This study evaluated safety and efficacy of chemotherapy (gemcitabine plus capecitabine) plus bevacizumab/erlotinib in advanced pancreatic cancer because dual epidermal growth factor receptor/vascular endothelial growth factor blockade has a rational biologic basis in this malignancy.

Patients with untreated, unresectable, locally advanced or metastatic pancreatic carcinoma were enrolled onto one of the following four sequential dose levels (DLs) of escalating capecitabine doses (days 1 to 21): DL1, 910 mg/m2; DL2, 1,160 mg/m2; DL3, 1,400 mg/m2; or DL4, 1,660 mg/m2. Doses of coadministered gemcitabine (1,000 mg/m2 on days 1, 8, and 15), bevacizumab (5 mg/kg on days 1 and 15), and erlotinib (100 mg/d) every 28 days (up to six cycles) were fixed. Using a 3+3 study design, dose-limiting toxicity (DLT) was assessed in cycle 1.

Twenty assessable patients were enrolled (DL1, n = 8; DL2, n = 3; DL3, n = 6; and DL4, n = 3); 97 cycles were administered. Median age was 63 years (range, 33 to 77 years), and male-to-female ratio was 10:10. Performance status was 0 and 1 in two and 17 patients, respectively; and nine and 11 patients had locally advanced and metastatic disease, respectively. DLT occurred in one patient at DL1 (grade 3 epistaxis) and two patients at DL4 (grade 3 diarrhea and grade 3 skin rash > 7 days). Common grade 3 and 4 toxicities (10% to 20%) were diarrhea, hand-foot syndrome, stomatitis, and skin rash. Grade 3 lethargy and grade 3 or 4 neutropenia occurred in 40% and 45% of patients, respectively. No GI perforation, grade 3 GI hemorrhage/hypertension, or pneumonitis occurred. Ten partial responses were observed. Median overall and progression-survival times (all patients) were 12.5 and 9.0 months, respectively.

The maximum-tolerated dose of capecitabine was 1,660 mg/m2. The recommended capecitabine dose in this cytotoxic doublet/biologic doublet regimen is 1,440 mg/m2; this regimen is under evaluation in an ongoing phase II study.

Pancreatic cancer is the eighth most common cause of cancer-related death worldwide1 and is associated with a dismal prognosis, with a 5-year survival rate of less than 5% to 6%.24 The majority of patients present with advanced unresectable disease, correlating with a median overall survival time of 3 to 4 months if untreated. Gemcitabine monotherapy was established as a palliative option based on improved clinical benefit for gemcitabine compared with bolus fluorouracil and was accompanied by marginal improvement in median overall survival (5.65 v 4.41 months, respectively, and 1-year survival rate, 18% v 2%, respectively; P = .0025). Subsequently, many alternative cytotoxic/biologic agents and gemcitabine doublets containing investigational agents have failed to demonstrate superiority in survival over gemcitabine alone in randomized evaluation. However, a recent meta-analysis of these trials indicated a likely survival benefit for gemcitabine doublets containing either platinum agents or the oral fluoropyrimidine capecitabine.5

The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor pathways are thought to play important roles in the initiation and growth of pancreatic cancer. Both EGFR and VEGF are overexpressed in pancreatic cancer and are associated with poor prognosis and disease progression,68 and antagonism of their signaling in preclinical models inhibits tumor growth.914 There is commonality and cross talk between the downstream signaling pathways of the EGFR and VEGF receptor. EGFR may modulate angiogenesis via effects on VEGF and vice versa.1517 These interactions include EGFR-mediated upregulation of VEGF expression18 and VEGF-mediated resistance to EGFR inhibition,16 thereby providing a biologic rationale for dual targeted therapy. This rationale is supported by preclinical studies in gastric, colon, and pancreatic xenograft models, which demonstrate at least additive effects,1921 and by early phase clinical studies in colon and non–small-cell lung cancer, which indicate antitumor activity for anti-EGFR/anti-VEGF doublets and favorable safety profiles.2224 These trials mostly assessed erlotinib (an EGFR small-molecule tyrosine kinase inhibitor) combined with bevacizumab (an anti-VEGF humanized monoclonal antibody). Both drugs have separately demonstrated clinical activity when administered with gemcitabine in pancreatic cancer, and erlotinib (plus gemcitabine) is licensed for advanced pancreatic cancer.25,26

This study was undertaken to evaluate the safety and efficacy of adding a biologic doublet (erlotinib plus bevacizumab) to a cytotoxic platform for treating advanced chemotherapy-naive pancreatic cancer. When this study was initiated, preliminary analysis of the United Kingdom National Cancer Research Institute randomized trial of gemcitabine versus gemcitabine plus capecitabine (GemCap) had reported a significant survival advantage for GemCap,27 with efficacy further being supported by subsequent meta-analysis.5 Therefore, GemCap comprised the cytotoxic platform in this study. Because of potential overlapping toxicity between erlotinib and capecitabine, a dose-escalation design was used to increase the dose of capecitabine toward the target daily dose of 1,660 mg/m2, with safety and efficacy as primary and secondary outcome measures, respectively.

Patients

Eligible patients had inoperable histologically/cytologically proven locally advanced or metastatic pancreatic ductal adenocarcinoma/undifferentiated carcinoma. Patients were older than 18 years; had Eastern Cooperative Oncology Group performance status (PS) ≤ 2; and had adequate renal (creatinine clearance ≥ 50 mL/min), bone marrow (platelets > 100 × 109/L, leukocytes > 3.0 × 109/L, and absolute neutrophil count [ANC] > 1.5 × 109/L), and liver (total bilirubin < 2× the upper limit of normal) function, a serum albumin ≥ 26 g/L, and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).28 Exclusion criteria included any prior chemotherapy, radiotherapy, or investigational agents; intracerebral/meningeal metastases; uncontrolled hypertension; significant cardiovascular comorbidity; major bleeding diathesis; full-dose anticoagulation before study; aspirin use (≥ 325 mg/d); major surgery/traumatic injury within 28 days; nonhealing wound/fracture; second malignancy; uncontrolled comorbid conditions; and pregnancy/lactation. After a protocol amendment, patients with duodenal invasion were permitted. All patients provided written informed consent, and the study was approved by the local scientific review and research ethics committees.

Trial Design and Treatment

This was an open-label, single-center study of the safety and tolerability of the gemcitabine, capecitabine, bevacizumab, and erlotinib combination. A 3+3 dose-escalation study design29 was used to determine the optimal dose of capecitabine in this regimen. All patients received gemcitabine 1,000 mg/m2 (intravenously over 30 minutes) on days 1, 8, and 15 of a 28-day cycle, together with bevacizumab 5 mg/kg intravenously on days 1 and 15 (over 90 minutes, reducing to 60 then 30 minutes for subsequent infusions if tolerated) and erlotinib 100 mg orally daily on days 1 through 28. These were coadministered with oral capecitabine (days 1 to 21), which was administered in escalating doses in sequential patient cohorts as follows: dose level (DL) 1 = 910 mg/m2, DL2 = 1,160 mg/m2, DL3 = 1,400 mg/m2, and DL4 = 1,660 mg/m2, representing 55%, 70%, 85%, and 100%, respectively, of the target dose of capecitabine in the GemCap regimen.27 The total daily dose was administered in two divided doses. Treatment continued for six cycles or longer in patients deriving clinical benefit.

Each DL comprised a minimum of three patients assessable for cycle 1 dose-limiting toxicities (DLT), expanding to six patients if one DLT occurred. Dose escalation proceeded to the subsequent DL in the absence of DLT in three patients or ≤ one DLT among six patients. The maximum-tolerated dose (MTD) of capecitabine in the four-drug regimen was the dose that induced first-cycle DLT in one third or more of patients (ie, at least two of a maximum of six patients), thereby terminating accrual to that DL. The DL below the MTD could be expanded by up to six patients and declared the recommended dose for capecitabine for phase II evaluation (if associated with ≤ one DLT among six patients).

DLTs were treatment-related grade 4 neutropenia lasting ≥ 7 days, neutropenic fever, grade 4 thrombocytopenia, grade 3 or 4 diarrhea despite optimal supportive care, any nonhematologic toxicity ≥ grade 3 lasting ≥ 7 days (except for transient increases in liver transaminases), grade 3 or 4 hemorrhage or GI perforation, and treatment delay of more than 4 weeks as a result of toxicity. Adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

Dose Modifications

DLT resulted in reduction of capecitabine to the next lower DL. For non–dose-limiting, nonhematologic toxicity, capecitabine therapy was interrupted until toxicity had resolved to ≤ grade 1 and then resumed at 75% of the intended dose, and on second occurrence, capecitabine was resumed at 50% of the intended dose. Re-treatment criteria required an ANC of more than 1.0 × 109/L and platelet count of more than 100 × 109/L. If the ANC was 0.5 to 1.0 × 109/L or the platelet count was 50 to 100 × 109/L, gemcitabine was dose reduced by 25%. Gemcitabine was omitted for a week for an ANC less than 0.5 × 109/L, platelets less than 50 × 109/L, or neutropenic sepsis. The latter or recurrent low ANC/platelet counts incurred a 25% dose reduction of gemcitabine. Full-dose gemcitabine was administered for nonhematologic toxicities ≤ grade 2, and a 25% dose reduction/omission was considered for grade 3 nonhematologic toxicity.

There were no dose reductions for bevacizumab. Patients developing new proteinuria (2+ on urinalysis) underwent 24-hour urinary protein measurement with ≥ 2 g protein/24 hours precluding further administration of bevacizumab until resolution to less than 2 g/24 hours. Bevacizumab was discontinued for grade 4 proteinuria, GI perforation, grade 3 or 4 hemorrhage, grade 4 hypertension, uncontrolled grade 3 hypertension, arterial thromboembolism, or symptomatic grade 4 venous thromboembolism. Erlotinib dosing was interrupted for related grade 3 nonhematologic toxicities and reduced to 50 mg once a day on resolution of toxicities to ≤ grade 1 or discontinued for grade 4 toxicities.

Patient Evaluation

Screening included a clinical history, physical examination, full blood count, biochemistry panel, urinalysis, calculated creatinine clearance, and ECG. At every treatment visit, toxicity and standard laboratory panels were assessed. Tumor response was evaluated by CA 19-9 markers every 4 weeks and by computed tomography of the chest/abdomen/pelvis (RECIST guidelines) at baseline (within 4 weeks of starting protocol therapy) and every 8 weeks thereafter. Responses were confirmed at least 4 weeks after responding scan.

Study End Points and Objectives

The primary objective was determination of the recommended dose for phase II evaluation of capecitabine in this regimen based on the end point of first-cycle DLT and establishment of the MTD. Response rates and overall and progression-free survival were secondary end points. Survival was calculated from the date of study registration to the date of death (overall survival) or progression/death (progression-free survival) using the Kaplan-Meier method, with patients censored at the date of last follow-up if still alive.

Patient Population and Dose Escalation

Twenty patients were enrolled between December 2005 and December 2007. Data were analyzed at least 6 months after accrual of the final patient. Table 1 lists patient characteristics; 95% of patients had PS of 0 or 1, 50% were male, and approximately half had metastatic disease.

Table

Table 1. Patient Demographics and Clinical Characteristics

Table 1. Patient Demographics and Clinical Characteristics

Patient Demographics and Clinical Characteristics No. of Patients
All Patients (N = 20)
DL1 (n = 8)* DL2 (n = 3) DL3 (n = 6) DL4 (n = 3) No. %
Age, years
    Median 65 71 49 67 63
    Range 41-74 64-76 33-69 56-77 33-77
Sex
    Male 5 2 3 0 10 50
    Female 3 1 3 3 10 50
Performance status
    0 2 0 0 0 2 10
    1 6 3 6 2 17 85
    2 0 0 0 1 1 5
Extent of disease
    Locally advanced 2 2 2 3 9 45
    Metastatic 6 1 4 0 11 55
Location of tumor
    Head of pancreas 3 2 4 2 11 55
    Body/tail 5 1 2 1 9 45
Duodenal/gastric invasion 0 0 1 1 2 10
Previous surgery 0 1 1 0 2 10

Abbreviation: DL, dose level.

*One patient was ineligible (increased bilirubin of 44 μmol/L), and one patient did not complete the first cycle as a result of disease progression; therefore, both patients were replaced in the cohort. All patients are included for survival and overall toxicity assessment.

DL1 was expanded to six patients as a result of one dose-limiting occurrence of grade 3 epistaxis that was successfully treated by surgical intervention. Two additional patients were recruited to DL1 to replace two patients who were not fully assessable for first-cycle DLT (disease-related deterioration and ineligibility as a result of increased bilirubin) with no further occurrence of DLT. No DLT was observed in the three patients each at DL2 or DL3. Capecitabine was escalated to the target therapeutic dose in DL4, wherein two DLTs occurred (grade 3 skin toxicity lasting > 7 days and grade 3 diarrhea despite optimal supportive measures). DL4 was declared the MTD, and DL3 was expanded by three patients, none of whom experienced DLT (zero DLTs among six patients at DL3). Thus, the recommended dose of capecitabine for phase II evaluation was 1,400 mg/m2.

Safety

Toxicities according to DL are listed in Table 2. In all patients (n = 20) and across all cycles, grade 3 toxicities with rates of 10% to 20% included diarrhea, stomatitis, hand-foot syndrome, and skin rash. Grade 3 lethargy was observed in eight (40%) of 20 patients, and grade 3 or 4 neutropenia was observed in nine (45%) of 20 patients. There were no other grade 4 toxicities or cases of febrile neutropenia, GI perforation, grade 3 GI bleeding, grade 3 hypertension/proteinuria, or interstitial pneumonitis. One patient developed pulmonary embolism (detected by computed tomography) and remained on protocol therapy with anticoagulation, and one patient developed a deep vein thrombosis associated with disease progression and came off study.

Table

Table 2. Adverse Events by DL

Table 2. Adverse Events by DL

Adverse Event No. of Patients by Grade
DL1 (n = 8)
DL2 (n = 3)
DL3 (n = 6)
DL4 (n = 3)
1 or 2 3 or 4 1 or 2 3 or 4 1 or 2 3 or 4 1 or 2 3 or 4
Neutropenia 5 2 1 2 2 3 1 2
Thrombocytopenia 5 0 3 0 5 1 3 0
Anemia 6 1 2 0 6 0 3 0
Diarrhea 4 1 2 0 4 2 2 1*
Stomatitis 5 2 2 0 4 0 3 0
Nausea/vomiting 7 0 3 0 6 0 1 1
Hand-foot syndrome 3 2 1 1 5 0 2 0
Rash (acneiform) 3 0 2 0 3 1 1 1*
Lethargy 5 3 2 1 4 2 1 2
Epistaxis 4 1* 3 0 4 0 1 0
Other bleeding 0 0 1 0 1 0 1 0
Thromboembolism 0 1 0 0 0 1 0 0
Hypertension 1 0 1 0 2 0 1 0
Proteinuria 1 0 1 0 3 0 2 0

Abbreviation: DL, dose level.

*Indicates dose-limiting toxicity during cycle 1.

There were five treatment-related serious adverse events, including two DLTs (grade 3 diarrhea and grade 3 epistaxis). The other serious adverse events included abdominal pain (etiology unknown), overnight admission with grade 3 neutropenia associated with fatigue but no fever, and skin infection secondary to erlotinib-induced skin rash.

Treatment Delivery

A total of 97 cycles (median, six cycles; range, one to eight cycles) have been administered. Two patients continue on protocol therapy. Nine patients completed six cycles (four patients at DL3), with one further patient continuing to receive treatment beyond six cycles in DL3. Two patients withdrew as a result of lethargy, one after three cycles and one after five cycles. The numbers of patients requiring at least one dose reduction of gemcitabine were as follows: DL1, n = 2; DL2, n = 3; DL3, n = 4; and DL4, n = 2. The numbers of patients requiring at least one dose reduction of capecitabine were as follows: DL1, n = 4; DL2, n = 2; DL3, n = 3; and DL4, n = 2. Treatment delays of greater than 1 week occurred in 19%, 0%, 9%, and 20% of cycles in DL1 to DL4, respectively. A dose reduction of erlotinib occurred in seven patients (DL1, n = 4; DL3, n =1; DL4, n = 2).

Efficacy

With a median follow-up time of 9.8 months, 14 patients have died and six remain alive. Median overall survival time (Fig 1A) for all patients was 12.5 months (95% CI, 10.9 to 14.1 months), and 1-year survival rate was 73.7% (95% CI, 47.9% to 88.1%). Survival according to metastatic versus locally advanced disease is shown in Appendix Figure A1 (online only). Progression-free survival time (Fig 1B) was 9.0 months (95% CI, 8.8 to 9.3 months), with a 1-year progression-free survival rate of 31.9% (95% CI, 12.1% to 53.9%). The overall response rate (unconfirmed; Table 3) was 50% (95% CI, 27% to 73%), and the disease control rate was 85% (95% CI, 62% to 97%). Responses by cohort were as follows: four of eight patients in DL1, two of three patients in DL2, three of six patients in DL3, and one of three patients in DL4. The overall confirmed response rate was 35%. CA 19-9 trends during treatment are indicated for all patients in Figure 2. In an exploratory analysis, 63% (95% CI, 38% to 84%) of 19 assessable patients (one nonsecretor) experienced a 50% reduction in CA 19-9 for 8 weeks (three of 20 patients had < 50% decrease; four of 20 patients had increased CA 19-9).

Table

Table 3. Summary of Radiologic Responses

Table 3. Summary of Radiologic Responses

Response No. of Patients
All Patients (N = 20)
DL1 (n = 8) DL2 (n = 3) DL3 (n = 6) DL4 (n = 3) No. %
Partial response 4 2 3 1 10 50
Stable disease 1 1 3 2 7 35
Disease control 5 3 6 3 17 85
Progressive disease 2 2 10
Nonassessable 1* 1 5

Abbreviation: DL, dose level.

*This patient did not complete one cycle of therapy.

The primary objective was to establish the toxicity profile and recommended phase II dose of capecitabine in the investigational GemCap plus erlotinib/bevacizumab regimen. The recommended dose of 1,400 mg/m2 represents a 15% dose reduction of the target dose of capecitabine of 1,660 mg/m2 used in the GemCap alone doublet. DLTs were predictably diarrhea and skin rash, occurring in two separate patients in the 1,660 mg/m2 cohort. At the recommend DL, no patients experienced first-cycle DLT, and the frequency of grade 3 or 4 toxicity in any cycle was relatively low, with mostly grade1 or 2 toxicities observed, except for grade 3 or 4 diarrhea and lethargy in two of six patients. Grade 3 or 4 toxicities occurring in 10% to 20% of all patients (n = 20) were diarrhea, skin rash, stomatitis, hand-foot syndrome, and lethargy, consistent with those observed in a phase II study of capecitabine plus erlotinib in chemotherapy-refractory pancreatic cancer.30 Grade 3 or 4 lethargy was experienced by 40% of patients, and it is not clear to what extent this is disease or treatment related. Grade 3 or 4 neutropenia (with no observed febrile neutropenia) occurred in 45% of patients; this toxicity was seen in 36% of patients treated with GemCap alone.27

Concerning bevacizumab-specific toxicities, no patients had GI perforation or grade 3 or 4 GI bleeding, but one patient experienced grade 3 epistaxis. A phase II study of gemcitabine in combination with bevacizumab in 52 patients reported an incidence of visceral perforation of 8% and bleeding of 2% and advised caution in administering bevacizumab in the presence of visceral invasion.26 This was originally an exclusion criterion in our study, but after a protocol amendment, two patients with duodenal/gastric invasion were included without complications. The frequency of grade 1 or 2 hypertension was consistent with other studies of bevacizumab in advanced pancreatic cancer,26,31,32 but unlike these studies, no patients experienced grade 3 or 4 hypertension. This could reflect the small sample size, but the lower dose of bevacizumab (5 mg/kg as opposed to 10 mg/kg) may be contributory. The incidence of interstitial lung disease with the combination of gemcitabine plus erlotinib is reported to be 2.4%,25 which is higher than with either drug alone, but no interstitial lung disease occurred in the present study.

A dose-escalation study design was used in the assessment of this four-drug regimen given the potential for overlapping toxicity between capecitabine and erlotinib because several phase II studies adding erlotinib to cytotoxic platforms in other tumors had observed excessive grade 3 or 4 diarrhea, resulting in upfront dose reductions of the cytotoxic drugs. In our study, capecitabine, rather than erlotinib, was dose-escalated to increase the scope for dose titration to toxicity. Pharmacokinetic interactions increasing drug exposure have not been observed with erlotinib plus bevacizumab,23 gemcitabine plus erlotinib,33 and capecitabine plus erlotinib,34,35 and hence, none were expected with the four-drug combination used in this study. Thus, the observed DLTs of grade 3 diarrhea and skin rash are likely to be a consequence of additive toxicity.

In one of the only positive randomized phase III studies to report results in advanced pancreatic cancer, the combination of gemcitabine with erlotinib produced a modest improvement in overall survival compared with gemcitabine alone (median overall time and 1-year survival rate were 6.24 months and 23%, respectively; hazard ratio [HR] = 0.82; 95% CI, 0.69 to 0.99; P = .038).25 However, despite promising activity in phase II evaluation,26,36 alternative doublets targeting EGFR or VEGF have failed to result in significantly improved survival in advanced pancreatic cancer in phase III evaluation; gemcitabine plus bevacizumab versus gemcitabine alone resulted in median survival times of 5.8 v 6.1 months, respectively (HR = 1.03, P = .78, 95% CI not reported),31 and gemcitabine plus cetuximab versus gemcitabine alone resulted in an HR for death of 1.09 (95% CI, 0.93 to 1.27; P = .14; median survival not reported).37

A third recently published study addressed the issue of dual EGFR/VEGF blockade, randomly assigning patients with metastatic disease between gemcitabine/erlotinib/bevacizumab and gemcitabine/erlotinib; median overall survival times were 7.1 and 6.0 months, respectively (HR = 0.89; 95% CI, 0.74 to 1.07; P = .21).38 In this study, however, progression-free survival, a secondary end point, was significantly better for combined EGFR/VEGF blockade (HR = 0.73; 95% CI, 0.61 to 0.86; P = .0002), but there was no significant difference in response rates (13.5% for gemcitabine/erlotinib/bevacizumab v 8.6% for gemcitabine/erlotinib). The rates of grade 3 or 4 diarrhea, rash, and neutropenia were 4%, 8%, and 21% for the triplet arm, suggesting that in our study, the addition of capecitabine increased these toxicities. In a randomized phase II study of dual blockade with gemcitabine/bevacizumab/erlotinib versus gemcitabine/bevacizumab/cetuximab, median survival times of 7.2 v 7.8 months, respectively, and response rates of 18% v 23%, respectively, were observed, leading the investigators to conclude that neither regimen demonstrated sufficient activity to warrant further evaluation.32

In our study, median survival, 1-year survival, and median progression-free survival were 12.5 months, 73.7%, and 9 months, respectively. These outcomes are much better than those observed with historical controls. However, the current study comprises a small number of patients with characteristics predictive of a more favorable outcome, including good PS (95% had PS of 0 or 1) and locally advanced disease (45%), which have been previously identified as being associated with better outcomes.31 The response rate of 50% was encouraging for a multitargeted approach in this patient population, particularly because radiologic response can be difficult to measure in pancreatic neoplasms as a result of associated desmoplastic reaction. Regimens that result in good tumor shrinkage could potentially have application in the neoadjuvant treatment of pancreatic cancer, which is currently an investigational area. The regimen also resulted in a 50% reduction in CA 19-9 for 8 weeks in 63% of patients.

Although the rationale and preclinical data for combined EGFR/VEGF blockade in pancreatic cancer and other tumor types seemed promising, this has not translated into a clear clinical benefit in pancreatic cancer based on the results of phase III evaluation where overall survival remains the standard efficacy measure. Similarly, in renal cell and colorectal cancer, superiority of a dual targeted approach was not demonstrated in randomized evaluation,3941 despite encouraging activity in single-arm studies.22,42 Nonetheless, tumorigenesis in pancreatic cancer is governed by the complex interplay of tumoral, stromal, and host factors; genetic and epigenetic events; and dysregulation of the molecular and growth pathways they control. Therefore, multitargeted approaches still seem logical; several phase III studies assessing gemcitabine plus or minus oral multitargeted tyrosine kinase inhibitors are ongoing, and alternative approaches including vaccine therapy are under investigation.

In conclusion, this study demonstrated that to combine GemCap with erlotinib plus bevacizumab, a 15% dose reduction of capecitabine was required as a result of overlapping toxicities with erlotinib. A follow-up phase II study of this regimen using the recommended dose of capecitabine and with response rate as the primary outcome measure has recently fully accrued.

© 2009 by American Society of Clinical Oncology

See accompanying editorial on page 5487 and articles on pages 5506, 5513, and 5660

Supported by Royal Marsden Hospital National Health Service (NHS) Foundation Trust. We acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre. Hoffman-La Roche provided an educational grant toward running the trial and provided capecitabine, erlotinib, and bevacizumab at no cost.

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: NCT00260364.

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: David Cunningham, Hoffmann-La Roche (C); Ian Chau, Hoffmann-La Roche (C) Stock Ownership: None Honoraria: David Cunningham, Hoffmann-La Roche; Ian Chau, Hoffmann-La Roche Research Funding: David Cunningham, Hoffmann-La Roche Expert Testimony: David Cunningham, Hoffmann-La Roche (U) Other Remuneration: None

Conception and design: Naureen Starling, David Cunningham

Administrative support: Jacqui Oates

Provision of study materials or patients: David Cunningham, Ian Chau

Collection and assembly of data: Naureen Starling, David Watkins, David Cunningham, Janet Thomas, Janine Webb, Karen Thomas, Jacqui Oates

Data analysis and interpretation: Naureen Starling, David Watkins, David Cunningham, Gina Brown, Karen Thomas, Ian Chau

Manuscript writing: Naureen Starling, David Watkins, David Cunningham, Ian Chau

Final approval of manuscript: Naureen Starling, David Watkins, David Cunningham, Janet Thomas, Janine Webb, Gina Brown, Karen Thomas, Jacqui Oates, Ian Chau

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Acknowledgment

This study was coordinated from the Gastrointestinal Unit, Royal Marsden Hospital. The study has also been adopted into the United Kingdom National Cancer Research Institute's Trial Portfolio.

COMPANION ARTICLES

No companion articles

ARTICLE CITATION

DOI: 10.1200/JCO.2008.21.5384 Journal of Clinical Oncology 27, no. 33 (November 20, 2009) 5499-5505.

Published online October 26, 2009.

PMID: 19858399

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