Comment
must be tempered by the numerous negative
combination studies already completed. Nevertheless,
the introduction of more efficacious agents could
mean that such studies might be revisited. The design
and limitations of the study would generally require
that the efficacy results be confirmed; however, the
suggestion by Kellokumpu-Lehtinen and colleagues of
additional phase 3 studies of this 2-weekly docetaxel
regimen might not be the best use of resources. With
current and likely future availability of additional
agents that improve overall survival and patient
reported outcomes, it seems more sensible to study
new drugs or combinations and to discover and
validate predictive biomarkers.
*David M Nanus, Scott T Tagawa
Division of Hematology and Medical Oncology, Department of
Medicine, Weill Cornell Medical College, New York, NY 10065, USA
dnanus@med.cornell.edu
Bevacizumab in breast cancer: fundamental questions remain
Use of bevacizumab with first-line chemotherapy for
treatment of metastatic breast cancer is controversial.
An open-label study1 (E2100) examined the role of
bevacizumab with weekly paclitaxel and showed a
6 month improvement in median progression-free
survival (PFS) compared with paclitaxel alone. As a
consequence, the US Food and Drug Administration
(FDA) granted accelerated approval for its use.
Subsequent double-blind studies with other
chemotherapies confirmed statistically significant but
more modest improvements in PFS.2,3 None of these
studies showed improvement in overall survival. In
view of the absence of survival benefit and the PFS
benefits noted in later studies, together with toxic
effects from all disease indications, the FDA took the
unusual step of withdrawing the label for bevacizumab
for the treatment of metastatic breast cancer.
Conversely, the European Medicines Agency (EMA)
approved its use with paclitaxel and capecitabine.
The question arises, for clinicians able to use
bevacizumab, as to which treatment regimen patients
might prefer. The TURANDOT study4 compares the
two bevacizumab-containing regimens approved
by the EMA—the rational basis being that patients
www.thelancet.com/oncology Vol 14 February 2013
STT has received honoraria from sanofi-aventis as a consultant and member
of the speakers’ bureau. DMN declares that he has no competing interests.
1 Extra JM, Rousseau F, Bruno R, Clavel M, Le BN, Marty M. Phase I and
pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a
short intravenous infusion. Cancer Res 1993; 53: 1037–42.
2 Petrylak DP. Docetaxel (Taxotere) in hormone-refractory prostate cancer.
Semin Oncol 2000; 27 (suppl 3): 24–29.
3 Beer TM, Pierce WC, Lowe BA, Henner WD. Phase II study of weekly
docetaxel in symptomatic androgen-independent prostate cancer.
Ann Oncol 2001; 12: 1273–79.
4 Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med
2004; 351: 1502–12.
5 Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine
compared with mitoxantrone and prednisone for advanced refractory
prostate cancer. N Engl J Med 2004; 351: 1513–20.
6 Kellokumpu-Lehtinen P-L, Harmenberg U, Joensuu T, et al, for the
PROSTY study group. 2-weekly versus 3-weekly docetaxel to treat
castration-resistant advanced prostate cancer: a randomised, phase 3
trial. Lancet Oncol 2013; published online Jan 4. http://dx/doi.
org/10.1016/S1470-2045(12)70537-5.
7 Hervonen P, Joensuu H, Joensuu T, et al. Biweekly docetaxel is better
tolerated than conventional three-weekly dosing for advanced
hormone-refractory prostate cancer. Anticancer Res 2012; 32: 953–56.
might prefer capecitabine on the grounds of
Steve Gschmeissner/Science Photo Library
tolerability and convenience, providing that survival
is not compromised. The investigators chose a non-
inferiority study design with a boundary of 1·33 for
hazard ratio (HR) for overall survival—ie, an increased
risk of death of 33% or more over the duration of
the study for the capecitabine-containing regimen
would be regarded as non-inferior. At this interim See Articles page 125
analysis, the HR for overall survival was 1·04 but with
an upper 97·5% CI boundary (1·69) that exceeded the
prespecified limit. The result of this study (with respect
to overall survival at least) is appropriately described as
“inconclusive”. The investigators suggest that survival
at 12 and 24 months are much the same between
groups but firm conclusions regarding survival must
await the final analysis, expected in 2014.
Other efficacy measures are of interest. Response
rates and PFS estimates are much the same as reported
data,1,3 being higher for paclitaxel plus bevacizumab
than for capecitabine plus bevacizumab (44% vs 27%
and 11·0 months vs 8·1 months, respectively). PFS
with paclitaxel plus bevacizumab (11·0 months) is
similar to the 11·4 months reported in the E2100 trial.
Together with data from other studies, PFS results
99
 Comment
from TURANDOT counter the view that the E2100
result was “an outlier”.5
The TURANDOT investigators documented use of
treatments after study therapy. At this analysis, more
than half of eligible patients received subsequent lines
of chemotherapy, most commonly with the agent not
previously received. Therapy after disease progression
and the relatively long (more than 12 months) post-
progression survival are recognised as reasons for the
failure, in breast cancer at least, of PFS to represent a
surrogate for overall survival.6
If overall survival is much the same between the
two regimens, what of tolerability and preference of
patients? The investigators report toxic effects with
differences commensurate with the known side-effects
of the chemotherapy drugs: more myelosupression,
neuropathy, alopecia, and nail disorders with paclitaxel
but more hand-foot syndrome and gastrointestinal
disturbances with capecitabine. Grade 3 and 4
hypertension was noted in 5% of patients, presumably
attributable to bevacizumab, but reassuringly, no
other major toxic effects were noted.
Quality of life was assessed with the EORTC Quality
of Life Core Questionnaire 30. Not all patients
completed quality-of-life forms and availability of
questionnaires decreased with time as patients came
off study. Analysis of mean scores of global health
status and individual domains showed no changes
over time or between the two treatment groups.
If overall survival and quality of life are indeed
similar, the investigators suggest that the choice of
regimen should be based on an individual’s treatment
goals. This suggestion raises questions of relevance
to patients, physicians, and licensing authorities: in
the absence of an effect on overall survival, what is
the intrinsic value of reduction of tumour burden
(response) and an increased time for which disease is
controlled (PFS)? Although researchers might assume
that increased response rates and improvement in PFS
might lead to better quality of life, this assumption
is rarely assessed. Description of the proportion
of patients who have a meaningful improvement
in quality-of-life scores and the time for which
improvement is sustained might be of more value
than quotation of mean values for the population.
Increasing use of patient-reported outcomes should
also contribute in this respect.7,8
100
The TURANDOT trial allows an informed discussion
with patients about the relative benefits of each
of these bevacizumab-containing regimens. In the
absence of obvious differences in overall survival, an
understanding of how other efficacy endpoints might
translate into meaningful consequences for quality of
life of patients requires clarification in this and indeed
most other studies.
As exemplified by the differing responses of the
licensing authorities, a fundamental controversy
remains, concerning the perceived value of
bevacizumab in the treatment of metastatic breast
cancer. Progress in this respect might involve the
identification of patients most likely to benefit.
Genomic, serological, and dynamic markers have
been implicated in retrospective analyses of clinical
trials of bevacizumab, but none have been assessed
prospectively. In two first-line randomised studies in
metastatic breast cancer, high plasma concentrations
of VEGF-A were associated with poor prognosis
and benefit of bevacizumab in terms of PFS.9,10 This
association is being assessed prospectively in a double-
blind, randomised study of weekly paclitaxel with or
without bevacizumab in which VEGF-A concentration
at study entry is a stratification factor (EUDRACT
2011-005335-97).
With more rational development of bevacizumab,
on the basis of an understanding of its biology and
mechanisms of action, researchers might ultimately
yield greater benefits for patients.
David W Miles
Mount Vernon Cancer Centre, Northwood, Middlesex HA6 2RN, UK
david.miles@doctors.org.uk
I have received honoraria from Roche and Genentech for advisory boards.
1 Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus
paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;
357: 2666–76.
2 Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus
docetaxel compared with placebo plus docetaxel for the first-line
treatment of human epidermal growth factor receptor 2-negative
metastatic breast cancer. J Clin Oncol 2010; 28: 3239–47.
3 Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind,
placebo-controlled, phase III trial of chemotherapy with or without
bevacizumab for first-line treatment of human epidermal growth factor
receptor 2-negative locally recurrent or metastatic breast cancer.
J Clin Oncol 2011; 29: 1252–60.
4 Lang I, Brodowicz T, Ryvo L, et al, on behalf of the Central European
Cooperative Oncology Group. Bevacizumab plus paclitaxel versus
bevacizumab plus capecitabine as first-line treatment for HER2-negative
metastatic breast cancer: interim efficacy results of the randomised,
open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol 2013;
14: 125–33.
www.thelancet.com/oncology Vol 14 February 2013

5 Fojo T, Wilkerson J. Bevacizumab and breast cancer: the E2100 outlier.
Lancet Oncol 2010; 11: 1117–19.
6 Saad ED, Katz A, Buyse M. Overall survival and post-progression survival
in advanced breast cancer: a review of recent randomized clinical trials.
J Clin Oncol 2010; 28: 1958–62.
7 Lee CK, Stockler MR, Coates AS, et al, for the Australian New Zealand
Breast Cancer Trials Group. Self-reported health-related quality of life is
an independent predictor of chemotherapy treatment benefit and
toxicity in women with advanced breast cancer. Br J Cancer 2010;
102: 1341–47.
8 Guyatt G, Schunemann H. How can quality of life researchers make their
work more useful to health workers and their patients? Qual Life Res
2007; 16: 1097–105.
Towards individualised treatment in ovarian cancer
Results of recent studies have greatly changed our
understanding of ovarian carcinogenesis. The time-
honoured notion that ovarian cancer originates
from epithelium on the surface of the ovaries that
invaginates into the underlying stroma, undergoes
malignant transformation, and then spreads from
the ovary to distant pelvic and intra-abdominal sites
has been abandoned. Instead, a dualistic model
was proposed for a group of rather indolent and
genetically stable tumours (type I) and a large group
of highly aggressive and genetically unstable tumours
(type II).1 Type I tumours often are diagnosed in
early stage, confined to the ovary, and develop from
precursors such as borderline ovarian tumours,2
whereas type II cancers present at an advanced stage
and originate from a putative precursor lesion in the
fallopian tube. On the molecular level, type II tumours
are characterised by a high rate of TP53 mutations and
often have deficient homologous recombination and
repair of double-strand DNA breaks.3 This difficiency
has led to promising new treatment approaches
with PARP inhibitors, both as a single agent4 and in
combination with cytotoxic drugs.5 So far, analogue-
targeted approaches for type I ovarian carcinomas
have not been established, although this subgroup is
also characterised by distinct molecular alterations.6 In
many of them, there is a constitutive activation of the
MAP-kinase signalling pathway because of mutations
in ERBB2, KRAS, or BRAF.7
Based on this knowledge, John Farley and
collaborators have tested selumetinib, a selective
inhibitor of the MAP kinases MEK 1/2, in patients with
recurrent low-grade serous ovarian cancer, representing
an important subgroup of type I tumours.8 Low-grade
www.thelancet.com/oncology Vol 14 February 2013
Comment
9 Miles DW, de Haas SL, Dirix L, et al. Plasma biomarker analyses in the
AVADO phase III randomized study of first-line bevacizumab plus
docetaxel in patients with human epidermal growth factor receptor
(HER) 2-negative metastatic breast cancer. Cancer Res 2010;
70 (suppl 24): S235 (abstr P2-16-04).
10 Gianni L, Romieu G, Lichinitser M, et al. First results of AVEREL,
a randomized phase III trial to evaluate bevacizumab (BEV) in
combination with trastuzumab (H) plus docetaxel (DOC) as first-line
therapy for HER2-positive locally recurrent/metastatic breast cancer
(LR/mBC). Cancer Res 2011; 71 (suppl 24): S109 (abstr S4–8).
serous ovarian cancer is known as a rather indolent
malignancy that has a favourable prognosis compared
with high-grade disease, but is more or less refractory
to cytostatic treatment. Farley and colleagues’ open-
Medical Rf.Com/Science Photo Library
label, single-arm phase 2 study is the first prospective
trial specifically undertaken in patients with low-grade
serous carcinoma. Single-agent selumetinib resulted in
an objective response rate of 15% and a very high rate
of disease stabilisation (an additional 65%), which is
particularly promising in a setting of heavily pretreated See Articles page 134
recurrent disease, with most patients having received
three or more previous lines of chemotherapy. In such
a population, it is often difficult to assess treatment-
related toxicities—in the current study, 42% of patients
had dose reductions and 25% discontinued selumetinib
because of toxicity. Future trials should, therefore,
define the optimum dose of selumetinib and the
application of supportive therapy.
A strength of the study is mandatory reference
pathology of recurrent disease to ensure exclusion
of patients with (progression to) high-grade disease
who are likely to benefit from chemotherapy and
recurrent borderline ovarian tumours that have
excellent prognosis with salvage surgery alone. Farley
and collaborators also analysed the mutation status
of BRAF and KRAS to validate the biological concept of
constitutive activation of the MAP-kinase signalling
pathway. However, sufficient paraffin-embedded tissue
was available for only 65% of the included patients.
This lack of availability might also have contributed to
the unexpected result of a lack of correlation between
mutation status and response and outcome, despite
the convincing biological hypothesis. One can only
speculate whether results were confounded by the
101