disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase iii trials Disease Course Patterns After Discontinuation of Bevacizumab: Pooled Analysis of Randomized Phase III Trials

Disease Course Patterns After Discontinuation of Bevacizumab: Pooled Analysis of Randomized Phase III Trials

  1. Florin Sirzén
  1. From the Mount Vernon Cancer Centre, Northwood, Middlesex; Beatson Oncology Centre, Glasgow, United Kingdom; Brustzentrum, Frauenklinik der Uniklinik Köln, Köln, Germany; Institut Gustav-Roussy, Villejuif, France; Duke University, Durham, NC; Memorial Sloan-Kettering Cancer Center, New York, NY; University Hospital Gasthuisberg, Leuven, Belgium; and F. Hoffmann-La Roche, Basel, Switzerland.
  1. Corresponding author: David Miles, MD, Mount Vernon Cancer Centre, Rickmansworth Rd, Northwood, London HA6 2RN, United Kingdom; e-mail: david.miles{at}doctors.org.uk.

  1. Presented in part at Angiogenesis: A Key Target in Oncology, October 30-31, 2009, Barcelona, Spain; the 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, TX; and the 7th Annual European Breast Cancer Conference, March 24-27 2010, Barcelona, Spain.

 
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Abstract

Purpose Preclinical studies have suggested accelerated tumor growth, local invasion, and distant metastasis after withdrawal of treatment with some antiangiogenic agents. To investigate whether discontinuation of bevacizumab treatment is associated with accelerated disease progression or increased mortality, we retrospectively analyzed five randomized, placebo-controlled phase III studies in 4,205 patients with breast, colorectal, renal, and pancreatic cancer.

Conclusion This retrospective analysis of five placebo-controlled clinical trials does not support a decreased time to disease progression, increased mortality, or altered disease progression pattern after cessation of bevacizumab therapy.

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INTRODUCTION

Macroscopic expansion of neoplastic tissue requires a supporting network of vasculature to maintain oxygenation and provide nutrients. Angiogenesis, the process whereby such vasculature develops, is complex and involves a balance between many stimulating and inhibiting factors. Key regulators of angiogenesis are vascular endothelial growth factor (VEGF) and the VEGF receptor system.1–3 VEGF is expressed throughout the growth and development of a tumor,4 and its inhibition prevents the formation of new blood vessels,5,6 causing regression of existing tumor vasculature7,8 and phenotypic normalization of the remaining blood vessels.9 Several classes of antiangiogenic agents have been developed, including monoclonal antibodies (eg, bevacizumab), which are directed against specific angiogenic growth factors or their receptors, and the less target-specific, small-molecule tyrosine kinase inhibitors of growth factor receptors (eg, axitinib, sunitinib, sorafenib).

The effects of antiangiogenic agents on tumor growth are well documented, but less is known about what happens when VEGF inhibition is suspended. In preclinical experiments, rapid reversible regrowth of blood vessels was demonstrated in RIP-Tag2 transgenic mice after cessation of treatment with axitinib, although regrowth did not exceed levels seen before treatment.10 Other preclinical studies have suggested the existence of a rebound phenomenon during treatment with or after withdrawal of some antiangiogenic agents, leading to accelerated tumor growth and increased local invasion and distant metastasis.11,12 Treatment with sunitinib resulted in tumor adaptation and a more malignant phenotype during therapy in mouse models,12 whereas short-term treatment with either sunitinib or sorafenib resulted in accelerated metastasis and reduced survival in another mouse model.11

These preclinical findings have raised general questions about accelerated disease course (ie, shorter progression-free survival [PFS] and overall survival [OS] and more aggressive metastasis pattern) in the clinical setting after cessation of antiangiogenic therapy.13 Similar concerns were also raised by health authorities that patients who discontinue such agents before disease progression might be put at risk of accelerated disease progression. The effect on clinical outcomes of discontinuing antiangiogenic treatment has not been systematically investigated to date; however, given the widely established use of bevacizumab in the clinic, the clinical course after discontinuation of this agent is of particular interest. To address this, we conducted an analysis of clinical outcomes after discontinuation of bevacizumab or placebo in five randomized, placebo-controlled clinical trials.14–19 Patients who discontinued treatment as a result of adverse events (AEs) other than disease progression were analyzed specifically because their disease had not progressed at the time of treatment discontinuation and the time from discontinuation could be measured. This population was a starting point for the present analysis; in addition, clinical outcomes were investigated in patients who discontinued treatment for any reason, and patterns of disease progression were studied in four individual studies where data were available.15–19

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METHODS

Inclusion Criteria

This retrospective analysis included data from five multicenter randomized controlled trials of bevacizumab in patients with a variety of cancers (studies BO17705 [metastatic renal cell carcinoma],15 BO17706 [metastatic pancreatic cancer],19 BO17708 [metastatic breast cancer],16,17 NO16966 [metastatic colorectal cancer],18 and AVF2107g [metastatic colorectal cancer]).14 Only data from double-blind, randomized phase III studies were used to ensure comparability of the bevacizumab and control groups. Only placebo-controlled trials were included because these trials allow a meaningful assessment of the effect of discontinuing bevacizumab. Patient eligibility criteria and study designs have been described in detail elsewhere.14–19 One placebo-controlled phase III study of bevacizumab in patients with lung cancer was excluded from the analysis (Avastin in Lung [AVAiL] study20) because the protocol allowed optional unblinding at completion of chemotherapy.

Analysis of Phase III Studies

The time from discontinuation of bevacizumab or placebo to disease progression or death (whichever occurred sooner) was analyzed in patients who discontinued bevacizumab or placebo prematurely as a result of AEs. Results were calculated for the individual studies and the pooled data from the five selected studies.

All-cause mortality rates were calculated at 30, 60, 90, 120, 150, 180, and 210 days after the last bevacizumab/placebo dose in the following two groups of patients: patients who discontinued bevacizumab or placebo as a result of AEs and patients who discontinued bevacizumab or placebo for any reason. Results were calculated for the individual studies as well as for the pooled data set. These landmark analyses were chosen based on the assumption of being less influenced by subsequent lines of therapy than a Kaplan-Meier analysis.

In the pooled data set, time to death was calculated for patients who discontinued bevacizumab or placebo as a result of AEs and for any reason to examine the long-term effect of bevacizumab discontinuation in a larger population. Pooled PFS and OS analyses based on the intent-to-treat populations of the five selected studies were performed to facilitate the interpretation of the aforementioned analyses.

Disease progression patterns were analyzed in studies BO17705, BO17706, BO17708, and NO16966. Records of patients with disease progression were analyzed to identify the site of disease recurrence. Two different sources of information concerning disease progression were available in the case report form; these were tumor assessment pages, which also contained information about new lesions, and survival follow-up pages, where only the date of disease progression was captured. Information in the tumor assessment pages was used for the analysis of disease progression patterns. As a result of limitations in data collection, the site of progressive disease could not be assessed in study NO16966.

Statistical Analysis

The analyses were performed at the Biometrics Department at F. Hoffmann-La Roche (Basel, Switzerland) using pooled individual patient data from the five studies. With the exception of the PFS and OS analyses, which were performed in the pooled intent-to-treat population of the five studies, the analyses presented are based on nonrandomized subgroups. These analyses are exploratory and not powered to detect statistically significant differences; therefore, no formal statistical testing was performed. In addition, the pooled analysis presented is based on the assumption that any accelerated disease progression is related to vascular regrowth that is independent of the tumor type and chemotherapy given, as well as the age, sex, and other baseline characteristics of the population. For these reasons, results should be interpreted with caution because pooling data from studies in a variety of tumors and populations is not optimal but allows investigation of the effect in question in an adequately sized population.

The Kaplan-Meier method was used to estimate median durations together with 95% CIs. Because the patient populations, treatment indications, and chemotherapy regimens differed in the five studies, a categoric variable of study was used to adjust for study-specific differences. The hazard ratio (HR) and corresponding 95% CIs for the combined bevacizumab group relative to the combined control group were estimated from the stratified Cox model including only treatment as covariate, stratified by study. Mortality rates were derived for 30, 60, 90, 120, 150, 180, and 210 days after the last bevacizumab/placebo dose (defined as the number of patients who died within 30, 60, 90, 120, 150, 180, or 210 days after the last bevacizumab/placebo dose divided by this number plus the number of patients known to be alive at 30, 60, 90, 120, 150, 180, or 210 days after the last bevacizumab/placebo dose).

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RESULTS

Data from 4,205 patients who were enrolled onto five randomized phase III studies of standard therapy plus bevacizumab or placebo were included in this analysis.14–19 Efficacy and safety results from these individual studies have been published elsewhere.14–19 Study details are listed in Table 1. The results of the pooled PFS and OS analyses of these five studies are provided in Appendix Table A1 (online only) and Figure 1.

View this table:
Table 1.

Median Time From Treatment Discontinuation As a Result of Adverse Events to Disease Progression or death

Reasons for discontinuation of treatment collected in these five studies included progressive disease, AEs, administrative/other causes, withdrawal of consent, refused treatment/did not cooperate, violation of selection criteria at entry, other protocol violations, failure to return, physician's decision, and death. Time from discontinuation of bevacizumab/placebo as a result of AEs to progression or death was similar in the two groups, both in the pooled data set (Fig 2A) and the individual studies (Appendix Fig A1, online only). In the pooled data set, median time from discontinuation as a result of AEs to progressive disease or death was 4.0 months (95% CI, 3.4 to 4.6 months) in the bevacizumab group and 3.0 months (95% CI, 2.6 to 3.8 months) in the placebo group (HR, 0.93; 95% CI, 0.79 to 1.10; Table 1).

Among patients who discontinued treatment because of AEs, mortality rates at 30, 60, 90, 120, 150, 180, and 210 days after the last dose of bevacizumab/placebo were similar in both groups of patients. The results of the pooled analysis (Fig 2B) were in agreement with the individual trial data (Appendix Fig A2, online only).

The analysis of time from discontinuation of bevacizumab/placebo as a result of an AE to death in the pooled data set revealed similar times from discontinuation to death in patients treated with bevacizumab compared with those in the placebo group (Fig 2C). Among patients who discontinued treatment as a result of AEs, the median time from discontinuation to death was 11.9 months (95% CI, 10.6 to 14.1 months) in the bevacizumab group and 11.7 months (95% CI, 8.8 to 14.1 months) in the placebo group (HR, 0.94; 95% CI, 0.77 to 1.14).

Similar results were observed when the analyses were expanded to include patients who discontinued treatment for any reason. Median time from discontinuation to death was 10.2 months (95% CI, 9.6 to 10.7 months) in the bevacizumab group and 9.3 months (95% CI, 8.7 to 10.0 months) in the placebo group (HR, 0.94; 95% CI, 0.86 to 1.02; Fig 3A). Mortality rates at 30, 60, 90, 120, 150, 180, and 210 days after the last dose of bevacizumab or placebo were also similar in bevacizumab- and placebo-treated patients who discontinued treatment for any reason (Fig 3B). The results of the pooled analysis were in agreement with the individual trial data (Appendix Fig A2).

Data on patterns of disease progression were available for studies BO17705, BO17706, BO17708, and NO16966. The number of new lesions was similar in bevacizumab-treated patients compared with patients receiving placebo. In BO17705, 120 (55%) of 217 bevacizumab-treated patients with progressive disease had evidence of a new lesion, and 143 (53%) of 269 placebo-treated patients with progressive disease had a new lesion. Similarly, there was no difference in studies BO17706, BO17708, and NO16966 between the bevacizumab and placebo groups regarding the proportion of patients who experienced progression with a new lesion or site of disease progression, as shown in Table 2. Sites of disease progression were similar in bevacizumab- and placebo-treated patients in the studies in which this information was available (BO17705, BO17706, and BO17708; Table 2).

View this table:
Table 2.

Disease Progression Patterns

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DISCUSSION

The analyses presented in this article were conducted to address the question of whether bevacizumab-treated patients who discontinued treatment prematurely were at an increased risk of an accelerated disease course. In the analysis of time to progressive disease or death after discontinuation of bevacizumab/placebo as a result of AEs, bevacizumab-treated patients had a similar median time from treatment discontinuation to progression or death as those who were treated with placebo. Analysis of mortality rates in patients discontinuing bevacizumab/placebo as a result of AEs did not identify any difference between the groups at any of the time points studied, either in the individual studies or in the pooled data set. Results seen at the earliest time points are of particular interest because they are less likely to be influenced by second and later lines of therapy. Nevertheless, in the longer term, the pooled analysis of the time from discontinuation to death in patients discontinuing treatment prematurely as a result of AEs did not show a decreased time from discontinuation to death in the bevacizumab group compared with the placebo group. Evaluation of postdiscontinuation outcome was then extended to the larger population of patients who ceased treatment for any reason. This group, however, consisted primarily of patients discontinuing treatment as a result of disease progression, and therefore, only mortality rates and time from bevacizumab/placebo discontinuation to death were examined. As with the previous analyses, there was no indication of increased mortality rates or decreased OS from the discontinuation time point in the bevacizumab group compared with the placebo group.

Disease progression patterns were analyzed where possible and provided further evidence that bevacizumab-treated patients experienced a similar pattern after withdrawal of treatment compared with patients in the placebo groups. In the four studies where such an analysis could be performed, similar proportions of patients in the bevacizumab and placebo groups had progressive disease defined by the presence of one or more new lesions. The pattern of new sites of disease was comparable in the three studies where this information was available.

Several of the analyses performed included a small number of patients, and the low power may have contributed to the fact that no differences were demonstrated. Moreover, data were obtained from different studies in different indications and study populations, and potential confounding factors were not collected in a uniform way. Because the analyses were not adjusted for potential confounding factors, bias cannot be ruled out. Although the current retrospective analyses were based on nonrandomized subgroups of patients with a variety of tumors, some including only a small number of patients, the results are consistent across all five individual studies and the pooled populations, with none of the analyses providing any indication of accelerated progression after bevacizumab discontinuation.

Additional clinical information is now available in the adjuvant colon cancer setting. The National Surgical Adjuvant Breast and Bowel Project C08 study randomly assigned patients with stage II or III colon cancer to either modified fluorouracil/leucovorin and oxaliplatin (mFOLFOX6) for 6 months or mFOLFOX6 for 6 months plus bevacizumab for 1 year.21 In a landmark analysis after 1 year of treatment, at which time bevacizumab was discontinued, there was no indication of an increased risk of subsequent relapse in the bevacizumab group. In addition, after a median follow-up time of 3 years, there was no apparent increase in rates of recurrence, death, secondary cancers, or multiple sites of recurrence in bevacizumab-treated patients compared with patients in the control group, and there was no difference in 2-year postrecurrence survival. Longer follow-up is required to establish a definitive outcome in this study.

In conclusion, this retrospective analysis of five placebo-controlled randomized phase III trials that investigated the efficacy and safety of bevacizumab in patients with metastatic breast, renal, colorectal, and pancreatic cancer does not support a decreased time to disease progression, increased mortality, or altered disease progression patterns after cessation of bevacizumab therapy.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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: Barbara Mueller, F. Hoffmann-La Roche (C); Florin Sirzén, F. Hoffmann-La Roche (C) Consultant or Advisory Role: David Miles, Roche (C); Nadia Harbeck, Roche (C), sanofi-aventis (C); Bernard Escudier, Roche (C), Bayer Pharmaceuticals (C), Pfizer (C); Herbert Hurwitz, Roche (C), Genentech (C), Bristol-Myers Squibb (C), Amgen (C); Leonard Saltz, Roche (C), Genentech (C), ImClone Systems (C), Bristol-Myers Squibb (C), Eli Lilly (C), Merck (C), Schering-Plough (C), Novartis (C), Biothera (C), Celgene (C), Alchemia (C); Eric Van Cutsem, Roche (C); Jim Cassidy, Roche (C), sanofi-aventis (C), Amgen (C) Stock Ownership: Barbara Mueller, F. Hoffmann-La Roche; Florin Sirzén, F. Hoffmann-La Roche Honoraria: David Miles, Roche; Nadia Harbeck, Roche, sanofi-aventis; Bernard Escudier, Roche, Genentech, Bayer Pharmaceuticals, Pfizer, Novartis; Herbert Hurwitz, Roche; Jim Cassidy, Roche, sanofi-aventis Research Funding: Nadia Harbeck, Roche, sanofi-aventis; Herbert Hurwitz, Roche, Bristol-Myers Squibb, Amgen; Leonard Saltz, Roche, Genentech, ImClone, Bristol-Myers Squibb, Eli Lilly, Merck, Amgen, Biothera, Bayer Pharmaceuticals; Eric Van Cutsem, Roche; Jim Cassidy, Roche, sanofi-aventis Expert Testimony: None Other Remuneration: None

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AUTHOR CONTRIBUTIONS

Conception and design: David Miles, Nadia Harbeck, Bernard Escudier, Florin Sirzén

Administrative support: Florin Sirzén

Provision of study materials or patients: David Miles, Nadia Harbeck, Bernard Escudier, Herbert Hurwitz, Leonard Saltz, Eric Van Cutsem, Jim Cassidy

Collection and assembly of data: David Miles, Nadia Harbeck, Bernard Escudier

Data analysis and interpretation: David Miles, Nadia Harbeck, Bernard Escudier, Herbert Hurwitz, Leonard Saltz, Eric Van Cutsem, Jim Cassidy, Barbara Mueller, Florin Sirzén

Manuscript writing: David Miles, Nadia Harbeck, Bernard Escudier, Herbert Hurwitz, Leonard Saltz, Eric Van Cutsem, Jim Cassidy, Barbara Mueller, Florin Sirzén

Final approval of manuscript: David Miles, Nadia Harbeck, Bernard Escudier, Herbert Hurwitz, Leonard Saltz, Eric Van Cutsem, Jim Cassidy, Barbara Mueller, Florin Sirzén

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Acknowledgment

Medical writing/editing support was provided by Lee Miller and Deirdre Carman of Miller Medical Communications, United Kingdom. The medical writing/editing support was funded by F. Hoffmann-La Roche.

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Appendix

⇓

Fig A2.
View larger version:
Fig A2.

Mortality at 30, 60, 90, 150, 180, and 210 days after discontinuation of bevacizumab/placebo in patients who discontinued bevacizumab/placebo as a result of adverse events (AEs) or for any reason in randomized controlled trials (A) BO17705, (B) BO17706, (C) BO17708, (D) NO16966, and (E) AVF2107g.

View this table:
Table A1.

Study Outcomes

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Footnotes

  • Supported in part by F. Hoffmann-La Roche, Basel, Switzerland.

  • 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: NCT00738530.

  • Received May 3, 2010.
  • Accepted October 4, 2010.
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  1. Published online before print November 22, 2010, doi: 10.1200/JCO.2010.30.2794 JCO vol. 29 no. 1 83-88
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