Gastrointestinal Cancers: June 16, 2010

Gastrointestinal Cancers

ASCO Symposium Presents Latest Research of Gastrointestinal Malignancies

The 5th Annual Gastrointestinal (GI) Cancers Symposium was held in January in Orlando, Florida. The event was cosponsored by the American Society of Clinical Oncology (ASCO), the American Gastroenterological Association (AGA) Institute, the Society of Surgical Oncology (SSO), and the American Society for Therapeutic Radiology and Oncology (ASTRO).

The symposium served as an opportunity for researchers to discuss the newest strategies related to the prevention, screening, and treatment of GI cancers. Educational sessions and abstract presentations focused on each type of GI cancer, including cancers of the esophagus, stomach, hepatobiliary tree, pancreas, small bowel, colon, and rectum. Key presentations are summarized below.

â–º Colon and Rectum

Capecitabine Versus 5-Fluorouracil/Leukovorin in Stage III Colon Cancer: Updated Five-Year Efficacy Data From the X-ACT

Chris Twelves, MD, University of Leeds and St. James Hospital, Leeds, United Kingdom (UK) and Beatson Oncology Centre, Glasgow, UK, presented Five-year follow-up overall survival (OS) data from the X-ACT (Xeloda in Adjuvant Colon Cancer Trial). These data showed that oral capecitabine (Xeloda) is as effective as the current standard treatment—intravenous bolus 5-fluorouracil/leucovorin (5-FU/ LV)—in the adjuvant treatment of Dukes’ C colon cancer.

The international, phase III X-ACT enrolled 1,987 patients, 1,004 of whom were randomized to receive capecitabine and 983 of whom were randomized to receive 5-FU/LV. Study enrollees were treated for a period of 24 weeks between 1998 and 2001 at 164 centers worldwide. The primary objective of the study was to show equivalence in disease-free survival (DFS) between oral capecitabine and intravenous 5-FU/LV. Secondary objectives included relapse-free survival (RFS), OS, and safety.

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Results show Five-year OS rates for capecitabine at 71.4%, compared with 68.4% in the 5-FU/LV arm ( = 0.06). Additional data presented at the meeting from a previous analysis showed that capecitabine is also comparable to 5-FU/LV with regard to DFS and RFS.

Capecitabine caused significantly less toxicity than 5-FU/LV, with the exception of hand—foot syndrome (HFS). Survival subanalysis was performed in a sample of 995 patients, 614 with Grade 1–3 HFS and 382 with no HFS. Five-year OS was 73.8% and 66.3% in the groups with and without HFS, respectively.

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Dr. Twelves concluded his presentation by stating the X-ACT demonstrated that oral capecitabine is an effective alternative to 5-FU/LV as adjuvant treatment for stage III colon cancer. This update shows that capecitabine is at least equivalent to 5-FU/LV, with a trend toward superiority ( = 0.06) for Five-year OS. The HFS subanalysis findings also suggest that it is important to individualize capecitabine dosing.

Capecitabine is the only FDA-approved oral chemotherapy for both metastatic breast cancer and adjuvant and metastatic colorectal cancer. Although inactive in pill form, capecitabine is enzymatically activated within the body; when it comes into contact with thymidine phosphorylase— a naturally occurring protein—it is transformed into 5-FU. Since many tumors have greater levels of thymidine phosphorylase than normal tissue, more 5-FU is delivered to the tumor than to other tissues.

Updated Analysis of Safety and Efficacy of Oxaliplatin/Bevacizumab With or Without Panitumumab for First-Line Treatment of Metastatic Colorectal Cancer

Joel R. Hecht, MD, University of California School of Medicine, Los Angeles, California presented the results of the randomized, controlled PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial, which was performed to evaluate the benefit of adding panitumumab (Vectibix) to either oxaliplatin/bevacizumab-based (e.g., FOLFOX) or irinotecan/bevacizumab-based (e.g., FOLFIRI) chemotherapy as first-line therapy for patients with metastatic colorectal cancer.

Previously, panitumumab treatment, in this study was discontinued. A decision based on a preliminary review of data from a preplanned interim efficacy analysis scheduled after the first 231 events (death or disease progression). This analysis revealed a statistically significant difference in progres- sion-free survival (PFS) in favor of the control arm. An unplanned analysis of overall survival (OS) also demonstrated a statistically significant difference favoring the control arm.

Dr. Hecht presented updated results from the PACCE trial. A total of 823 patients were randomized to receive either oxaliplatin/bevacizumab/ panitumumab (N = 413) or oxaliplatin/bevacizumab (N = 410). At data cutoff, 94% of patients had ended first-line treatment. Median follow-up was 12.2 months. Baseline demographic and disease characteristics were generally well balanced between the two groups. Median PFS in the oxaliplatin/bevacizumab/ panitumumab and oxaliplatin/bevacizumab arms was 9.5 months and 11.0 months, respectively. Median OS in these two groups was 19.3 months and 20.6 months, respectively.

Grade 3/4 adverse events in the oxaliplatin/ bevacizumab/panitumumab and oxaliplatin/bevacizumab groups, respectively, included diarrhea (24% vs. 13%), infections (19% vs. 10%), dehydration (18% vs. 6%), skin toxicity (39% vs. 2%), hypokalemia (10% vs. 4%), and pulmonary embolism (6% vs. 4%). Panitumumab-treated patients with poorer ECOG performance status and elderly age (>80 years) appeared to have less favorable outcomes.

Based on these results, the investigators of the trial concluded that oxaliplatin/bevacizumab/panitumumab was associated with shorter PFS and increased toxicity, indicating that this combination has an unfavorable benefit:risk profile in unselected patients with metastatic colorectal carcinoma. Further data collection and analyses are ongoing.

Phase III Trial of Chemotherapy With or Without Irinotecan in the Front-Line Treatment of Metastatic Colorectal Cancer in Elderly Patients

Emmanuel Mitry, MD, Service d’hépatogastro-entérologie et oncologie digestive; Hôpital Ambroise-Paré, Boulogne, France, presented the results of an interim analysis of the phase III Fédération Francophone de Cancérologie Digestive (FFCD) 2001—02 trial. This trial evaluated 5-FU–based chemotherapy, either alone (LV5-FU2 or simplified LV5-FU2) or in combination with irinotecan (Camptosar) (LV5-FU2-CPT11 or FOLFIRI), in elderly patients (≥75 yr) with previously untreated metastatic colorectal cancer.

The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival, safety, tumor response, quality of life, and geriatric evaluation. Between June 2003 and August 2007, 196 patients were randomized. Data from 142 patients (median age, 79.5 yr) with at least eight weeks of follow-up were included in the interim analysis. Overall response was 31% in the group receiving 5-FU plus irinotecan, compared with 18% in the group receiving 5-FU alone. Grade 3/4 neutropenia occurred in 28% of patients receiving 5-FU plus irinotecan, compared with 1% in those receiving 5-FU alone. Grade 3/4 febrile neutropenia occurred in 9% and 0% of patients in these groups, respectively.

Based on these interim results, the investigators concluded that patients aged ≥75 years can be treated with standard CT regimens with manageable toxicity. Dr. Mitry suggested that a phase III trial specific to patients with metastatic colorectal cancer is feasible, and should be considered.

â–º Esophagus and Stomach

Randomized, Phase III Study of Irinotecan Plus S-1 (IRIS) Versus S-1 Alone as First-Line Treatment of Advanced Gastric Cancer

Irinotecan (Campto) is active as a single agent and in combination with S-1, an oral fluoropyrimidine, in phase I/II studies for advanced gastric cancer.

Hiroshi Imamura, MD, PhD, Department of Surgery, Sakai Municipal Hospital, Osaka, Japan, presented the results of a phase III trial of irinotecan plus S-1 (IRIS) vs S-1 alone as first-line treatment for advanced gastric cancer.

Patients with previously untreated gastric cancer were randomized to one of two study arms: Arm A (oral S-1 80 mg/m²/ day from day 1 to 28, followed by a 14-day rest period) or Arm B (oral S-1 80 mg/m²/ day from day 1 to 21 and intravenous irinotecan 80 mg/ m² on days 1 and 15, followed by a 14-day rest). Treatment was continued unless disease progression was observed. The primary endpoint was overall survival (OS).

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A total of 326 patients were randomized— 162 to arm A and 164 to arm B. Median age of enrollees was 63 years. There were 315 evaluable patients for median survival time (160 in Arm A and 155 in Arm B). Median survival time in Arms A and B were 318 days and 389 days, respectively ( = 0.023). Among 187 patients evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), one-year survival was 44.9% in Arm A and 52.0% in Arm B ( = 0.035).

Grade 3/4 toxicities in Arm A and Arm B, respectively, included neutropenia (10.6% vs. 27.1%), diarrhea (5.6% vs. 16.1%), anorexia (18.8% vs. 17.4%), nausea (5.6% vs. 7.1%), and vomiting (1.9% vs. 3.2%).

Dr. Imamura and his team concluded that additional follow-up is needed to confirm the OS benefit of IRIS as a first-line treatment for advanced gastric cancer.

Final Results of a Phase II Trial of Docetaxel/Caarboplatin/5-FU in Locally Advanced Gastric Carcinoma

Yasser M. Elkerm, MD, Department of Clinical Oncology, Medical Research Institute, Alexandria University, Alexandria, Egypt, presented final results of a phase II study comparing the efficacy and tolerability of docetaxel, 5-fluorouracil (5-FU), and carboplatin (DF-Carbo) with that of a reference protocol of epirubicin, cisplatin, and 5-FU (ECF).

A total of 64 patients with previously untreated metastatic adenocarcinoma of the stomach were enrolled and assessed for toxicity, tumor response, progression-free survival (PFS) and overall survival (OS). DF-Carbo (docetaxel 75 mg/m² on day 1, carboplatin AUC=6 on day 2, and continuous infusion 5-FU 1,200 mg/m² per day on days 1—3) every three weeks. Of the 64 enrollees, 30 were randomized to receive DF-Carbo and 34 to ECF. Granulocyte-colony stimulating factor (G-CSF) 5 μg/kg SC was also given to all patients on days 4 through 9.

The overall response rate was 47.1% with ECF and 66.7% with DF-Carbo. The median survival was 8.7 months with ECF and 12.4 months with DF-Carbo (P = 0.0005). The two-year survival rates were 14% for the ECF arm and 20% for the DF-Carbo arm (P = 0.03). Historically complete surgical resection following chemotherapy was achieved in two patients in the ECF arm (pathological complete responses to chemotherapy) and five patients in the DF-Carbo arm.

Dr. Elkerm stated that the DF-Carbo regimen resulted in a response and survival advantage compared with ECF chemotherapy. He added that the probability of long-term survival following surgical resection of residual disease is increased by DF-Carbo treatment.

The high response rates seen with the DFCarbo regimen support its use in the adjuvant as well as neoadjuvant settings in patients with locally advanced gastric cancer.

Efficacy of Adjuvant Imatinib Mesylate Following Complete Resection of Localized, Primary Gastrointestinal Stromal Tumor in Patients at High Risk of Recurrence

Prior to the availability of tyrosine kinase inhibitors, patients with high-risk primary gastrointestinal stromal tumor (GIST) had a two-year overall survival (OS) of roughly 50%. Imatinib mesylate (Gleevec) is known to provide clinical benefit in more than 80% of patients with metastatic GIST.

Ronald P. DeMatteo, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York City, and colleagues performed a multicenter, single-arm, open label, phase II study to evaluate the effectiveness of imatinib in the adjuvant setting following resection of localized, primary GIST.

Patients underwent complete gross resection of a kit-expressing primary GIST that was at high risk of recurrence (tumor size >10 cm, tumor rupture, or <5 peritoneal metastases). Histology was confirmed prospectively by a central pathologist. Imatinib was prescribed at a daily dose of 400 mg for one year. The primary endpoint was OS.

One hundred seven evaluable patients were enrolled. Imatinib was initiated at a median of 59 days after operation (range, 25 to 84 days). Median age of enrollees was 58 years (range, 19 to 79 yr). The median tumor size was 13 cm (range, 3 to 42 cm). Half of the tumors originated from the stomach and 42% arose in the small intestine.

At a median follow-up of four years, the 1-, 2-, and 3-year OS rates were 99%, 97%, and 97%, respectively. The 1-, 2-, and 3-year recurrence- free survival (RFS) rates were 94%, 73%, and 61%, respectively. Imatinib therapy was well tolerated.

The investigators concluded that imatinib given at a daily oral dose of 400 mg for one year following the resection of a high-risk primary GIST prolongs RFS and is associated with improved OS compared with historical controls.

Safety and Efficacy of Sunitinib in a Worldwide Treatment-Use Trial of Patients with Gastrointestinal Stromal Tumor: Interim Results of an Open-Label Study

Jeffrey A. Morgan, MD, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts presented interim results of a worldwide, open-label, treatment-use study of sunitinib for the treatment of imatinib-resistant or -intolerant gastrointestinal stromal tumor (GIST). Sunitinib 50 mg/day is administered in six-week cycles (4 wk on treatment, 2 wk off). Assessment parameters include safety, antitumor response (as per local standard of care), time to progression (TTP), and overall survival (OS).

The primary objectives of this ongoing study are to grant access to sunitinib to patients who are ineligible to participate in sunitinib clinical trials, or who live in countries where sunitinib is pending regulatory approval, and to obtain safety and efficacy data from a large, broad population.

Dr. Morgan reported that as of April 2007, 1,097 patients had been enrolled in the trial, and 1,091 had received at least one dose of sunitinib. Patients started a median of four treatment cycles (range, 1 to 23 cycles), with a median follow-up of 261 days (range, 1 to 872 days). Dose reductions occurred in 39% of patients. Dose interruptions—79% of which were caused by adverse events (AEs)&mdash; occurred in 57% of patients.

The most common all-causality AEs were fatigue (48%), diarrhea (45%), and nausea (35%). The most common grade >3 AEs were fatigue (10%), abdominal pain (10%), and hand—foot syndrome (9.2%). Grade >3 hematologic AEs included anemia (8%), neutropenia (8%), and thrombocytopenia (5%). Hypothyroidism occurred in 7% of patients. Elevated creatinine levels (predominantly Grade 1-2) were noted in 23% of patients. Congestive heart failure was reported in <5% of patients. At data cutoff, 697 patients (64%) were still alive.

Median TTP was 37 weeks. Median estimated OS was 73 weeks.

Dr. Morgan and his team of researchers concluded that sunitinib was generally well tolerated in patients with imatinib-resistant or -intolerant, advanced GIST who were ineligible for other sunitinib trials. The safety profile was considered consistent with that observed with sunitinib in other GIST trials. Sunitinib was considered an effective treatment in this population, corroborating the results of previous studies.

Correlation of Imatinib Plasma Levels With Clinical Benefit in Patients with Unresectable or Metastatic Gastrointestinal Stromal Tumor

George G. Demetri, MD, Ludwig Center at Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, reported that in a randomized, phase II study, 147 patients with unresectable or metastatic GIST were randomized 1:1 to imatinib (Gleevec) 400 or 600 mg daily. Fifty-two percent of patients now survive for >5 years, regardless of initial imatinib dose.

Dr. Demetri presented the results of a pharmacodynamic subanalysis of imatinib that demonstrates the correlation of imatinib levels with clinical response.

Imatinib plasma levels were analyzed in a subset of patients for whom pharmacokinetic data at steady state (day 29) were available. Data from 73 patients, 34 of whom received imatinib 400 mg and 39 of whom received imatinib 600 mg, were analyzed and grouped into quartiles according to imatinib trough plasma concentrations (TPC) (Q1: C_min <1,110 ng/mL; Q2+Q3: C_min >1,110 to <2,040 ng/mL; Q4: C_min >2,040 ng/mL) for correlation with clinical outcomes. Correlation was tested between imatinib TPC quartiles and overall response (OR), time to progression (TTP), overall survival (OS), and kit mutations. OR was defined as complete response (CR) plus partial response (PR).

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Of the 73 patients, 21 (28.8%) remain on study at five years. OR was achieved by eight of 18 patients in Q1 (44%), compared with 24 of 36 (67%) and 14 of 19 (74%) of those in Q2-Q3 and Q4, respectively (P = 0.15 for all groups; P = 0.060 for Q1 vs Q2-Q4). Inclusion of stable disease (SD) in the responder group (CR+PR+SD) did not affect the correlation with imatinib TPC. However, differences in OR between Q1 versus Q2-Q4 were significant for 39 patients with exon-11 kit mutations— 55.6% for Q1 versus 94.1% and 92.3% for Q2-Q3 and Q4, respectively ( = 0.022 for all groups; = 0.006 for Q1 versus Q2-Q4). Exon-9 kit mutation was found in 12 patients with TPC data, thereby limiting the power of any correlative analyses in this subset. Median TTP was 11.3 months for patients in Q1, 30.6 months for those in Q2-Q3, and 33.1 months for those in Q4 ( = 0.011 overall; = 0.0029 for Q1 versus Q2-Q4). No significant difference in median OS was identified between quartiles.

The imatinib plasma AUC, peak concentration, and TPC were highly correlated, with imatinib TPC showing the best correlation with response.

The investigators concluded that exposure to adequate drug levels of imatinib appears to correlate with clinical benefit. Patients with the lowest imatinib levels show the lowest OR and shortest TTP. Dr. Demetri noted that these results suggest that monitoring pharmacokinetic/pharmacodynamic relationships may provide novel predictive markers and that exposure to adequate imatinib TPC (>1,110 ng/mL) is important for optimal clinical response.

â–º Pancreas, Small Bowel, and Hepatobiliary Tree

Final Results From a Phase II, Randomized, Double-Blind Study of Sorafenib Plus Doxorubicin Versus Placebo Plus Doxorubicin in Patients With Advanced Hepatocellular Carcinoma

Ghassan K. Abou-Alfa, MD, Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, presented final results from a phase II, randomized, double-blind study conducted to assess the relative efficacy and safety of sorafenib (Nexavar) plus doxorubicin (SD) versus placebo plus doxorubicin (PD) in patients with advanced hepatocellular carcinoma (HCC) and no prior systemic therapy.

Patients received doxorubicin 60 mg/m² intravenously every 21 days plus either sorafenib 400 mg orally twice daily or placebo, for a maximum of six cycles (18 weeks) of doxorubicin. Patients could continue on single-agent sorafenib or placebo beyond 18 weeks until disease progression. The primary efficacy endpoint was time to progression (TTP) by independent review.

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Ninety-six patients were randomized (S+D, = 47; P+D, = 49); 76% were male, 91% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and the median age of enrollees was 65 years. Baseline patient characteristics were balanced between treatment arms.

Median TTP was 8.6 months and 4.8 months in the SD and PD groups, respectively. Median overall survival (OS) in these groups was 13.7 months and 6.5 months, respectively, and median progression-free survival was 6.9 months and 2.8 months, respectively. The TTP and OS of the PD arm fell within the range of historically reported data for doxorubicin alone.

Grade 3/4 fatigue occurred in 15% of patients in each arm. Grade 3/4 neutropenia occurred in 53% of patients in the SD group and 46% of those in the PD group. Grade 2/3 left ventricular dysfunction was limited to one event on the SD arm.

This randomized phase II study of SD and PD showed encouraging TTP and OS outcomes for patients with advanced HCC treated with SD. Dr. Abou-Alfa stated that this trial supports the growing body of evidence of the activity of sorafenib in advanced HCC. He added that a possible synergistic role between sorafenib and doxorubicin needs to be further defined.

Subset Analysis of a Phase II Study of Sorafenib in Advanced Hepatocellular Carcinoma: Safety and Effectiveness in Patients With Child-Pugh A and Those With Child-Pugh B Cirrhosis

Sorafenib (Nexavar) is known to prolong overall survival (OS) and time to progression (TTP) in patients with hepatocellular carcinoma (HCC) and Child-Pugh A cirrhosis.

Dr. Abou-Alfa, detailed in the previous news item, presented the results of a subset analysis of patients with either Child-Pugh A (CPA) or B (CPB) cirrhosis enrolled in a phase II study evaluating the efficacy and safety of sorafenib.

The trial accrued 137 patients—98 with CPA cirrhosis, 38 with CPB cirrhosis, and one with cirrhosis of unknown Child-Pugh score. Enrollees received sorafenib 400 mg PO bid continuously. Blood samples from 28 patients (21 with CPA and 7 with CPB cirrhosis) were collected for pharmacokinetic analysis on day 1 of cycle 2 at 0.5, 1, 2, 4, 8, and 12 hours. Dr. Abou-Alfa and his colleagues analyzed toxicity and clinical outcomes data.

AUC_0—8 was comparable between patients with CPA (25.4 mg•h/L) and CPB (30.3 mg•h/L) cirrhosis. C_max (mg/L) was also comparable between these groups (4.9 mg/L and 6 mg/L, respectively). Stable disease for ≥4 months was noted in 49% of patients with CPA cirrhosis and 26% of those with CPB cirrhosis. Median TTP for patients with CPA cirrhosis was 21 weeks, compared with 13 weeks for those with CPB cirrhosis. OS for patients with CPA cirrhosis was 41 weeks, compared with 14 weeks for those with CPB cirrhosis.

Incidence rates for all adverse events (AEs) and serious AEs (52% vs. 68%) were similar in patients with CPA and those with CPB cirrhosis. Common sorafenib-related AEs in the CPA and CPB groups, respectively, included fatigue (41% vs. 37%), diarrhea (59 % vs. 47%), hand-foot skin reaction (30% vs.13%), and elevated serum bilirubin concentration (18% vs. 40%). Notably, the elevation of serum bilirubin concentration was not associated with worsening of aspartate transaminase, alanine transaminase, or alkaline phosphatase. However, patients with CPB cirrhosis had an increased rate of encephalopathy (11% vs 2%) and ascites (18% vs 11%).

Despite a shorter course of therapy for patients with CPB cirrhosis (12.9 wk) compared with those with CPA cirrhosis (24.9 wk), sorafenib discontinuation rates (21% and 31%, respectively) and dose reduction (21% and 31%, respectively) were similar.

Dr. Abou-Alfa and his colleagues concluded that patients with CPB cirrhosis and HCC did worse than those with CPA cirrhosis and HCC, and experienced more frequent worsening of their liver cirrhosis. (It was unclear whether the worsening of cirrhosis was drug-related or disease— related progression.) Dr. Abou-Alfa added that the elevated bilirubin concentrations may be related to the inhibition by sorafenib of UGT1A1 activity.

In this phase II study subanalysis, the pharmacokinetic profile of sorafenib and the incidence of known sorafenib-related toxicities were similar in patients with CPA cirrhosis and those with CPB cirrhosis. Dr. Abou-Alfa said that more data will be needed to confirm the safety and efficacy of sorafenib in patients with HCC and CPB cirrhosis.

Gemcitabine, Bevacizumab, and Erlotinib in Locally Advanced and Metastatic Adenocarcinoma of the Pancreas: Results of a Phase II Study

Lawrence S. Blaszkowsky, MD, Department of Medicine, Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts, presented the results of a phase II study evaluating the effectiveness and tolerability of combination therapy with gemcitabine (Gemzar), bevacizumab (Avastin), and erlotinib (Tarceva) in locally advanced and metastatic adenocarcinoma of the pancreas.

Dr. Blaszkowsky stated that the vast majority of previous clinical trials evaluating combination therapy for pancreatic cancer have yielded disappointing results. He noted that the addition of erlotinib to gemcitabine has resulted in a modest, yet statistically significant improvement in progression-free, overall, and one-year survival, without an improvement in response rate, while the addition of bevacizumab to gemcitabine has failed to prove beneficial.

In an attempt to capitalize on the lack of overlapping toxicities and potential enhancement of activity of epidermal growth factor receptor inhibitors as demonstrated in colorectal cancer, Dr. Blaszkowsky and his team of investigators initiated the current study to determine the safety and efficacy of adding bevacizumab to gemcitabine and erlotinib.

Twenty-four patients with locally advanced or metastatic adenocarcinoma of the pancreas who had adequate hepatic, renal, and hematopoietic function and ECOG performance status <1 were registered. Treatment consisted of gemcitabine 1,000 mg/m² intravenously (IV) on days 1, 8, and 15, erlotinib 100 mg orally on days 1—28, and bevacizumab 10 mg/kg IV on days 1 and 15, every 28 days. Tumor measurements were performed every eight weeks. Patients were assessed for radiologic response, time to tumor progression (TTP), median overall survival (MS), one-year survival, and toxicity.

Of 22 treated patients, three had locally advanced disease and 19 had metastatic disease. Response data were reported for 20 patients. There were four confirmed partial responses (20%), five unconfirmed partial responses (25%), 10 patients with stable disease (45%), and six with progressive disease (27%). Median TTP was 154 days. MS was 368 days. Grade 3—4 toxicities included neutropenia (6 patients; 27%), transaminitis (3 patients; 14%), acneform rash (2 patients; 9%), duodenal hemorrhage (1 patient; 4.5%), pulmonary embolism (1 patient; 4.5%), and an arterial event (1 patient; 4.5%).

The investigators of the study concluded that the combination of gemcitabine, erlotinib, and bevacizumab was well tolerated and showed modest activity in patients with locally advanced or metastatic pancreatic cancer.

Preoperative Gemcitabine Plus Bevacizumab-Based Chemoradiation for Resectable Adenocarcinoma of the Pancreas: Interim Analysis of a Phase II Study

More than 80% of patients who undergo potentially curative pancreaticoduodenectomy for pancreatic adenocarcinoma develop local or distant recurrence. Preoperative therapy maximizes the number of patients who receive multimodality therapy and have to undergo a historically complete resection.

Gauri R. Varadhachary, MD, Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX, presented the results of a prospective, phase I study evaluating the effectiveness and tolerability of preoperative gemcitabine (Gemzar) plus bevacizumab (Avastin)-based chemoradiation for resectable pancreatic adenocarcinoma.

A previous phase I study (conducted by the same team of researchers) using bevacizumab and capecitabine-based chemoradiation for locally advanced pancreatic adenocarcinoma showed that the combination was safe and well tolerated.

In this trial, patients with stage I/II adenocarcinoma of the pancreatic head or uncinate process received six weekly infusions of gemcitabine (400 mg/m²) and three infusions of bevacizumab (10 mg/ kg, every 2 wk) with concomitant radiation therapy (RT), 50.4 Gy at 1.8 Gy per fraction. Patients were restaged 4—6 weeks after the last dose of RT. Those without disease progression and with good performance status underwent surgery. Patients with adequate recuperation received bevacizumab (10 mg/kg) every two weeks for three months starting about six weeks after surgery.

Eleven patients (median age, 64 yr) have been enrolled to date. All completed chemoradiation, 10 underwent restaging, and one died from cardiac arrest before restaging. At restaging, one patient (10%) had distant metastases, and 9 (90%) underwent a successful pancreaticoduodenectomy. Pathologic partial response rate (>50% tumor kill) was 56%.

Preoperative grade 3-4 toxicities were infrequent and included stent-related cholangitis (1 patient), gastrointestinal toxicity (1 patient), neutropenia (4 patient), hypertension (1 patient), and pulmonary embolism (1 patient). Major postoperative complications occurred in five of the nine patients (56%) who underwent pancreaticoduodenectomy; they included wound dehiscence requiring reoperation (3 patients), large ventral hernia related to fascial dehiscence (1 patient), and biliary anastomotic leak (1 patient).

Interim analysis after accrual of 11 patients suggests that the rate of major postoperative complications— previously unforeseen&mdash;is significant. Dr. Varadhachary stated that the combined use of bevacizumab and radiation may have contributed to poor wound healing, causing fascial dehiscence. He added that optimal use of antivascular endothelial growth factor therapy in the preoperative setting requires further study.

â–º Breast CancerSeparate Studies Highlight Efficacy of Ixabepilone (Ixempra) in Patients with Anthracycline- and Taxane-Resistant HER2-Negative Breast Cancer and in Those With HER2-Positive Metastatic Breast Cancer

Ixabepilone, a novel epothilone that was developed to have less susceptibility to tumor-resistance mechanisms, has demonstrated activity in phase II studies of anthracycline- and taxane-pretreated metastatic breast cancer, including estrogen receptor (ER)/progesterone receptor (PR)/HER2-negative disease. Ixabepilone binds to β-tubulin, and also shows activity in paclitaxel-resistant cell lines and patients with taxane-refractory, HER2-positive metastatic breast cancer.

In a poster session, Hope S. Rugo, MD, Breast Oncology Clinical Trials Program, Comprehensive Cancer Center, University of California at San Francisco, presented the results of a sub-analysis of data from a phase III trial of patients with anthracycline/taxane-resistant metastatic breast cancer. Ixabepilone, 40 mg/m2 IV over 3h q3wk, in combination with capecitabine, 2,000 mg/m² PO d1 14 q3wk, was compared with capecitabine alone, 2,500 mg/m² on the same schedule. Progression-free survival (PFS) and overall response rate (ORR) were prospectively analyzed for the ER/PR/ HER2-negative subgroup (25% of patients) and compared with the group as a whole.

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The combination of ixabepilone with capecitabine prolonged PFS and improved ORR, compared with capecitabine monotherapy in patients with ER/PR/HER2-negative metastatic breast cancer, as well as in the total population ( = 0.0003 for all patients). Grade 3/4 treatment-related adverse events for the total population in the combination arm were: sensory neuropathy (21%), fatigue (9%), and neutropenia (68%). The investigators concluded that ixabepilone plus capecitabine was superior to capecitabine alone in anthracycline/taxane-resistant metastatic breast cancer, and a similar result was evident in patients with ER/PR/HER2-negative tumors. They suggested that the combination of ixabepilone and capecitabine may offer a specific advantage in this subset of breast cancer and should be further explored in the less heavily pretreated population.

In a separate poster session, Stacy Moulder, MD, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, presented the results of an Eastern Oncology Cooperative Group (ECOG) phase II trial of trastuzumab, weekly ixabepilone, and carboplatin in patients with HER2/neu-positive (HER2-positive) metastatic breast cancer.

Patients with HER2-positive metastatic breast cancer, no prior chemotherapy regimens for metastatic breast cancer, ECOG performance status of 0-1, and left-ventricular ejection fraction of 50% or more were treated with ixabepilone (15 mg/m² IV) and carboplatin (AUC = 2 IV) on days 1, 8, and 15 of a 28-day cycle for a maximum of six cycles. Trastuzumab was administered weekly (4 mg/kg loading dose, then 2 mg/kg IV) during chemotherapy, then every three weeks (6 mg/kg IV) until disease progression. Response was measured using Response Evaluation Criteria in Solid Tumors (RECIST) every three months.

Fifty-nine eligible patients were enrolled. Median age was 50 years. Slightly more than one-half (54%) were ER-negative. Of the 57 patients evaluated for response, two (3.5%) had a complete response, 22 (38.65) had a partial response, and 13 (22.8%) had stable disease for six months or more. Median PFS was eight months. Grade 3/4 toxicities included anemia, neutropenia, thrombocytopenia, non-neutropenic infection, fatigue, nausea, and neuropathy. One patient died of therapy-related complications during cycle 1 of treatment; this was the only case of fever/ infection with neutropenia reported. The median number of cycles administered was six (range, 1—22). Common reasons for discontinuation were progression of disease (65%) and toxicity (12%).

The investigators concluded that ixabepilone, carboplatin, and trastuzumab combination is an active regimen with an acceptable toxicity profile for the treatment of patients with HER2-positive metastatic breast cancer. Collectively, these studies highlight the clinical utility and versatility of ixabepilone in the treatment of breast cancer.