Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial

doi:10.1016/S1470-2045(12)70567-3

The Lancet Oncology

Volume 14, Issue 3, March 2013, Pages 236-243

https://doi.org/10.1016/S1470-2045(12)70567-3 Get rights and content

Summary

Background

In the Gynecologic Cancer Intergroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, bevacizumab improved progression-free survival in patients with ovarian cancer when used in combination with first-line chemotherapy and as a single-drug continuation treatment for 18 cycles. In a preliminary analysis of a high-risk subset of patients, there was also an improvement in overall survival. This study aims to describe the health-related quality-of-life (QoL) outcomes from ICON7.

Methods

ICON7 is a randomised, multicentre, open-label phase 3 trial. Between Dec 18, 2006, and Feb 16, 2009, after a surgical procedure aiming to debulk the disease, women with International Federation of Gynecology and Obstetrics (FIGO) high-risk stage I–IV epithelial ovarian cancer were randomly allocated (1:1) by computer program and block randomisation to receive either six cycles of standard chemotherapy (total 18 weeks) with carboplatin (area under the curve 5 or 6) and paclitaxel (175 mg/m²) alone or with bevacizumab (7·5 mg/kg) given intravenously with chemotherapy and continued as a single drug thereafter (total 54 weeks). The primary QoL endpoint was global QoL from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire–core 30 at week 54, analysed by ANOVA and adjusted for baseline score. Analyses were by intention to treat. The ICON7 trial has completed recruitment and remains in follow-up. This study is registered, number ISRCTN91273375.

Findings

764 women were randomly assigned to the standard chemotherapy group and 764 to the bevacizumab group. At baseline, 684 (90%) of women in the standard chemotherapy group and 691 (90%) of those in the bevacizumab group had completed QoL questionnaires. At week 54, 502 (66%) women in the bevacizumab group and 388 (51%) women in the standard chemotherapy group provided QoL data. Overall, the mean global QoL score improved during chemotherapy by 7·2 points (SD 24·4) when analysed for all women with data at baseline and week 18. The mean global QoL score at 54 weeks was higher in the standard chemotherapy group than in the bevacizumab group (76·1 [SD 18·2] vs 69·7 [19·1] points; difference 6·4 points, 95% CI 3·7–9·0, p<0·0001).

Interpretation

Bevacizumab continuation treatment seems to be associated with a small but clinically significant decrement in QoL compared with standard treatment for women with ovarian cancer. The trade-off between the prolongation of progression-free survival and the quality of that period of time needs to be considered in clinical practice when making treatment decisions.

Funding

Roche and the National Institute for Health Research through the UK National Cancer Research Network.

Introduction

Angiogenesis is central to the process of cancer growth and metastasis and has a role in the progression and prognosis of ovarian cancer.1, 2 VEGF is an important promoter of angiogenesis produced by normal and neoplastic cells. Bevacizumab is a recombinant humanised version of a murine anti-human VEGF monoclonal antibody and has been studied in the management of many tumours.³ The International Collaboration on Ovarian Neoplasms 7 (ICON7) trial is a Gynecologic Cancer Intergroup phase 3 trial that assessed the effects of adding bevacizumab, concurrently and as a continuation, to standard chemotherapy with carboplatin and paclitaxel in patients with primary peritoneal carcinoma, fallopian tube carcinoma, and epithelial ovarian carcinoma (ovarian cancer). Patient characteristics, progression-free survival, toxicity, and preliminary overall survival data and a summary of quality-of-life (QoL) data have been reported from ICON7.⁴ In the standard chemotherapy group, 696 (91%) of 764 women received 18 weeks of chemotherapy by protocol. In the bevacizumab group, 719 (94%) of 764 women received 18 weeks of chemotherapy and bevacizumab and 472 (62%) continued bevacizumab to protocol completion at 54 weeks. The hazard ratio for progression-free survival with standard chemotherapy and bevacizumab was 0·81 (95% CI 0·70–0·94, p=0·004). In patients at high risk of progression, defined as International Federation of Gynecology and Obstetrics (FIGO) stage IV disease or stage III disease with greater than 1·0 cm of residual disease after debulking surgery, the hazard ratio for death in the bevacizumab group was 0·64 (95% CI 0·48–0·85; p=0·002). We noted consistent differences in QoL between the two groups that were less than a 10-point difference, and referred to the evolving interpretations of that difference as QoL data have been described in more detail.

The evaluation of treatments that achieve such gains in survival needs to include a comprehensive understanding of the other effects of these treatments on patients. Detailed health-related QoL assessment can provide a distinct and broad evaluation of the health, function, and wellbeing of people with cancer and of the functional and symptomatic benefits and losses that might result from the medical interventions. QoL is important in advanced ovarian cancer, where treatments can be effective but are only rarely curative.⁵ Even when treatments prolong progression-free or overall survival, an analysis of the effects on QoL using validated patient self-reported measures is needed to understand the life quality of that additional period. There are few detailed QoL analyses of outcomes in large first-line ovarian cancer treatment trials, which tend to publish outline data only.6, 7, 8 However, detailed descriptions of QoL can guide clinicians and patients to make informed treatment decisions and describe the experience of receiving novel cancer treatments.9, 10, 11 Moreover, well-designed, detailed, and rigorous QoL analyses are increasingly needed for regulatory approvals.12, 13 We report findings from a QoL substudy, designed at the outset of ICON7, that examined the effect of adding bevacizumab to standard chemotherapy in patients with ovarian cancer.

Section snippets

Study design

ICON7 is a randomised, multicentre, open-label phase 3 trial designed to assess the safety and efficacy of adding intravenous bevacizumab (7·5 mg/kg, intravenous over 30–90 min on day 1 of every 3-week cycle; F Hoffmann-La Roche, Basel, Switzerland) to standard intravenous chemotherapy with carboplatin (area under the curve 5 or 6 intravenous over 1 h on day 1 of every 3-week cycle) and paclitaxel (175 mg/m², intravenous over 3 h on day 1 of every 3-week cycle) in the management of patients

Results

All 1528 women (764 in both the standard chemotherapy and the bevacizumab groups) enrolled in ICON7 were asked to provide data on QoL. Table 1 shows concordance with data collection by group. At baseline, 684 (90%) women in the standard chemotherapy group and 691 (90%) in the bevacizumab group provided complete data. By 54 weeks, 388 (51%) women in the standard chemotherapy group and 502 (66%) in the bevacizumab group had provided data; 254 (33%) women who received standard chemotherapy and 147

Discussion

We present findings from detailed QoL analyses from the ICON7 study of the role of bevacizumab in the first-line treatment of epithelial ovarian cancer. Global QoL at 54 weeks was better for women receiving standard chemotherapy than for those receiving standard chemotherapy plus bevacizumab. The difference between groups was clinically small by modern criteria¹⁸ but statistically significant. Global QoL improved over the period after surgery in both groups, when cytotoxic chemotherapy was

References (27)

FA Eskens et al.
The use of bevacizumab in colorectal, lung, breast, renal and ovarian cancer: where does it fit?
Eur J Cancer
(2008)
A Bottomley et al.
Patient-reported outcomes: assessment and current perspectives of the guidelines of the Food and Drug Administration and the reflection paper of the European Medicines Agency
Eur J Cancer
(2009)
E Greimel et al.
An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian cancer
Eur J Cancer
(2003)
S Mesiano et al.
Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization
Am J Pathol
(1998)
J Yoneda et al.
Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice
J Natl Cancer Inst
(1998)
S Huang et al.
Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8
Cancer Res
(2000)
TJ Perren et al.
A phase 3 trial of bevacizumab in ovarian cancer
N Engl J Med
(2011)
A Bezjak et al.
Quality of life in ovarian cancer patients: comparison of paclitaxel plus cisplatin, with cyclophosphamide plus cisplatin in a randomized study
J Clin Oncol
(2004)
DM Chase et al.
Health-related quality of life in ovarian cancer patients and its impact on clinical management
Expert Rev Pharmacoecon Outcomes Res
(2011)
Paclitaxel plus carboplatin versus standard chemotherapy with either single-drug carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial
Lancet
(2002)

MK Parmar et al.

Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial

Lancet

(2003)

LB Wenzel et al.

Health-related quality of life during and after intraperitoneal versus intravenous chemotherapy for optimally debulked ovarian cancer: a Gynecologic Oncology Group Study

J Clin Oncol

(2007)

A Bottomley et al.

International perspective on health-related quality-of-life research in cancer clinical trials: the European Organisation for Research and Treatment of Cancer experience

J Clin Oncol

(2007)

Cited by (119)

Synthesis and electrochemical study of enzymatic graphene oxide-based nanocomposite as stable biosensor for determination of bevacizumab as a medicine in colorectal cancer in human serum and wastewater fluids
2023, Chemosphere
This work's goal was the fabrication of a graphene oxide-based nanocomposite biosensor for the determination of bevacizumab (BVZ) as a medicine for colorectal cancer in human serum and wastewater fluids. For the fabrication electrode, graphene oxide was electrodeposited on GCE (GO/GCE), and then DNA and monoclonal anti-bevacizumab antibodies were immobilized on the GO/GCE surface, respectively (Ab/DNA/GO/GCE). Structural characterization using XRD, SEM, and Raman spectroscopy confirmed the binding of DNA to GO nanosheets and the interaction of Ab with the DNA/GO array. Electrochemical characterization of Ab/DNA/GO/GCE using CV and DPV indicated immobilization of antibodies on DNA/GO/GCE and sensitive and selective behavior of modified electrodes for determination of BVZ. The linear range was obtained 10–1100 μg/mL, and the sensitivity and detection limit values were determined to be 0.14575 μA/μg.mL⁻¹ and 0.02 μg/mL, respectively. To verify the applicability of the planned sensor for determination of BVZ in human serum and wastewater fluid specimens, the outcomes of DPV measurements using Ab, DNA, GO, and GCE and the results of the Bevacizumab ELISA Kit for determination of BVZ in prepared real specimens showed good conformity between the outcomes of both analyses. Moreover, the proposed sensor showed considerable assay precision with recoveries ranging from 96.00% to 98.90% and acceptable relative standard deviations (RSDs) below 5.11%, illustrating sufficiently good sensor accuracy and validity in the determination of BVZ in prepared real specimens of human serum and wastewater fluids. These outcomes demonstrated the feasibility of the proposed BVZ sensor in clinical and environmental assay applications.
Real-world outcomes associated with use of front-line bevacizumab in ovarian cancer
2023, Journal of Cancer Policy
In the pivotal ICON7 study, addition of bevacizumab to front-line treatment of ovarian cancer (OC) significantly improved overall survival (OS) (p = 0.03) in a high-risk subgroup of patients with suboptimally debulked/unresectable stage III or IV disease, leading to approval in Ontario, Canada in March 2016. Here we describe utilization of bevacizumab for front-line, high-risk OC and determine outcomes in routine clinical practice.
Provincial administrative databases were utilized to identify all patients treated with front-line bevacizumab following its approval. Median OS (mOS) was determined using the Kaplan-Meier method. Factors associated with OS were identified using a Cox proportional hazard model. A comparative effectiveness analysis was performed to determine mOS pre- (2006–2016) and post- (2016–2019) approval.
From March 2016 to October 2019, 282 patients received bevacizumab. Mean age was 64 years old, and 58% had stage IV disease. Median survival was 29 months and was longer in stage III (37 months) compared to stage IV disease (28 months). In a comparative effectiveness analysis of patients with stage IV serous OC, post-approval uptake of bevacizumab was low (23%). Median OS was similar pre (26 months) and post (27 months) approval (HR 0.92, 0.75–1.12, p = 0.383).
Survival in real-world patients treated with front-line bevacizumab is shorter than in pivotal clinical trials. Survival in stage IV serous patients has not significantly improved post public reimbursement of bevacizumab. This analysis was limited by poor uptake, however mOS was similar in patients who did and did not receive bevacizumab.
The role of surgery in platinum-resistant ovarian cancer: A call to the scientific community
2021, Seminars in Cancer Biology
In the last decade, a growing attention has been focused on identifying effective therapeutic strategies also in the orphan clinical setting of women with platinum-resistant disease. In this context, secondary cytoreductive surgery (SCS) remains a potential approach only in women with platinum sensitive relapse, but experimental data have been published supporting the role of SCS also in patients with platinum-resistant recurrence. In particular, surgery is emerging as a potential option in specific subgroups of women, such as those patients with low-grade serous histology, or low-volume relapse with disease located in the so-called pharmacological sanctuaries. Furthermore, contrasting evidences have suggested a potential role in this clinical setting of SCS combined with intraperitoneal hyperthermic chemotherapy.
In this complex scenario we review here the available evidences regarding the role surgery in ovarian cancer patients with platinum resistant disease, trying also to understand which patients may benefit from this challenging, experimental approach.
Consolidation or maintenance systemic therapy for newly diagnosed stage II, III, or IV epithelial ovary, fallopian tube, or primary peritoneal carcinoma: A systematic review
2021, Critical Reviews in Oncology/Hematology
Citation Excerpt :
Berek et al., 2008; Markman et al., 2003; Monk et al., 2013; Sabbatini et al., 2013) Thus, the benefit of starting bevacizumab or veliparib in conjunction with adjuvant chemotherapy as a maintenance therapy is not clear. ( Burger et al., 2011; Coleman et al., 2019; Monk et al., 2013; Norquist et al., 2018; Tewari et al., 2019) Third, only the two trials assessing bevacizumab had subgroup analysis for different histological subtypes and showed that patients with low-grade serous or clear cell tumors (Gonzalez Martin et al., 2019; Oza et al., 2015; Perren et al., 2011; Stark et al., 2013) did not have benefit from bevacizumab. However, each group in the subgroup analysis had less than 110 patients and there was not a preplanned sample size calculation for subgroup analysis.
To systematically review the effectiveness and harm of consolidation or maintenance therapy in patients with newly diagnosed stage II-IV EOC.
MEDLINE, EMBASE, PubMed, Cochrane Library, and PROSPERO databases, and four relevant conferences were systematically searched. We adhered to PRISMA guidelines, and used the GRADE approach to aggregate data.
Among 12,675 citations, 28 comprising 16,310 patients were analyzed. The certainty of aggregated study evidence ranged from high to low.
The existing evidence does not find overall survival benefit for consolidation therapy with chemotherapy. For maintenance therapy, comparing with placebo, olaparib, niraparib, veliparib, and bevacizumab are effective as maintenance therapy for certain patients with newly diagnosed stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma respectively without reducing quality of life. Longer follow-up with more mature results of overall survival will better define the effect of these agents.
Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial
2021, The Lancet Oncology
Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug.
In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m² on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m² on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m² on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17.
Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related.
Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice.
Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.
When will I feel normal again? Trajectories and predictors of persistent symptoms and poor wellbeing after primary chemotherapy for ovarian cancer
2020, Gynecologic Oncology
Citation Excerpt :
The comparison of quality of life to population norms is important. Increasingly, clinical trials compare quality of life between treatment arms, but without meaningful comparison to normative data [34,37,38]. Normative comparisons may help in setting expectations for patients on treatment, if, for example, a given treatment is associated with comparable quality of life to the general population, or if quality of life deficits are likely to be confined to specific domains.
After treatment for ovarian cancer, women want to know when they will feel ‘normal’ again. Our objective was to document the proportions of women with high levels of physical and emotional symptoms at the end of treatment, determine if/when they return to normal and identify groups at risk of persistent symptoms/delayed recovery.
Women in the OPAL (Ovarian cancer Prognosis And Lifestyle) study who received ≥3 cycles of first-line chemotherapy and completed patient-reported outcome (PRO) questionnaires on or < 6 weeks after completing chemotherapy (baseline) were included in this analysis (n = 527). PRO measures included anxiety, depression, insomnia, fatigue and wellbeing (quality-of-life) at baseline, 3, 6, 9 and 18 months post-baseline. Group-based trajectory models identified clusters of individuals who followed similar patterns. Logistic and Cox regression identified factors associated with persistent symptoms and delayed recovery, respectively.
At baseline, 57% of women reported moderate-to-severe fatigue, 22% anxiety, 20% depression, 14% clinical insomnia and 45% had quality-of-life scores significantly lower than the general population. Between 50 and 75% of individual PRO scores normalised within six months, with the exception of emotional wellbeing (42%), but approximately two-in-five women still had at least one persistently poor PRO at 18 months. Women with more severe symptoms at baseline, who were younger, or had a history of anxiety/depression were more likely to have persistent symptoms or delayed recovery.
Two-in-five women might never fully return to ‘normal’ after completing primary treatment for ovarian cancer. Those with risk factors should be triaged for early supportive interventions.

View all citing articles on Scopus

View full text

ArticlesStandard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design

Results

Discussion

Eur J Cancer

Eur J Cancer

Eur J Cancer

Am J Pathol

Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice

J Natl Cancer Inst

Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8

Cancer Res

A phase 3 trial of bevacizumab in ovarian cancer

N Engl J Med

Quality of life in ovarian cancer patients: comparison of paclitaxel plus cisplatin, with cyclophosphamide plus cisplatin in a randomized study

J Clin Oncol

Health-related quality of life in ovarian cancer patients and its impact on clinical management

Expert Rev Pharmacoecon Outcomes Res

Paclitaxel plus carboplatin versus standard chemotherapy with either single-drug carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial

Lancet

Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial

Lancet

Health-related quality of life during and after intraperitoneal versus intravenous chemotherapy for optimally debulked ovarian cancer: a Gynecologic Oncology Group Study

J Clin Oncol

International perspective on health-related quality-of-life research in cancer clinical trials: the European Organisation for Research and Treatment of Cancer experience

J Clin Oncol

Articles
Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial