 12.8 months; P = 0.010) than those with de novo metastatic disease and it was validated by multivariate analysis.Patients with isolated PAN metastasis showed an excellent prognosis compared with patients with metastasis at other sites and it was primarily evident in patients with recurrent PAN metastasis.

Docetaxel and cisplatin combination chemotherapy is established first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). We evaluated a weekly schedule of docetaxel and cisplatin for efficacy and tolerability in patients with chemotherapy-naive NSCLC.Patients enrolled in this study had stage IIIB or IV NSCLC with measurable disease, no prior chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2. Treatment consisted of docetaxel 40 mg/m(2) and cisplatin 35 mg/m(2) given on D1 and D8 every 3 weeks. Patients were evaluated for response after every 2 cycles of treatment.Thirty six patients were enrolled, and 35 underwent treatment. Of these, 29 were males and 7 females, median age was 61 years (range, 38-68). About 31 patients had ECOG PS 0-1 and 4 patients had ECOG PS 2. Fifty seven percentage (20/35) of patients had adenocarcinoma and 74.3% (26/35) had stage IV disease. A total of 153 cycles of chemotherapy were administered. Of the 35 patients treated, 17 (48.6%) achieved partial response, 11 (31.4%) showed stable disease, and 6 (17.1%) had progressive disease. Median duration of response was 5.3 months (95% CI: 4.2-6.2 months), and median time to disease progression was 4.6 months (95% CI: 2.9-6.3 months). Estimated overall survival at 1 year was 65.7%. The major hematologic toxicity was myelosuppression. Grade 3 or 4 anemia occurred in 6 cycles, and grade 3 or 4 neutropenia was observed in four cycles. Major non-hematologic toxicities were grade 3 nausea in three patients and grade 3 fatigue in two patients. Three patients developed pneumonia and one patient had infectious colitis. There were no treatment-related deaths in this study.Weekly schedule of docetaxel and cisplatin as first-line treatment for NSCLC had good efficacy and manageable toxicity.

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.

PURPOSE Paclitaxel and cisplatin, active drugs in the treatment of non-small-cell lung cancer (NSCLC), have been found to be synergistic and less myelotoxic in combination when the paclitaxel is given 24 hr prior to the cisplatin. Their antitumor activity and toxicity in patients with advanced NSCLC has been evaluated herein. MATERIALS AND METHODS Seventy-four chemonaive patients, with advanced NSCLC, were enrolled. Paclitaxel, 175 mg/m2, was administered on day 1, followed 24 hr later by cisplatin, 75 mg/m2, on day 2. RESULTS The overall response rate, median time to progression and median survival time were 51%, 7.1 months (95% confidence interval (CI), 5.5~8.7 months) and 13.7 months (95% CI, 11.3~16.1 months), respectively. There were significant differences in the overall survival rates in relation to stage and the ECOG performance status(PS). The toxicity was mainly nonhematological. Grade > or =3 neuropathy occurred in 2 (3%) patients, myalgia in 3 (4%), and bone pain in 3 (4%). The hematological toxicity was mild, and no grade 3 or 4 neutropenia was observed. CONCLUSION The combination of paclitaxel and cisplatin is an effective and tolerable treatment regimen for advanced NSCLC during first line chemotherapy. The main toxicity was nonhematological, such as peripheral neuropathy, myalgia and bone pain, whereas the hematological toxicity itself was mild.

e22195Background: Oxaliplatin (OX)-based chemotherapy is known to cause hepatic sinusoidal injury, resulting portal hypertension with splenomegaly (SM). We compared this OX-induced hepatopathy, SM,...

Purpose Tumor bleeding is a major complication in inoperable gastric cancer. The study aim was to investigate the effects of proton pump inhibitor (PPI) treatment for the prevention of gastric tumor bleeding. Materials and Methods This study was a prospective double-blind, randomized, placebo-controlled trial. Patients with inoperable gastric cancer were randomly assigned to receive oral lansoprazole (30 mg) or placebo daily. The primary endpoint was the occurrence of tumor bleeding, and the secondary endpoints were transfusion requirement and overall survival (OS). Results This study initially planned to enroll 394 patients, but prematurely ended due to low recruitment rate. Overall, 127 patients were included in the analyses: 64 in the lansoprazole group and 63 in the placebo group. During the median follow-up of 6.4 months, tumor bleeding rates were 7.8% and 9.5%, in the lansoprazole and placebo groups, respectively, with the cumulative bleeding incidence not statistically different between the groups (P=0.515, Gray's test). However, during the initial 4 months, 4 placebo-treated patients developed tumor bleeding, whereas there were no bleeding events in the lansoprazole-treated patients (P=0.041, Gray's test). There was no difference in the proportion of patients who required transfusion between the groups. The OS between the lansoprazole (11.7 months) and the placebo (11.0 months) groups was not statistically different (P=0.610). Study drug-related serious adverse event or bleeding-related death did not occur. Conclusions Treating patients with inoperable gastric cancer with lansoprazole did not significantly reduce the incidence of tumor bleeding. However, further studies are needed to evaluate whether lansoprazole can prevent tumor bleeding during earlier phases of chemotherapy (ClinicalTrial.gov, identifier No. NCT02150447).

We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 plus docetaxel in locally advanced gastric cancer (LAGC) and to investigate the association between CYP2A6 genotype and outcome. Patients with LAGC [clinical stage III–IV (M0) by the Japanese staging system] received three cycles of pre- and postoperative chemotherapy (S-1 40 mg/m2 twice daily on days 1–14; intravenous docetaxel 35 mg/m2 on days 1 and 8, every 3 weeks) followed by gastrectomy with D2 dissection. We also performed a pharmacokinetic and CYP2A6 genotyping study (*1, *4, *7, *9, *10) for S-1. From October 2006 to June 2008, 44 patients entered the study. 43 eligible patients completed preoperative chemotherapy and 40 completed postoperative chemotherapy. The most common G3/4 toxicities during pre- and postoperative chemotherapy were neutropenia, stomatitis, and abdominal pain. The clinical response rate by RECIST was 74.4 % (95 % CI, 61.4–87.4 %), and the R0 resection rate was 97.7 %. Clinical downstaging in T or N occurred in 41.9 % of patients. The 3-year progression-free survival (PFS) rate was 62.8 % and 5-year overall survival (OS) rate was 69.6 %. PFS and OS differed significantly according to clinical response, clinical downstaging, and CYP2A6 genotype. Patients with CYP2A6 variant/variant genotypes had a higher tegafur C max and worse survival than those with wild/wild or wild/variant genotypes. Perioperative S-1 plus docetaxel is active with a manageable toxicity in patients with LAGC receiving D2 surgery. Clinical tumor response, clinical downstaging, and CYP2A6 genotype may predict efficacy.

BACKGROUND A Phase I study of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane] platinum(II) (SKI 2053R), a new platinum derivative, was performed to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetic profile of SKI 2053R in patients with advanced, refractory malignancies. METHODS Twenty-one patients were entered into the study. SKI 2053R was administered with an intravenous infusion over 1 hour every 4 weeks. The SKI 2053R dose was escalated from 40 mg/m2 up to 480 mg/m2 using a modified Fibonacci scheme. Pharmacokinetic analysis was done in all patients to determine the total and ultrafiltrable platinum concentrations in both the plasma and the urine. RESULTS All patients were evaluable for toxicity and response. There was no significant toxicity with dosages up to 360 mg/m2. At 480 mg/m2, two of three patients developed Grade 4 hepatotoxicity, Grade 3 leukopenia and thrombocytopenia, and Grade 2 azotemia and proteinuria. Other toxicity included nausea and emesis, but it was controlled with antiemetics. SKI 2053R did not cause significant neurotoxicity or mucositis. There were 4 patients with stable disease among the 21 patients. Plasma decay of the total and free platinum concentrations was best fitted by using a two-compartment, open model. The terminal plasma half-life of the total platinum after SKI 2053R administration ranged from 63.4 hours to 114.1 hours in dosages ranging from 40 mg/m2 to 480 mg/m2 without significant dose dependency. However, the terminal plasma half-life of the free platinum concentration showed a significant dose dependent, incremental pattern. The renal excretion of SKI 2053R measured as platinum ranged from 49% to 75% of the administered dose. CONCLUSIONS The MTD of SKI 2053R was 480 mg/m2. The major DLTs were hepatotoxicity, nephrotoxicity, and myelosuppression. The recommended starting dose for a subsequent Phase II study is 360 mg/m2 once every 4 weeks. Cancer 2001;91:1549–56. © 2001 American Cancer Society.

Lessons Learned Oraxol, a novel oral formulation of paclitaxel, displayed modest efficacy as second-line chemotherapy for gastric cancer. Considering its favorable toxicity profiles, further studies are warranted in various solid tumors including gastric cancer. Background. Oraxol consists of paclitaxel and HM30181A, a P-glycoprotein inhibitor, to increase the oral bioavailability of paclitaxel. This phase I/II study (HM-OXL-201) was conducted to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Oraxol. In addition, we investigated the efficacy and safety of Oraxol as second-line chemotherapy for metastatic or recurrent gastric cancer (GC). Methods. In the phase I component, paclitaxel was orally administered at escalating doses (90, 120, or 150 mg/m2 per day) with a fixed dose (15 mg/day) of HM30181A. Oraxol was administrated 6 times per cycle (days 1, 2, 8, 9, 15, and 16) every 4 weeks. In the phase II component, the efficacy and safety of Oraxol were evaluated. Results. In the phase I component, the MTD could not be determined. Based on toxicity and pharmacokinetic data, the RP2D of oral paclitaxel was determined to be 150 mg/m2. In the phase II component, 4 of 43 patients (9.3%) achieved partial responses. Median progression-free survival and overall survival were 2.6 and 10.7 months, respectively. Toxicity profiles were favorable, and the most common drug-related adverse events (grade ≥3) were neutropenia and diarrhea. Conclusion. Oraxol exhibited modest efficacy and favorable toxicity profiles as second-line chemotherapy for GC.

Gastric cancer bleeding is not rare complication in patients with advanced gastric cancer (AGC). The aim of this study was to evaluate the efficacy and clinical outcomes of endoscopic therapy (ET) for upper gastrointestinal bleeding (UGIB) from unresectable AGC.Data from 113 patients with UGIB from unresectable AGC who underwent ET at the National Cancer Center, Korea were analyzed retrospectively. Success rates of endoscopic hemostasis, rebleeding rates, mortality at 30 days, and overall survival (OS) rate after initial hemostasis were investigated.The initial hemostasis rate was 92.9% (105/113). Electrocoagulation was the most common method used (92.0%, 104/113), and combination ET was required in 34 patients (30.1%). Rebleeding occurred in 43 patients (41.0%); 3-day and 30-day rebleeding rates were 18.1% and 29.5%, respectively. Multivariate logistic regression analysis showed that transfusion of packed red blood cells ( 5 units) was associated with early rebleeding (≤ 3 days after initial hemostasis) (odd ratio, 4.75; 95% confidential interval, 1.45-15.57; P = 0.010). ET was attempted in 18 patients with rebleeding; hemostasis was achieved in 88.9%. The 30-day mortality rate after initial bleeding event was 15.9%. Median OS after initial hemostasis was 3.2 months. OS was lower for patients with early rebleeding than for those with late rebleeding ( 3 days after initial hemostasis) or without rebleeding (1.0, 3.1, and 4.3 months, respectively; P = 0.004).ET, primarily endoscopic electrocoagulation, achieved a high initial hemostasis rate for UGIB in patients with unresectable AGC. However, rebleeding frequently occurred, and early rebleeding was associated with poor survival.

We conducted a phase I study of S-1 combined with irinotecan and oxaliplatin (TIROX) to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety, pharmacokinetics, pharmacogenetics, and preliminary efficacy in patients with metastatic colorectal cancer (MCRC) or metastatic gastric cancer (MGC).Patients received escalating doses of S-1 (30-40 mg/m² b.i.d.) orally on days 1-14, an escalating dose of intravenous irinotecan (120-150 mg/m²) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m²) on day 1 every 3 weeks.Twenty-three patients (10 MCRC, 13 MGC; 13 chemonaive, 10 previously treated for metastatic disease) were treated across six dose levels. Because only one patient experienced a dose-limiting toxicity of grade 3 anorexia at the highest dose level (S-1 40 mg/m² b.i.d., irinotecan 150 mg/m², and oxaliplatin 85 mg/m²) (n = 8), the MTD was not obtained, and this level was established as the RD. With a median of 10 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (43 %), diarrhea (13 %), and nausea (13 %). In 22 efficacy-evaluable patients, the objective tumor response rate was 59.1 % (75 % for both MCRC and MGC in the first-line setting) and the disease control rate was 100 %. The exploratory pharmacokinetic/pharmacogenetic study showed that CYP2A6 variants (*4, *7, *9) are associated with a lower metabolic ratio of S-1 (exposure ratio of 5-fluorouracil to tegafur).The new triplet TIROX regimen has shown promising antitumor activity and a favorable toxicity profile in patients with MCRC and MGC.

4016Background: Paclitaxel is currently only available as an IV formulation. DHP107 is a novel oral formulation composed of lipid ingredients and paclitaxel. DHP107 has demonstrated comparable effi...

4015Background: S-1 plus cisplatin (SP) is one of the standard first-line chemotherapies for AGC in the East Asia. Oxaliplatin is generally less toxic and more convenient than cisplatin. This study...

TPS4135Background: Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers. Avelumab* is a fully human anti-PD-L1 ...

4057Background: Adjuvant chemotherapy improves survival after curative D2 gastrectomy in patients with operable gastric cancer. However, the optimal timing of initiation of adjuvant chemotherapy af...

Self-expandable metallic stents (SEMSs) provide effective palliation for inoperable malignant gastric outlet obstruction (GOO). The objective of this study was to evaluate the effectiveness of SEMSs in patients with recurrent gastric cancer after radical gastrectomy. We retrospectively analyzed data from patients with gastric cancer who underwent endoscopic SEMS placement. The patients had obstructive symptoms due to recurrent gastric cancer after curative-intent subtotal or total gastrectomies. Technical and clinical success rates of stent placement were evaluated and clinical outcomes were compared according to operation types. A total of 15 patients underwent total gastrectomies with esophagojejunostomies and Roux-en-Y reconstructions, 8 underwent subtotal gastrectomies with Billroth I reconstructions, and 12 underwent subtotal gastrectomies with Billroth II reconstructions. Four patients in the Billroth II group received stents in afferent and efferent loops, so a total of 39 stents were placed. Technical success was achieved with 92% (36/39) of stents, and clinical success occurred with 90% (35/39) of stents, with no significant differences among surgery groups or between stent types (covered vs. uncovered). The GOO score (preprocedure: 0.45 ± 0.62) increased by 1 week (2.06 ± 0.51, p

To evaluate the association between Helicobacter pylori (H. pylori) infection and gastric cancer (GC) according to tumor subtype in Korea.H. pylori status was determined serologically using the enzyme-linked immunosorbent assay. In total, 2,819 patients with GC and 562 healthy controls were studied. A logistic regression method was used after adjusting for possible confounders.The prevalence of H. pylori infection was significantly higher in the GC patients (84.7%) than in the controls (66.7%) (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.46-3.97). The adjusted OR was significantly higher in H. pylori-infected patients aged60 years (OR, 4.69; 95% CI, 3.44-6.38) than in those aged ≥60 years (OR, 1.48; 95% CI, 0.88-2.46; p0.001). Subgroup analyses revealed no differences in seroprevalence between early gastric cancer (84.8%; OR, 3.01; 95% CI, 2.27-4.01) and advanced gastric cancer (84.6%; OR, 2.94; 95% CI, 2.24-3.85), cardia cancer (83.8%; OR, 2.98; 95% CI, 2.16-4.02) and noncardia cancer (84.8%; OR, 3.17; 95% CI, 2.48-4.04), and differentiated carcinoma (82.7%; OR, 2.99; 95% CI, 2.21-4.04) and undifferentiated carcinoma (86.8%; OR, 3.05; 95% CI, 2.32-4.00).The seroprevalence of H. pylori was higher in GC patients than in healthy controls, especially in younger patients. H. pylori infection is associated with GC, regardless of the tumor location, stage, or differentiation.

We conducted the current study to investigate the clinical outcomes of metastatic gastric carcinoma (MGC) patients who experienced gastrointestinal (GI) perforation during palliative chemotherapy and to examine the prognostic factors associated with survival after perforation. We reviewed the medical records of patients at the Center for Gastric Cancer of the National Cancer Center, Korea who developed GI perforation during palliative chemotherapy between January 2001 and December 2008. Of the 1,856 patients who received palliative chemotherapy for MGC, 32 patients (1.7%) developed GI perforation during chemotherapy. Patients with perforation at the primary gastric site were more likely to have ulcerative gastric cancer lesion (90.5 vs. 40.0%, P = 0.034) or gastric tumor bleeding (28.6 vs. 0%, P = 0.298), and less likely to have Bormann type IV (14.3 vs. 60.0%, P = 0.062), than patients with perforation at nongastric sites. In 14 patients (43.8%) who resumed chemotherapy after perforation, the disease control rate was 57.1%, and median overall survival (OS) after perforation was 7.5 months [95% confidence interval (CI), 6.0–9.0 months]. In all patients, median OS following perforation was 4.0 months (95% CI, 1.5–6.6 months), and multivariate analysis revealed that differentiated tumor histology, response to chemotherapy before perforation, and absence of septic shock at time of perforation were significantly associated with favorable OS after perforation. As patients experiencing GI perforation during palliative chemotherapy have heterogeneous clinical presentation, we need to adopt different approaches in the management of the patients that are compatible with the favorable prognostic factors.

Background Self-expandable metallic stents (SEMSs) provide effective palliation of malignant pyloric obstruction in patients with inoperable gastric cancer. Objective To compare the effectiveness and side effects of covered and uncovered SEMSs for the palliation of malignant pyloric obstruction. Design Prospective, randomized, single-center study. Setting Tertiary-care cancer center hospital. Patients This study involved 80 patients with pyloric obstruction related to inoperable gastric cancer. Intervention Covered or uncovered SEMS placement. Main Outcome Measurements Technical and clinical success rates as well as the patency rate at 8 weeks after placement. Results Both groups had a technical success rate of 100% with no immediate complications. Both groups also had comparable clinical success rates (covered SEMS, 95% [38 of 40] and uncovered SEMS, 90% [36 of 40], P = .68) and 8-week patency rates (covered SEMS, 61.3% [19 of 31] and uncovered SEMS, 61.1% [22 of 36], P > .99). Stent migration within 8 weeks was more common in the covered SEMS group (25.8% [8 of 31]) than in the uncovered SEMS group (2.8% [1 of 36], P = .009), whereas re-stenosis because of tumor ingrowth was more common in the uncovered SEMS group (25.0% [9 of 36] vs 0% [0 of 31] in the covered SEMS group, P = .003). Overall patient survival and stent patency did not differ between groups ( P = .27 and 0.61 by log-rank test, respectively). Limitations The study population was limited to gastric cancer patients, and stent designs were changed in the midst of the study period. Conclusion Both the covered and uncovered SEMSs are effective and have comparable 8-week patency in patients with malignant pyloric obstruction, despite different patterns of late stent failure.

Advanced or metastatic gastric cancer, which is one of the most common malignancies in Korea, is difficult to cure by surgery alone and generally requires combination chemotherapy. Paclitaxel is active against gastric cancer and when combined with 5-fluorouracil/leucovorin and/or cisplatin is effective in the treatment of gastric cancer. We attempted to determine the effect and safety with the combination of paclitaxel with split cisplatin and 5-fluorouracil/leucovorin in advanced or metastatic gastric cancer. Patients with histologically-proven locally advanced/metastatic or recurrent gastric cancer with an ECOG performance status 0-2 were enrolled. The patients received 135 mg/m(2) of paclitaxel as a 3-h intravenous infusion on day 1 and 5-fluorouracil (1200 mg/m(2)) plus leucovorin (20 mg/m(2)) as an intravenous infusion over 12 h plus cisplatin (30 mg/m(2)) by continuous intravenous infusion on days 1-3, every 21 days. Between September 2003 and April 2005, 30 patients (26 evaluable patients) with a median age of 57 years (range 34-74) were enrolled and underwent 111 completed treatment cycles (a median of 3 cycles per patient). Of the evaluable patients, 12 patients showed a partial response and 8 patients had stable disease. The overall response rate was 46.2%. The median progression-free survival was 5.6 months (95% CI. 3.76-7.4 months), and the median overall survival was 9.6 months (95% CI. 6.67-12.47 months). The hematologic and non-hematologic toxicities were tolerable. The grade III and IV hematologic toxicities were anemia (6.8%) and neutropenia (2.6%). Febrile neutropenia was observed in 1 patients and 1 cycle. Other hematologic toxicities and grade III and IV non-hematologic toxicities, except nausea (66.7%) and vomiting (33.3%) were uncommon and not severe. TPFL combination chemotherapy is effective and tolerable with acceptable toxicities in patients with advanced/metastatic, recurrent gastric cancer.

We performed a retrospective study to evaluate the efficacy of cetuximab plus chemotherapy in metastatic gastric cancer (MGC) patients previously treated with chemotherapy and to investigate potential predictors of treatment efficacy in those patients. Thirty-two patients with MGC were included in this study. Cetuximab was delivered, often combined with irinotecan-based chemotherapy. Thirty patients were analyzed for K-ras mutations via direct sequencing of the tumor DNA. Patients were heavily pretreated with a median number of three previous lines of palliative chemotherapy (56% of the patients were refractory to all of the following drugs: fluoropyrimidines, cisplatin, irinotecan, oxaliplatin, and docetaxel) and 53% of the patients displayed poor performance status. Of 28 response-assessable patients, the overall response rate to cetuximab plus chemotherapy was 3.6% [95% confidence interval (CI) 0–10.5%] and the disease control rate was 28.6%. The median progression-free survival (PFS) was 1.7 months (95% CI 1.3–2.1 months), and the median overall survival (OS) was 3.2 months (95% CI 1.4–5.0 months). Multivariate analyses revealed that skin rash and performance status were significantly associated with PFS and OS. The presence of a K-ras mutation (13.3%) was not associated with either PFS or OS. Our study suggests that MGC patients with good performance status and skin rash benefit most from salvage cetuximab combined with chemotherapy, even in heavily pretreated status.

TPS4138 Background: Paclitaxel is an antineoplastic agent widely used for treating cancer patients. However, only IV paclitaxel is available on the market. DHP107, a novel oral formulation, is comp...

Intracardiac metastasis as the initial presentation of malignant neoplasm is very rare. We report here on a 64-year-old man with non-small cell lung cancer (NSCLC) initially presenting with intracardiac metastasis which was identified with 18-F fluorodeoxyglucose positron emission tomography (FDG PET). The patient was admitted with complaints of exertional dyspnea and vague chest discomfort that had developed a few weeks ago. Two-dimensional echocardiography revealed a heart mass attached to its akinetic wall in the right ventricular chamber. CT and MRI demonstrated a large tumor involving the epicardium and myocardium in the right ventricle, and there was a mass in the right lower lobe of the lung along with multiple lymphadenopathies. Cytologic examination of the percutaneous needle aspiration of a lymph node in the anterior mediastinum revealed malignant epithelial cell nests, and this was strongly suggestive of squamous cell carcinoma. Subsequent FDG PET confirmed that the intracardiac mass had an abnormally increased FDG uptake, and again this was strongly suggestive of malignancy. By systemically considering these imaging studies, we were able to diagnose the mass as intracardiac metastasis of NSCLC.

The authors report the case of a 24-year-old man who presented with a solitary dural extramedullary plasmacytoma (EMP) with inv(9)(p13q21). Chromosome 9 aberrations may be associated with the pathogenesis. This is the first reported case of solitary dural EMP associated with inv(9)(p13q21).

Purpose To evaluate the efficacy, safety, and pharmacokinetics of multiple doses of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma (RCC). Patients and Methods Patients (n = 111) were randomly assigned to receive 25, 75, or 250 mg CCI-779 weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, survival, and adverse events. Blood samples were collected to determine CCI-779 pharmacokinetics. Results CCI-779 produced an objective response rate of 7% (one complete response and seven partial responses) and minor responses in 26% of these advanced RCC patients. Median time to tumor progression was 5.8 months and median survival was 15.0 months. The most frequently occurring CCI-779–related adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level. Patients were retrospectively classified into good-, intermediate-, or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa. Within each risk group, the median survivals of patients at each dose level were similar. Conclusion In patients with advanced RCC, CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested.