Search tips
Search criteria 


Logo of jcoHomeThis ArticleSearchSubmitASCO JCO Homepage
J Clin Oncol. 2010 July 20; 28(21): 3491–3497.
Published online 2010 June 7. doi:  10.1200/JCO.2010.28.4075
PMCID: PMC2917213

Report of a Multicenter Phase II Trial Testing a Combination of Biweekly Bevacizumab and Daily Erlotinib in Patients With Unresectable Biliary Cancer: A Phase II Consortium Study



Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras.

Patients and Methods

Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction.


Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes.


Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.


Biliary tract carcinoma is a rare but highly lethal malignancy. Estimated incidence of bile duct and gallbladder cancer approached 10,000 cases in 2009, with nearly 3,400 estimated deaths.1 Median age at presentation is 65 years. Risk factors for gallbladder cancer include gallstones, choledochal cysts, porcelain gallbladder, and adenomatous gallbladder polyps, along with obesity and female sex. For bile duct cancer, cholelithiasis, choledochal cysts, primary sclerosing cholangitis, ulcerative colitis, and parasitic infections (Clonorchis sinensis, Opisthorcis viverrini) are the most often cited risk factors.2,3

Only one fourth to one third of patients are eligible for potentially curative surgery; even among patients treated surgically, relapse rates are high. If not resectable, median survival for biliary cancer is approximately 6 months.2,4

Data regarding chemotherapy are disappointing, but new combinations show promise. ABC-02, a randomized phase III study recently published by Valle et al,5 enrolled more than 300 patients and compared gemcitabine plus cisplatin with gemcitabine alone. The median overall survival (OS) and progression-free survival (PFS) were greater for gemcitabine plus cisplatin than for gemcitabine alone without significantly increased toxicity (OS: 11.7 v 8.2 months; log-rank P = .002; PFS: 8.5 v 6.5 months; log-rank P = .003).5 This drug combination set a new international standard of care for advanced biliary tract cancers.

Phase II trials showed activity among chemotherapeutic agents including gemcitabine, platinum analogs, and capecitabine.6,7 A phase II study by Knox et al8 demonstrated a response rate of 31% with gemcitabine plus capecitabine, and an additional 42% of patients had stable disease (SD). Other phase II studies explored the activity of biologic agents. Philip et al9 suggested a benefit from the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib (Tarceva, OSI-774; OSI Pharmaceuticals, Melville, NY), with 8% of patients (3 of 36) demonstrating a partial response (PR), 25% of patients (7 of 36) with no progression at 6 months, and minimal therapy-related toxicity. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin; Genentech, South San Francisco, CA) demonstrated efficacy in a number of other solid tumors, including colorectal cancer, renal cell cancer, non–small-cell lung cancer, and metastatic breast cancer.1013 VEGF has been identified as overexpressed in biliary tract cancers and has been suggested as a potential prognostic marker and therapeutic target.14,15 The combination of bevacizumab and erlotinib has been studied in phase I and II trials in metastatic breast, lung, and hepatocellular cancers; no pharmacokinetic interaction between the two agents was demonstrated.1619 In colorectal malignancies, the addition of anti-EGFR therapy with cetuximab to bevacizumab worsened outcomes of PFS and quality of life.20 In vitro and murine models have shown that EGFR agents downregulate VEGF production; the combination of bevacizumab and erlotinib may be synergistic in this regard.2124

This study reports the results of a multi-institution phase II trial of bevacizumab and erlotinib combination therapy for patients with advanced biliary cancers. The objectives were to determine response rate, time to progression (TTP), OS, and safety of this novel combination. Correlative analysis was performed to examine the effect of bevacizumab on VEGF levels and evaluate EGFR mutations/polymorphisms as predictors of response. Descriptive analysis of the correlates relative to antitumor effect was also explored.


Patients were eligible if they had histologically or cytologically confirmed cholangiocarcinoma or gallbladder carcinoma, either surgically unresectable or metastatic at time of diagnosis. Disease had to be measurable by computed tomography scan (≥ 1.0 cm by spiral computed tomography, ≥ 2.0 cm by conventional techniques), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST).25 No prior chemotherapy for advanced disease was allowed, but adjuvant/neoadjuvant therapy was allowed. Additional inclusion criteria included age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, estimated life expectancy of ≥ 3 months, absolute neutrophil count ≥ 1,500/μL, platelets ≥ 75,000/μL, total bilirubin < 2× upper limit of normal (ULN), serum AST ≤ 2.5× ULN, serum ALT ≤ 2.5× ULN, serum creatinine ≤ 2 mg/dL, serum albumin ≥ 2.5 g/dL, alkaline phosphatase ≤ 5× ULN, and 24-hour urine protein < 1,000 mg/24 hours if spot urine protein/creatinine ratio was abnormal. Use of anticoagulants for other conditions was allowed, provided the dose of anticoagulants was stable and the coagulation parameters were within acceptable limits. Written informed consent was obtained from each patient. The protocol and informed consent were reviewed by the Phase II Consortium and the institutional review board at each registering institution.

Exclusion criteria included ampulla of Vater tumors, prior chemotherapy or radiotherapy for biliary cancer, chemotherapy/radiotherapy within 4 weeks of enrollment (6 weeks for mitomycin or nitrosoureas), known sensitivity to investigated agents or components, nonhealing wounds, impairment of GI function that would alter the absorption of erlotinib, significant GI bleeding ≤ 3 months before registration, GI fistula/perforation in the previous ≤ 28 days, recent invasive procedure, history of other malignancy, evidence of CNS diseases/tumors, corneal abnormalities, and clinically significant cardiovascular disease. HIV patients on antiretroviral therapy, pregnant or breastfeeding women, or patients receiving CYP 3A4 inducers were also excluded.

Treatment Plan

Patients were treated on a 28-day cycle. Bevacizumab was administered intravenously at 5 mg/kg on days 1 and 15. Erlotinib was administered at 150 mg by mouth once daily on days 1 through 28. Treatment was continued until disease progression, unacceptable adverse events, withdrawal of patient consent, illness preventing additional administration of treatment, or a change in condition rendering the patient unacceptable for additional treatment in the investigator's judgment. Adverse events were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

Dose delays were allowed for adverse events in patients taking bevacizumab, but dose reductions were not allowed by the protocol. Doses were held for grade 3 infusion reactions, symptomatic hypertension, urine protein/creatinine ratio > 3.5, or grade 3 hemorrhage. For grades 1 to 3 infusion reactions, premedications were administered with the next dose, and the patient was closely monitored at the next administration. If venous thromboembolism occurred, bevacizumab was stopped until a stable anticoagulation regimen was administered. Bevacizumab was discontinued for any grade 4 adverse event.

Dose interruptions and reductions were allowed for erlotinib. Specifically, for grade 2 skin rashes, the dose was held until the rash resolved to grade 0 to 1; a dose reduction was not automatically mandated for the first grade 2 rash. Recurrent or intolerable grade 2 rashes required dose reduction by one level. Grade 3 rashes required dose reduction by one level, and the dose was held until resolution to grade 0 to 1. The first reduction was to 100 mg/d for adverse events, and a second reduction to 50 mg/d was allowed. If patients experienced additional toxicity at 50 mg/d, therapy was discontinued and the patient was taken off study.

Patients were given pill diaries for erlotinib and asked to bring the pill diary, their bottle, and any unused pills with them to each appointment, with a new diary given with each new cycle of therapy. The patients were instructed to take the medication on an empty stomach, either 1 or 2 hours before a meal. Missed doses were allowed to be taken up to 12 hours late, and patients were instructed not to double dose for missed doses.

Disease Assessment

All eligible patients who initiated treatment and had at least one post-baseline disease assessment were evaluable for the primary end point. Tumor response was assessed using RECIST, with re-evaluation every 8 weeks.25 Patients were re-evaluated for disease status 4 weeks after initial documentation of complete response (CR) or PR to confirm the assessment. Similarly, SD was reassessed at a minimum interval of 8 weeks. Patients with global deterioration of health status that required discontinuation of treatment without objective evidence of disease progression at that time and that was not related to study treatment or other medical conditions were considered to have progressive disease (PD) due to symptomatic deterioration. For the primary end point of the study, a confirmed tumor response was defined to be either a CR or PR on two consecutive evaluations at least 4 weeks apart during the first six cycles of treatment.

Duration of response was calculated from the first date of a patient's objective status of either CR or PR to the date of PD (or last tumor assessment). Duration of SD was calculated from the date of registration to the date of PD (or last tumor assessment if no PD) for patients having achieved a best response of SD. Patients were censored for progression (survival) at their date of last assessment (last contact) if no progression (death) occurred. Time to PD was calculated from the date of registration to the date of PD. Survival or time to death was calculated from the date of registration to the date of death. All patients were followed for a maximum of death or 3 years after registration, whichever was earlier.

Molecular Analyses

Laboratory measures included the presence of EGFR mutations in tumor tissue and measurement of VEGF serum levels. Analyses were performed on all evaluable samples. For analysis of the EGFR mutation, cells were prepared by laser capture microdissection and polymerase chain reaction size exclusion or pyrosequencing. Deletions in exon 1 (EGFR variant vIII) 2235 to 2249, 2240 to 2251, and 2240 to 2257 were analyzed by amplifying the exon containing the deletion and running the polymerase chain reaction product by capillary electrophoresis. VEGF levels were measured by a commercially available sandwich immunoassay (Quantikine human VEGF; R&D Systems, Minneapolis, MN).

Statistical Design

A two-stage Fleming phase II design, with no suspension for interim analysis, was used to test whether there was sufficient evidence to determine that the proportion of confirmed tumor responses was at least 25% (ie, warranted additional study) versus 10% (ie, clinically inactive).26 Eligible patients were considered evaluable for the primary end point if they had at least one postbaseline disease assessment. Patients having died or progressed before their first postbaseline assessment were still considered evaluable for the primary end point. Three confirmed responses in the initial 21 evaluable patients warranted the expansion of enrollment to 50 patients. Nine confirmed responses among 50 evaluable patients was considered sufficient evidence of promising activity to recommend additional testing of this regimen. This design yielded 85% power at 0.04 level of significance to detect a true response rate of 25%. CIs were calculated using the method of Duffy and Santner.27 Unless otherwise specified, analyses were conducted per protocol.

Summary statistics and frequency tables were used to summarize baseline patient characteristics and adverse event rates. Adverse events were reported as a maximum severity per patient and type across all cycles of treatment. All attributions collected for adverse events were reported unless otherwise noted. The Kaplan-Meier method was used to estimate the distributions of TTP and time to death. All analyses were conducted using SAS version 9.0 (SAS Institute, Cary, NC).28 Cox proportional hazard models were used to evaluate associations with tumor progression and survival.29 Nonparametric tests were used when the underlying distributional assumptions were not satisfied. Laboratory measures were correlated with clinical and study end points using frequency tables, logistic regression, and Cox proportional hazards modeling. Two-sided P values were reported, and P < .05 was considered statistically significant.


Patient Characteristics

Fifty-six patients were enrolled between August 2006 and April 2008 at eight sites in the Phase II Consortium. The data are reported as of November 2009. Three patients were ineligible after starting treatment (brain metastases, alteration in pathologic diagnosis, colitis) and were included in the toxicity analysis but not the primary end point analysis. Median age was 63 years (range, 31 to 87 years). A majority of patients were female (30 patients, 57%) and white (48 patients, 91%). At study entry, 52 patients (98%) had a performance status of 0 or 1, 43 patients (81%) had cholangiocarcinoma, and 10 patients (19%) had gallbladder cancer. Metastatic disease was seen in 58% of patients, with the liver being the most common site of metastasis (13 patients; Table 1).

Table 1.
Baseline Characteristics of Eligible Patients (N = 53)

Efficacy and Patient Outcome

Fifty-three patients completed a total of 327 cycles of treatment (median, 4 cycles; range, 1 to 33 cycles). The primary end point was confirmed tumor response. Forty-nine patients were evaluable for assessing response. Nine patients achieved a best response of PR while six patients (12%; 95% CI, 6% to 27%; five at University of Wisconsin Carbone Cancer Center, one at Mayo Clinic [Rochester, MN]) had prolonged responses confirmed 4 weeks after their initial response was observed. Each PR was reviewed and confirmed by an independent investigator. Twenty-five and 15 patients achieved a best response of SD and PD, respectively. Among the six patients with confirmed PRs, median duration of response was 8.4 months (95% CI, 6.0 to 11.7 months). At the time of data cutoff, three patients remained on study medication, having received 18, 29, and 33 cycles of therapy. Eighty-seven percent of patients progressed with a median time to disease progression of 4.4 months (95% CI, 3.0 to 7.8 months). Median OS was 9.9 months (95% CI, 7.2 to 13.6 months; Table 2, Fig 1).

Table 2.
Patient Outcomes (N = 53)
Fig 1.
Time to progression and overall survival.

Adverse Events

Grade 4 adverse events which were at least possibly related to study treatment were experienced by four patients (8%), including cerebral ischemia and thrombosis (two patients each). Fourteen patients (27%) experienced grade 3 adverse events considered at least possibly related, including rash/desquamation (three), anorexia (three), fatigue (three), hyponatremia (three), nausea (three), ALT (one), bilirubin (one), diarrhea (one), dizziness (one), hypertension (one), nail changes (one), prothrombin time (one), and alkaline phosphatase (one). Details on toxicity are provided in Table 3. The most common of these events included (number of patients experiencing grade 1, 2, or 3): rash/desquamation (16, 21, three), diarrhea (15, six, one), fatigue (18, six, two), nausea (seven, four, two), anorexia (six, five, two), and oral mucositis (10, two, zero).

Table 3.
Maximum Severity of Adverse Events (N = 53)

Two patients (4%) died during treatment of causes felt to be unrelated to study treatment. A 79-year-old male died suddenly on day 21 of the first cycle, experiencing grade 4 cerebral ischemia (possibly related) and grade 1 blood bilirubin increase (possibly related). Bevacizumab was held on day 15. This death was considered unlikely to be related to study treatment. A 69-year-old male died within 30 days of initiating treatment, possibly due to disease progression. Adverse events before death included unrelated grade 3 anorexia, dyspnea, epigastric and back pain, and nausea; treatment-related grade 2 rash/desquamation combined; and unrelated grade 1 vomiting. This patient received full doses of both study agents during treatment.

Correlative Data

Evaluable tissue was submitted from 26 patients, four of whom had a confirmed response. Characteristics of this subset were comparable to the larger study population in terms of age, sex, performance status, and enrolling site. Fewer patients had gallbladder tumors (8% v 19%) or poorly differentiated tumors (4% v 15%) in the subset with available tissue (Appendix Table A1, online only).

Mutation on EGFR vIII, ≤ 16 C>A repeats for the EGFR intron 1 polymorphism, a G>G genotype measured by EGFR-Q787 single nucleotide polymorphisms, and wild-type (ie, nonmutant) KRAS measured by 38G primer I were hypothesized to be positively correlated with patient outcome (ie, confirmed response, tumor progression, and survival). Although only four patients experienced a confirmed response in this group and the results were not statistically significant, the data appeared to be in the direction of our hypotheses (Appendix Tables A2 and A3, online only), albeit with a limited sample size. VEGF expression did not change significantly from baseline between the responding and nonresponding patients (Appendix Table A2 and Appendix Fig A1, online only).

Desirable results (responders v nonresponders) were most often observed in patients having low repeats (≤ 16) for the EGFR intron 1 polymorphism (75% v 55%) or G>G K-ras Q38 genotype (100% v 82%). In univariate models, EGFR-Q787 genotype of G>G trended toward lower hazard rates for TTP (hazard ratio [HR], 0.7; 95% CI, 0.3 to 2.0; P = .56) and survival (HR, 0.6; 95% CI, 0.2 to 1.7; P = .34), although it was not statistically significant. VEGF 38Q genotype of G>G (ie, nonmutant) may be associated with a lower hazard rate for TTP (HR, 0.4; 95% CI, 0.1 to 1.4; P = .13). Conversely, EGFR vIII mutation is suggestive of worsened TTP (HR, 2.0; 95% CI, 0.6 to 7.1; P = .27) and survival (HR, 1.7; 95% CI, 0.5 to 6.1; P = .39; Appendix Table A3).


The combination of bevacizumab and erlotinib produced nine PRs in patients with biliary tract cancers, six of which were sustained (12%; 95% CI, 6% to 27%). When compared with that in other published trials of combination chemotherapy, the confirmed PR plus SD rate of 64% (31 of 49) is comparable with that for gemcitabine plus capecitabine, gemcitabine plus oxaliplatin, and gemcitabine plus cisplatin.5,79,30 In responders, the duration of best response for an average of 7.6 months is similarly comparable to that in other published trials. TTP and OS are also consistent with previously published data as summarized in Appendix Table A4 (online only).

From the safety analysis, the majority of adverse effects were grade 1 or 2. While there were two deaths on study and four patients with grade 4 toxicity, the regimen was not associated with prolonged neutropenia or GI adverse effects. The results of this trial suggest that a biologic-only combination of bevacizumab and erlotinib has activity in biliary tract cancers and demonstrates a different adverse event profile that merits additional exploration.

The molecular analyses performed in this study suggest that patients whose tumors have mutations in EGFR vIII, or have non–wild-type k-ras may be less likely to respond to erlotinib therapy. These findings are consistent with trials in lung cancer and colon cancer relative to k-ras mutants and EGFR-based biologic therapy.31,32 Similar trials have been published in abstract form in biliary tract cancer relative to the use of cetuximab, but they did not demonstrate any difference between PFS/OS or response to cetuximab.33 Additional exploration into the EGFR pathway as a potential therapeutic target is warranted, particularly in patients with intron 1 polymorphism and Q787 genotype.

Shortcomings of this combination (bevacizumab and erlotinib) include a lack of demonstrable improvement in OS compared with that of historical controls, a problem plaguing many trials in biliary tract cancers. The trial included both cholangiocarcinoma and gallbladder cancer; historically, gallbladder cancers have had poorer prognoses, potentially underestimating disease-free survival.34 The relatively few gallbladder cases in the trial may mitigate that estimation. Additionally, this combination is associated with significant cost. On the basis of prior cost analyses in other tumor types and on pricing effective October 2009, this regimen would cost nearly $10,000/month (estimating ≈$5,000/month for bevacizumab and $4,500 for erlotinib).35,36 We did not perform a cost analysis on this trial, but the expense of this combination could be explored relative to the cost of combinations of gemcitabine plus platinum.

In conclusion, the biologic-only combination of bevacizumab and erlotinib has demonstrable activity in advanced biliary tract cancers with few grade 3 or 4 adverse events. Given the demonstrated efficacy and safety profile, we believe that this combination could be additionally explored in future trials as a combination with gemcitabine plus cisplatin, an alternative first-line regimen or a salvage regimen after progression on standard cytotoxic therapy.


Fig A1.

An external file that holds a picture, illustration, etc.
Object name is zlj9991002220002.jpg

Vascular endothelial growth factor (VEGF) expression; percent change from baseline (N = 26).

Table A1.

Population Characteristics of Subgroup With Analyzed Tumor Samples

CharacteristicPatients With Samples (n = 26)
All Patients (N = 53)
Age, years
Male sex10392343
ECOG performance status
Primary tumor site
    Intrahepatic cholangiocarcinoma19733566
    Extrahepatic cholangiocarcinoma519815
Previous radiotherapy519611
Site of previous radiotherapy*
    Abdomen and liver120117
Previous systemic adjuvant cancer therapy41959
Type of previous systemic therapy*
    Fluorouracil and gemcitabine125120
Any previous cancer2859
Type of previous cancer
Registration location
    University of Wisconsin (Madison, WI)16622955
    Mayo Clinic (Jacksonville, FL)28611
    Mayo Clinic (Rochester, MN)2848
    Washington University (St. Louis, MO)31248
    Wayne State University (Detroit, MI)2848
    National University Hospital (Singapore)48
    Royal Prince Alfred Hospital (Sydney , Australia)12
    Sir Charles Gairdner Hospital (Perth, Australia)1412
Status of primary tumor
    Resected with no residual31259
    Resected with known residual519815
Distant metastases
Sites of extrahepatic metastases*
    Pleura and diaphragm1412
    Nodal, peritoneum, duodenum, and gallbladder12
    Liver and peritoneum1424
    Nodal and liver1459
    Nodal and bone12
    Bone and liver1412

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

*Patients are reflected once in each classification.

Table A2.

Correlative Results by Confirmed Response Status (N = 26)

ClassificationConfirmed Response
Yes (n = 4)
No (n = 22)
VEGF percent change from baseline.46*
    Q1, Q3−53, 37−79, −2
    Mutation (best)12529
    No mutation3752091
EGFR intron 1 polymorphism.61
    ≤ 16 (best)3751255
    > 161251045
EGFR-Q787 genotype.20
    G>G (best)250418
EGFR-Q787 genotype (grouped).22
    G>G (best)250418
    A>G and A>A2501882
KRAS 38Q genotype1.00
    Mutant (A>G)00418
    Wild type (G>G) (best)41001882
Having three desirable correlative results.22
    ≥ 3250418
    < 32501882

Abbreviations: VEGF, vascular endothelial growth factor; Q1, Q3, first quartile, third quartile; EGFR, epidermal growth factor receptor.

*Wilcoxon rank sum test.
Fisher's exact test.
χ2 test.

Table A3.

Univariate Cox Models of TTP (21 events) and OS (16 events) by Correlative Results (N = 26)

Desirable Result of CorrelativeTTP HR95% CIP*OS HR95% CIP*
EGFR vIII mutation2.00.6 to to 6.1.39
EGFR intron 1 polymorphism ≤ 161.30.5 to 3.1.551.20.5 to 3.1.66
EGFR-Q787 G>G genotype0.70.3 to 2.0.560.60.2 to 1.7.34
KRAS 38Q G>G genotype (nonmutant)0.40.1 to to 3.6.93
Having three desirable correlative results0.70.3 to 2.0.560.60.2 to 1.7.34

Abbreviations: TTP, time to progression; OS, overall survival; HR, hazard ratio; EGFR, epidermal growth factor receptor.

*Score statistic.
Mutation of EGFR vIII is suggestive of an increased hazard of TTP (HR, 2.0; 95% CI, 0.6 to 7.1; P = .27) and an increased hazard of OS (HR, 1.7; 95% CI, 0.5 to 6.1; P = .39).

Table A4.

RR, PFS, and OS of Published Regimens for Biliary Tract Cancer

TotalCholangiocarcinomaGallbladderRR (%)PFS/TTP (months)OS (months)
Knox et al8Gemcitabine/capecitabine45232231714
Philip et al9Erlotinib42241682.67.5
Valle et al30Gemcitabine442812234N/A
Valle et al5Gemcitabine142865615.56.58.2
André T, et al: Br J Cancer 99:862-867, 2008Gemcitabine/oxaliplatin704525153.48.8
Kim HJ, et al: Cancer Chemother Pharmacol 64:371-377, 2009Gemcitabine/oxaliplatin40154.09.7
Santini D, et al: J Clin Oncol 27, 2009 (suppl; abstr e15510)Gemcitabine (FDR)/capecitabine307.415
Zhu A, et al: J Clin Oncol 27:4578, 2009 (suppl; abstr 4578)Gemcitabine/oxaliplatin/bevacizumab35251045713.2
Nakamura K, et al: J Clin Oncol 27, 2009 (suppl; abstr e15527)Gemcitabine/S-13023730N/A13
Gruenberger et al33Gemcitabine/oxaliplatin/cetuximab30638.312.7
Current studyBevacizumab/erlotinib534310124.49.9

Abbreviations: RR, response rate; PFS, progression-free survival; OS, overall survival; TTP, time to progression; N/A, not applicable; FDR, fixed dose rate.


Supported by P2C Contract No. NCI N01 CM62205.

Presented at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00356889.


Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Philip A. Philip, OSI Pharmaceuticals (C); Joel Picus, Genentech (C); Guy Van Hazel, Roche (C) Stock Ownership: None Honoraria: Philip A. Philip, OSI Pharmaceuticals, Genentech Research Funding: George P. Kim, Genentech Expert Testimony: None Other Remuneration: Guy Van Hazel, Roche


Conception and design: Charles E. Erlichman, Kyle D. Holen

Financial support: Charles E. Erlichman

Administrative support: Charles E. Erlichman

Provision of study materials or patients: Noelle K. LoConte, George P. Kim, Henry C. Pitot, Philip A. Philip, Joel Picus, Wei-Peng Yong, Lisa Horvath, Guy Van Hazel, Kyle D. Holen

Collection and assembly of data: Michelle R. Mahoney, Jill L. Kolesar, Kyle D. Holen

Data analysis and interpretation: Sam J. Lubner, Michelle R. Mahoney, Jill L. Kolesar, Kyle D. Holen

Manuscript writing: Sam J. Lubner, Michelle R. Mahoney, Kyle D. Holen

Final approval of manuscript: Sam J. Lubner, Michelle R. Mahoney, Jill L. Kolesar, Noelle K. LoConte, George P. Kim, Henry C. Pitot, Philip A. Philip, Joel Picus, Wei-Peng Yong, Lisa Horvath, Guy Van Hazel, Charles E. Erlichman, Kyle D. Holen


1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–249. [PubMed]
2. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med. 1999;341:1368–1378. [PubMed]
3. Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol. 1999;10(suppl 4):308–311. [PubMed]
4. De Vita VT, Lawrence TS, Rosenberg SA, et al. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. ed 8. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
5. Valle JW, Wasan H, Palmer D, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–1281. [PubMed]
6. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: A pooled analysis of clinical trials. Br J Cancer. 2007;96:896–902. [PMC free article] [PubMed]
7. André T, Tournigand C, Rosmorduc O, et al. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: A GERCOR study. Ann Oncol. 2004;15:1339–1343. [PubMed]
8. Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with advanced biliary cancer: A phase II trial. J Clin Oncol. 2005;23:2332–2338. [PubMed]
9. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol. 2006;24:3069–3074. [PubMed]
10. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. [PubMed]
11. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342. [PubMed]
12. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349:427–434. [PMC free article] [PubMed]
13. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–2676. [PubMed]
14. Möbius C, Demuth C, Aigner T, et al. Evaluation of VEGF A expression and microvascular density as prognostic factors in extrahepatic cholangiocarcinoma. Eur J Surg Oncol. 2007;33:1025–1029. [PubMed]
15. Park BK, Paik YH, Park JY, et al. The clinicopathologic significance of the expression of vascular endothelial growth factor-C in intrahepatic cholangiocarcinoma. Am J Clin Oncol. 2006;29:138–142. [PubMed]
16. Dickler MN, Rugo HS, Eberle CA, et al. A phase II trial of erlotinib in combination with bevacizumab in patients with metastatic breast cancer. Clin Cancer Res. 2008;14:7878–7883. [PMC free article] [PubMed]
17. Herbst RS, Johnson DH, Mininberg E, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005;23:2544–2555. [PubMed]
18. Herbst RS, O'Neill VJ, Fehrenbacher L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol. 2007;25:4743–4750. [PubMed]
19. Thomas MB, Morris JS, Chadha R, et al. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009;27:843–850. [PubMed]
20. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–572. [PubMed]
21. Ciardiello F, Bianco R, Damiano V, et al. Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res. 2000;6:3739–3747. [PubMed]
22. Jung YD, Mansfield PF, Akagi M, et al. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer. 2002;38:1133–1140. [PubMed]
23. Perrotte P, Matsumoto T, Inoue K, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 1999;5:257–265. [PubMed]
24. Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer. 2001;85:584–589. [PMC free article] [PubMed]
25. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. [PubMed]
26. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982;38:143–151. [PubMed]
27. Duffy DE, Santner TJ. Confidence intervals for a binomial parameter based on multistage tests. Biometrics. 1987;43:81–93.
28. Kaplan EL, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc. 1958;53:457–481.
29. Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187–202.
30. Valle JW, Wasan H, Johnson P, et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: A multicentre randomised phase II study—The UK ABC-01 Study. Br J Cancer. 2009;101:621–627. [PMC free article] [PubMed]
31. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–1765. [PubMed]
32. Zhu CQ, da Cunha Santos G, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008;26:4268–4275. [PubMed]
33. Gruenberger B, Schueller J, Tamandl D, et al. K-ras status and response in patients with advanced or metastatic cholangiocarcinoma treated with cetuximab plus gemcitabine-oxaliplatin (GEMOX): A single center phase II study. J Clin Oncol. 2009;27(suppl):223s. abstr 4586.
34. Gallardo J, Rubio B, Villanueva L, et al. Gallbladder cancer, a different disease that needs individual trials. J Clin Oncol. 2005;23:7753–7754. [PubMed]
35. Schrag D. The price tag on progress: Chemotherapy for colorectal cancer. N Engl J Med. 2004;351:317–319. [PubMed]
36. Drug prices and information on Tarceva.
37. André T, Reyes-Vidal JM, Fartoux L, et al. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: A phase II study. Br J Cancer. 2008;99:862–867. [PMC free article] [PubMed]
38. Kim HJ, Lee NS, Bae SB, et al. A phase II study of gemcitabine in combination with oxaliplatin as first-line chemotherapy in patients with inoperable biliary tract cancer. Cancer Chemother Pharmacol. 2009;64:371–377. [PubMed]
39. Santini D, Vincenzi V, Vasile E, et al. Fixed dose rate (FDR) gemcitabine (G) and capecitabine (C) in patients with metastatic biliary tract cancer (BTC): Final results of phase II trial. J Clin Oncol. 2009;(suppl):27. abstr e15510.
40. Zhu A, Meyerhardt J, Blaszkowky L, et al. Phase II and fluorodeoxyglucose positron emission tomography (FDG-PET) study in patients with advanced biliary tract cancers (BTCs) receiving bevacizumab (B) in combination with gemcitabine (GEM) and oxaliplatin (OX) J Clin Oncol. 2009;27(suppl):221s. abstr 4578.
41. Nakamura K, Yamaguchi T, Sudo K, et al. A phase II trial of oral S-1 combined with gemcitabine in patients with unresectable biliary tract cancer. J Clin Oncol. 2009;(suppl):27. abstr e15527.

Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology