Manish A. Shah

Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

PURPOSE The Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized, placebo-controlled trial designed to evaluate the efficacy of adding bevacizumab to capecitabine-cisplatin in the first-line treatment of advanced gastric cancer. PATIENTS AND METHODS Patients received bevacizumab 7.5 mg/kg or placebo followed by cisplatin 80 mg/m(2) on day 1 plus capecitabine 1,000 mg/m(2) twice daily for 14 days every 3 weeks. Fluorouracil was permitted in patients unable to take oral medications. Cisplatin was given for six cycles; capecitabine and bevacizumab were administered until disease progression or unacceptable toxicity. The primary end point was overall survival (OS). Log-rank test was used to test the OS difference. RESULTS In all, 774 patients were enrolled; 387 were assigned to each treatment group (intention-to-treat population), and 517 deaths were observed. Median OS was 12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo plus fluoropyrimidine-cisplatin (hazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002). Both median progression-free survival (6.7 v 5.3 months; hazard ratio, 0.80; 95% CI, 0.68 to 0.93; P = .0037) and overall response rate (46.0% v 37.4%; P = .0315) were significantly improved with bevacizumab versus placebo. Preplanned subgroup analyses revealed regional differences in efficacy outcomes. The most common grade 3 to 5 adverse events were neutropenia (35%, bevacizumab plus fluoropyrimidine-cisplatin; 37%, placebo plus fluoropyrimidine-cisplatin), anemia (10% v 14%), and decreased appetite (8% v 11%). No new bevacizumab-related safety signals were identified. CONCLUSION Although AVAGAST did not reach its primary objective, adding bevacizumab to chemotherapy was associated with significant increases in progression-free survival and overall response rate in the first-line treatment of advanced gastric cancer.

Phase II Study of Modified Docetaxel, Cisplatin, and Fluorouracil With Bevacizumab in Patients With Metastatic Gastroesophageal Adenocarcinoma

PURPOSE To evaluate the safety and efficacy of a modified administration schedule of docetaxel, cisplatin, and fluorouracil (mDCF) with bevacizumab in patients with advanced gastroesophageal malignancies. PATIENTS AND METHODS Previously untreated patients with metastatic gastroesophageal adenocarcinoma received bevacizumab 10 mg/kg, docetaxel 40 mg/m², fluorouracil 400 mg/m², leucovorin 400 mg/m² on day 1, fluorouracil 1,000 mg/m²/d × 2 days intravenous continuous infusion beginning on day 1, and cisplatin 40 mg/m² on day 3. The primary objective was to improve 6-month progression-free survival (PFS) from 43% (historical DCF control) to 63% with the addition of bevacizumab. The target accrual was 44 patients to have 10% type I and II error rates. RESULTS In total, 44 eligible patients with cancer were enrolled from October 2006 to October 2008: 22 gastric, 20 gastroesophageal junction (GEJ), and two esophagus. In 39 patients with measurable disease, the confirmed response rate was 67% (95% CI, 50% to 81%). Six-month PFS was 79% (95% CI, 63% to 88%), and median PFS was 12 months (95% CI, 8.8 to 18.2 months). With 26-month follow-up, median overall survival (OS) was 16.8 months (95% CI, 12.1 to 26.1 months), and 2-year survival was 37%. Treatment-related grade 3 to 4 toxicity was as follows: neutropenia without fever (50%), fatigue (25%), venous thromboembolism (39%), and nausea, vomiting, mucositis, neuropathy, and febrile neutropenia less than 10% each. In subset analysis, diffuse gastric cancer had significantly worse PFS and OS, and the response rate in proximal/GEJ tumors was 85% (95% CI, 62% to 97%). CONCLUSION mDCF with bevacizumab appears tolerable and has notable patient outcomes in patients with advanced gastroesophageal adenocarcinoma. Six-month PFS was 79%, surpassing our predefined efficacy end point, and median and 2-year OS were 16.8 months and 37%, respectively.

Phase I Trial of the Cyclin-Dependent Kinase Inhibitor and Protein Kinase C Inhibitor 7-Hydroxystaurosporine in Combination With Fluorouracil in Patients With Advanced Solid Tumors

PURPOSE Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. PATIENTS AND METHODS FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m(2) over 72 hours in cycle 1 and 67.5 mg/m(2) over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. RESULTS We escalated the weekly FU dose to 2,600 mg/m(2) in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 micromol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. CONCLUSION The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m(2).

A Phase I Clinical Trial of the Sequential Combination of Irinotecan Followed by Flavopiridol

Purpose: Flavopiridol potently enhances the effect of irinotecan with cures in colorectal cancer xenografts, and is associated with modulation of several molecular targets, including p21, Differentiation-related gene 1 (Drg1), and p53. We initiated a phase I trial of the sequential combination of irinotecan followed by flavopiridol to determine the maximal tolerated dose of this combination therapy. Patients and Methods: Forty-five patients with advanced solid tumors were enrolled. Irinotecan was administered first (100 or 125 mg/m2) followed 7 hours later by escalating flavopiridol (10-70 mg/m2) given weekly over 1 hour for 4 of 6 weeks. At the maximal tolerated dose, the pharmacokinetic analysis was expanded and pre- and posttreatment tumor biopsies were done. Results: At irinotecan 100 mg/m2, dose-limiting diarrhea and myelosuppression were observed with flavopiridol 70 mg/m2. At irinotecan 125 mg/m2, we observed dose-limiting hyperbilirubinemia, fatigue, and myelosuppression at flavopiridol 60 mg/m2. Peak flavopiridol concentrations of ≥2 μmol/L were achieved above flavopiridol 50 mg/m2. No significant pharmacokinetic interactions with irinotecan were noted. Baseline serum bilirubin significantly predicted cycle 1 dose-limiting toxicity and neutropenia. We observed partial responses in three patients and prolonged stable disease (i.e., >6 months) in 36% of patients including adrenocortical cancer and hepatocellular cancer. Patients with wild-type p53 and either no change or low posttreatment biopsy p21 and a decrease in Drg1 expression showed stable or responsive disease to the combination therapy. Conclusions: The recommended phase II dose with irinotecan 100 mg/m2 is flavopiridol 60 mg/m2 and with irinotecan 125 mg/m2 is flavopiridol 50 mg/m2. Toxicity can be predicted by baseline bilirubin. Clinical activity is encouraging and may correlate to changes in p21 and Drg1 levels in patients with wild type p53 tumors following therapy.

Phase I Dose-Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced Solid Tumors

Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors. Experimental Design: Docetaxel at a fixed dose of 35 mg/m2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m2 in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle. Results: Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from 1.49 ± 0.69 μmol/L (flavopiridol 20 mg/m2) to 4.54 ± 0.08 μmol/L (flavopiridol 60 mg/m2) in cycle 1. Conclusions: Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer.

A phase 2 trial of erlotinib in patients with previously treated squamous cell and adenocarcinoma of the esophagus

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) have activity in solid tumors. The authors evaluated an oral EGFR TKI, erlotinib, in patients with previously treated esophageal cancer.

Gastric Cancer—An Enigmatic and Heterogeneous Disease

GASTRIC CANCER IS A COMPLEX AND ENIGMATIC disorder noted for marked global variations in etiology, incidence, natural course, and management. Many factors likely lead to and discriminate among biologically and clinically relevant gastric cancer subsets: antecedent tumorigenic conditions (Helicobacter pylori gastritis, CDH1 mutation, and other chronic gastric disorders), location of the primary tumor (proximal or distal), subtypes of adenocarcinoma (diffuse, intestinal, or mixed), ethnicity of the afflicted population (differing levels of susceptibility and aggressiveness of the tumors), and a predictive biomarker (ERBB2). In essence, gastric cancer is a heterogeneous condition that represents several diseases. Additional complexities are introduced by the prevailing therapeutic approaches that differ across the globe, including types and extent of resection, including endoscopic approaches, laparoscopic approaches, or open gastrectomy with varying extents of lymph nodal dissection, and types of adjunctive strategies, including perioperative chemotherapy, postoperative chemotherapy, and postoperative chemoradiation. In endemic areas, particularly in Japan, Korea, and China, localized gastric cancer (clinical stage T1a) is often treated by primary surgery that includes more extensive lymph nodal dissection, referred to as D2 dissection when level 2 lymph nodes are removed. However, in nonendemic areas, such as the United States, the extent of lymph node dissection is often suboptimal (referred to as D0 or D1 dissection). Are the outcomes in Asian patients different because of differences in tumor biology and patient genetics, differing therapeutic strategies, or both? Although adjunctive therapeutic strategies vary by region, each strategy has improved the cure rates compared with surgery alone by approximately 10%, and therefore, adjunctive therapies should be offered to all high-risk gastric cancer patients. In the West, most high-risk patients often receive postoperative chemoradiation or preoperative and postoperative chemotherapy, whereas in Japan, such patients receive adjuvant S-1 chemotherapy following a D2 dissection. The Japanese adjuvant strategy with S-1 appears appropriate for patients with gastric cancer in China and Korea because these tumors are biologically similar and the extent of surgery is similar. Whether the level 1 evidence established in Asia can be applied to Western patients is a quandary. Similarly, Asian gastric cancer experts have reservations regarding the level 1 evidence established in the West, primarily due to concerns related to suboptimal results and the extent of surgery. In this issue of JAMA, the GASTRIC (Global Advanced/ Adjuvant Stomach Tumor Research International Collaboration) Group reports findings from a patient-level metaanalysis of postoperative chemotherapy adjuvant trials. The investigators examined primary patient data from 60% of patients from randomized trials completed over a 30-year period to examine the role of adjuvant chemotherapy following gastric cancer resection. Collective analyses for overall survival and disease-free survival suggest a statistically significant benefit for patients who received chemotherapy after surgery compared with those who were only observed after surgery (hazard ratio, 0.82). The authors also analyzed data by region and type of chemotherapy (single agent vs combination), but the results were not consistent. This could be due to subgroups with small numbers of patients or other differences (eg, tumor biology combined with therapy variables). However, the authors suggest that singleagent adjuvant chemotherapy is justified as a control group (presumably for a future randomized trial). A number of caveats to their analysis and conclusions should be considered. Meta-analyses are considered hypothesis generating and are not performed to test a hypothesis or establish a standard of care. Moreover, the exploratory results reported by the GASTRIC group have the limitations inherent in post hoc subgroup analyses. The authors included trials conducted from the 1970s; trials that were underpowered; trials with flawed designs (some without stratifications or with unrealistic expectations); trials with various chemotherapy agents and combi-

Endoscopic Ultrasound Can Improve the Selection for Laparoscopy in Patients with Localized Gastric Cancer

BACKGROUND The majority of newly diagnosed patients with gastric cancer have disease that is not resectable because of local extension or metastatic (M1) disease. Laparoscopy is a recommended staging evaluation to identify occult peritoneal metastatic disease. We determined if endoscopic ultrasound (EUS) could improve the selection of patients for laparoscopy. STUDY DESIGN Gastric cancer patients being screened for a preoperative chemotherapy clinical trial were prospectively examined. Patients underwent standard preoperative assessment. Those without obvious metastatic disease were referred for EUS and laparoscopy. EUS divided patients into risk categories for metastatic disease: low risk (T1-2, N0) and high risk (T3-4, N+, or both). Laparoscopy categories were M1 and M0. The ability of EUS to predict subradiographic peritoneal metastatic disease was evaluated. RESULTS Ninety-four patients were studied. The majority were EUS high risk (72%). Occult metastatic disease was identified in 19 patients, 18 of whom had high-risk EUS stage. The yields of identifying M1 disease by laparoscopy in EUS high- and low-risk patients were 25% (95% CI, 15% to 37%) and 4% (95% CI, 0.1% to 20%), respectively. The negative predictive value of low-risk EUS for laparoscopy and pathologic M0 was 96% (exact 95% CI, 80% to 100%). CONCLUSIONS This study suggested that laparoscopy can be avoided in patients with EUS early-stage gastric cancer. Patients with more advanced disease are at higher risk of occult peritoneal disease and require laparoscopy. Validation with greater numbers is warranted, but, based on these data, we propose a new staging algorithm allowing EUS low-risk patients to proceed directly to resection.

Management of advanced gastric cancer

The management of advanced gastric cancer has only evolved a little over the last 15 years: platinum and fluoropyrimidine chemotherapy remains the backbone of therapy with ongoing debate as to the benefit of triplet therapy with either an anthracycline or taxane. Recently published trials of biological agents, in particular those targeting the Her2 receptor, have provided some signs of improvement. This article summarizes the relevant literature, discusses the role of these agents, as well as geographical variations in use, and provides recommendations regarding both ‘standard chemotherapy’ and the role of biological agents in advanced gastric cancer. Given the relative lack of progress for gastric cancer over the last 15 years, the focus for the next 5 years should be on an improved understanding of the molecular basis of gastric cancer, thus allowing rational integration of new molecular agents.

Human Epidermal Growth Factor Receptor 2 Testing in Gastroesophageal Cancer: Correlation Between Immunohistochemistry and Fluorescence In Situ Hybridization

CONTEXT Patients with advanced gastroesophageal cancer have poor survival with current therapy. Human epidermal growth factor receptor 2 (HER2) represents a promising therapeutic target, but the optimal HER2 testing strategy is not yet defined. OBJECTIVES To evaluate the concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) and to determine if the American Society of Clinical Oncology/College of American Pathologists HER2 scoring system is applicable to gastroesophageal carcinomas. DESIGN Formalin-fixed paraffin-embedded tumor samples from patients with advanced stage gastroesophageal cancer were tested by IHC and FISH and scored according to the American Society of Clinical Oncology/College of American Pathologists criteria for breast cancer. Concordance between IHC and FISH was evaluated. A subset of cases was subjected to array comparative genomic hybridization to verify the positive and negative HER2 results. RESULTS A total of 135 cases with paired IHC and FISH results were evaluated. The majority of samples (84%) were biopsies. HER2 amplification was detected in 20 tumors (15%). Using the American Society of Clinical Oncology/College of American Pathologists scoring system, IHC-FISH concordance was 97% for IHC 0, 93% for IHC 1+, and 100% for IHC 3+. Human epidermal growth factor receptor 2 positivity was strongly associated with tumor grade (moderately differentiated > poorly differentiated, P < .001) and histologic subtype (intestinal > diffuse, P  =  .007). Array comparative genomic hybridization analysis was successful in 31 tumors (14 FISH+ and 17 FISH-). Fluorescence in situ hybridization and array comparative genomic hybridization results were highly concordant in both HER2-positive and HER2-negative groups (93% and 100% concordance, respectively). CONCLUSIONS Human epidermal growth factor receptor 2 testing in gastroesophageal cancer can be performed using standard breast cancer procedures and the American Society of Clinical Oncology/College of American Pathologists scoring criteria. Although IHC 0 and IHC 3+ provide clear stratification, reliable separation of IHC 1+ and IHC 2+ may be difficult, especially in biopsy samples. The latter 2 groups are best referred to FISH for definitive classification.