Vergote 2014.
| Methods | Open‐label international phase III RCT (125 institutions in 10 countries). Recruitment from October 2005 to February 2008, with median follow‐up time of 51 months | |
| Participants | 835 women with EOC or primary peritoneal or fallopian tube cancer (of whom 420 were allocated to receive erlotinib, and 415 to observation) Participants were not selected for EGFR expression. Women had to have histologically confirmed high‐risk FIGO stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) or stage II to IV disease. Women also had to have completed first‐line therapy within the past 6 weeks (consisting of 6 to 9 cycles of a platinum derivative alone or in combination with other agents), and had to have achieved complete response, partial response, or stable disease (according to RECIST or GCIG criteria). Baseline characteristics Erlotinib
Observation
Inclusion criteria: eligible women had histologically confirmed high‐risk International Federation of Gynecology and Obstetrics (FIGO) stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) or stage II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer (women with adenocarcinoma of unknown origin were not eligible). Exclusion criteria: other malignancy within the past 5 years (except adequately treated basal cell or squamous cell skin cancer or cone biopsied carcinoma in situ of the cervix) Pretreatment: participants were randomly assigned to maintenance erlotinib 150 mg orally daily for 2 years (or until disease progression) or to observation. No significant differences between study populations were noted in terms of FIGO stage, tumour histology, serum CA‐125 at entry, and response to first‐line chemotherapy/prior surgery. |
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| Interventions |
Intervention Erlotinib 150 mg orally daily for 2 years (or until disease progression). If adverse events occurred, the dose could be reduced to 100 mg/d or 75 mg/d, or treatment could be stopped; dose re‐escalation was not allowed. Comparison Observation |
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| Outcomes |
Primary: PFS Secondary: OS, toxicity, occurrence of rash, quality of life Toxicity was graded according to National Cancer Institute Common Toxicity Criteria version 3.0. Quality of life was defined by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ‐C30) and OV28 (Ovarian Cancer Module) questionnaires. Overall survival (OS) erlotinib vs observation arms HR = 0.99 (95% CI 0.81 to 1.20; P = 0.903), adjusted for stratification parameters Progression‐free survival (PFS) erlotinib vs observation arms HR = 1.05 (95% CI 0.90 to 1.23; P = 0.525), adjusted for stratification parameters Median PFS 12.7 months in the erlotinib group vs 12.4 months in the observation arm QoL "QOL results were limited by low compliance (85% at baseline, ranging from 72% to 51% during the first year and < 50% during the second year); therefore, longitudinal modelling was limited to the first year only. QOL compliance was similar between the two treatment arms. Global health/QOL scores showed a significant overall difference between the two treatment arms during the first year (P = 0.0102) in favour of the observation arm. In addition, the QLQ‐C30 found statistically significant differences at the 5% level in symptom levels for diarrhoea, loss of appetite, nausea/vomiting, and fatigue, with worse symptom scores for the erlotinib arm. None of the scales, however, reported differences of ≥ 10 points except for the diarrhoea scale, in which differences of more than 20 points were observed at most assessments during the first year. Sensitivity analyses by means of imputation revealed similar results". Toxicity data Adverse events have been reported only for the intervention (erlotinib) arm, not for the observation arm, and thus cannot be included in comparison analyses. Investigators were contacted, but no further data were provided. 420 were originally assigned to erlotinib; of these, 415 received the allocated treatment. 107/415 (25.8%) participants stopped treatment because of unacceptable adverse events. Detailed toxicities for the intervention arm are listed below, with details of toxicity grade if known. Gastrointestinal toxicity Diarrhoea: grade 1: 142 (34.2%), grade 2: 87 (21.0%), grade 3: 19 (4.6%), grade 4: 1 (0.2) Abdominal pain: grade 3 or 4: 10 (2.4%) Increased γ‐glutamyl transpeptidase: grade 3 or 4: 14 (3.4%) Skin Rash: grade 1: 120 (28.9%), grade 2: 154 (37.1%), grade 3: 51 (12.3%), grade 4: 2 (0.5%) Dry skin: grade 3 or 4: 7 (1.7%) Haematological, genitourinary, neurological, or other: not reported Median follow‐up: 51 months |
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| Notes | ClinicalTrials.gov identifier: NCT00263822 This study was mentioned as an ongoing trial (MRC OV07, the Tarceva trial) in the original review; results have been published since that time. Funding source Financial support statement from the published paper "Supported by a donation from the Vlaamse Liga Tegen Kanker through the European Organisation for Research and Treatment of Cancer (EORTC) Charitable Trust, by Grant No. SCIE2006‐29 from the Stichting Tegen Kanker of Belgium (to the Katholieke Universiteit Leuven [sic], and by an unrestricted educational grant from F. Hoffmann‐La Roche (Basel, Switzerland) to the EORTC". Declarations of interest Study authors' disclosures of potential conflicts of interest from the published paper "Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(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 advisor role: Ignace B. Vergote, Roche (C); Marcia Hall, Roche (C); Christopher B. Steer, Janssen Pharmaceutica (C), Roche (C); John Green, Roche (C); Eric Pujade‐Lauraine, Roche (C) Stock ownership: none Honoraria: Ignace B. Vergote, Roche; Christopher B. Steer, Eli Lilly; Nick Simon Reed, Roche Research funding: Ignace B. Vergote, Roche; Evelyn Despierre, European Organisation for Research and Treatment of Cancer Network of Core Institutions Expert testimony: none Patents: none Other remuneration: Christopher B. Steer, Janssen Pharmaceutica, Eli Lilly Country: Belgium Setting: multi‐centre RCT Comments: funding from European Organisation for Research and Treatment of Cancer Network of Core Institutions Author's name: Ignace Vergote, MD, PhD Institution: University Hospital Leuven Email: ignace.vergote@uzleuven.be Address: University Hospital Leuven, Katholieke Universiteit Leuven, Herestraat49, B‐3000 Leuven, Belgium, European Union |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Stratified randomisation by algorithm (details kindly provided by study investigators) |
| Allocation concealment (selection bias) | Low risk | Stratified randomisation by algorithm (details kindly provided by study investigators). Allocation should not have been predictable by investigators. |
| Blinding of participants and personnel (performance bias) Objective outcome measures (Overall Survival) | Low risk | Outcome unlikely to be affected by blinding |
| Blinding of participants and personnel (performance bias) Subjective outcome measures (PFS; Toxicity; QoL) | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) Objective outcome measures (overall survival) | Low risk | Outcome unlikely to be affected by blinding |
| Blinding of outcome assessment (detection bias) Subjective outcome measures (PFS, Toxicity, QoL) | High risk | Open‐label study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Low attrition |
| Selective reporting (reporting bias) | Low risk | Prespecified and expected outcomes were reported. |
| Other bias | Unclear risk | Several investigators involved in the study received compensation from the company producing the investigated study drug (Roche, erlotinib); conflicts of interest have been declared in the study report (and are detailed in the 'Notes' section of the study table above). |
AUC: area under the curve CA‐125: cancer antigen‐125 CBR: clinical benefit rate CI: confidence interval CT: cytotoxic chemotherapy D: docetaxel ECOG: Eastern Cooperative Oncology Group EGFR: epidermal growth factor receptor EOC: epithelial ovarian cancer EORTC QLQ‐C30: European Organization for Research and Treatment of Cancer core quality of life questionnaire FACT‐O: Functional Assessment of Cancer Therapy – Ovarian FIGO: International Federation of Obstetrics and Gynecology FOSI: FACT‐O Symptom Index G6‐PDH: G6‐phosphate dehydrogenase GCIG: Gynecologic Cancer Intergroup HER: human epidermal growth factor receptor HR: hazard ratio ITT: intention‐to‐treat NOS: not otherwise specified. ORR: overall response rate OS: overall survival OV28: Ovarian Cancer Module P: pertuzumab or paclitaxel PFS: progression‐free survival QLQ‐OV28: EORTC Module for Ovarian Cancer QoL: quality of life RCT: randomised controlled trial RECIST: Response Evaluation Criteria in Solid Tumours S: seribantumab SWOG: Southwest Oncology Group TFI: treatment‐free interval ULN: upper limit of normal V: vandetanib VTE: venous thromboembolism WHO PS: World Health Organization Performance Status