letter to the editor - Annals of Oncology

letter to the editor
Reply to ‘Conclusions regarding
relative cost–utility of alternative
strategies for use of aromatase
inhibitors in postmenopausal
women with early breast cancer
are premature’ by Delea et al.
The letter by Delea et al. [1] raises several interesting questions
with respect to cost–utility assessment. In principle, such
analyses may be conducted in two different ways: we may
calculate utilities based on actual data from the literature, which
is the most common practice, or we may do what I did [2], i.e.
assume a certain long-term effect and see whether that should
provide a reasonable cost–utility estimate. For reasons to be
explained below, I believe the second option is of particular
value when assessing use of aromatase inhibitors at this stage.
In the first part of their letter, Delea et al. discuss the relapse
rates detected in the different phase III studies. This is an
interesting topic indeed; nevertheless, it is difficult to see the
relevance to the discussion of the model applied in this study.
Here, the assumption was that each approach (an aromatase
inhibitor upfront or following 2–3 or 5 years on tamoxifen)
would cause a 2% absolute improvement in long-term relapsefree
survival and, if so, what would be the difference with
respect to cost–utility? The reason for using such an approach is
the uncertainty regarding long-term effects with aromatase
inhibitors. Neither the data from the MA17 or any of the other
phase III trials allow us to estimate long-term effects with
respect to efficacy or toxicity. A few examples may illustrate
this. Based on safety data, the argument has been raised that
there could be a difference in cardiovascular morbidity between
anastrozole and letrozole. If so, it may be related to a more
potent aromatase inhibition of letrozole compared with
anastrozole [3]. In case this has an impact on the side-effect
profile, we could assume a difference with respect to antitumor
efficacy as well. Similarly, the minor androgen-agonistic activity
of exemestane [4] may impact not only on bone density, but
could explain the lack of complete cross-resistance between the
individual aromatase inhibitors [5], enhancing antitumor
efficacy.
Thus, we are left with a number of open questions regarding
potential differences between individual drugs, regimen of
application (monotherapy versus sequential) as well as longterm
effects. Using a model as applied—comparing cost–utility
between different approaches based on assumption of similar
efficacy as well as side-effects between compounds—may allow
ª 2006 European Society for Medical Oncology
Annals of Oncology Advance Access published July 27, 2006
Annals of Oncology
the reader to compare follow-up results to the assumptions
included in the model. It is difficult to see why the details
provided by Delea et al. with respect to short-time results
should refute this approach. On the contrary, the fact that
annual risk of breast cancer relapse is a non-linear process
invalidates any form of indirect comparison of benefits between
trials as indicated by Delea et al.
Next, they criticize the study for not including a potential
impact on contralateral breast cancer and costs of recurrence.
With due respect, these data are provided in Table 4 and
Figure 4, respectively [2]. The reason for not including them
in the initial analysis is the uncertainties with respect to these
parameters. While preliminary results from the phase III studies
indicate a dramatic reduction in contralateral breast cancer, we
lack information as to whether this could be a short- or longterm
effect. Considering costs of treatment of relapse, this
scenario is rapidly changing due to implementation of novel,
expensive targeted therapies as well as cytotoxic compounds.
Also, there are reasons to believe that these costs may vary
considerably between different countries. Accordingly, the
result of this analysis is presented as a separate diagram. As
pointed out by Delea et al., tamoxifen has a beneficial effect on
BMD in postmenopausal women [6], although its effect with
respect to preventing fractures is more difficult to estimate.
Furthermore, it is not obvious that treating patients with
tamoxifen for 5 years before implementing an aromatase
inhibitor may prevent potential detrimental effects on bone
metabolism. Considering data from the MA 17 [7], the
difference in annual bone loss between the letrozole arm and
the placebo arm was greater than that recorded in the 027
protocol comparing exemestane with placebo in tamoxifennaive
patients [8, 9]. Assessing the impact of an increased
fracture risk on cost–utility, similar to that for survival, these
are theoretical assumptions, illustrating different scenarios.
Again, by providing these estimates, it allows future readers to
assess cost–utility based on follow-up results.
Considering potential effects of tamoxifen on cardiovascular
events and death, this is a complex issue. Looking at the most
recent Oxford meta-analysis [10], the number of trials by which
the exact cause of CV mortality was reported is low with
a limited number of observations. Looking at the risk of CV
death, there seems to be a small benefit in favor of tamoxifen in
comparison to placebo, although the statistical significance is
border-line. While recent evidence suggests potential benefits
may appear several years after terminating tamoxifen [11],
hence further complicating this issue, evidence from the WHI
study [12] indirectly suggests hormonal manipulation may
have minor effects on CV death. I concur with the statement by
Delea et al. that we need more information, in particular with
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letter to
the editor

letter to the editor
respect to long-term data to learn all the details with respect to
effectiveness. I do not, however, concur with their negative and
unsubstantiated statement claiming this analysis fails with
respect to assumptions and interpretation of results.
E. Lonning*
Institute of Medicine Haukeland University Hospital, Department of
Oncology, Bergen, Norway
(*E-mail: per.lonning@helse-bergen.no)
references
1. Delea TE, Karnon J, Goss PE. Conclusions regarding relative cost-utility of
alternative strategies for use of aromatase inhibitors in postmenopausal women with
early breast cancer are premature. Ann Oncol; doi:10.1093/annonc/mdl171.
2. Lønning PE. Comparing cost/utility of giving an aromatase inhibitor as
monotherapy for 5 years versus sequential administration following 2–3 or 5
years of tamoxifen as adjuvant treatment for postmenopausal breast cancer. Ann
Oncol 2006; 17: 217–225.
3. Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE. Influence of letrozole
(Femara) and anastrozole (Arimidex) on total body aromatization and plasma
estrogen levels in postmenopausal breast cancer patients evaluated in
a randomized, cross-over-designed study. J Clin Oncol 2002; 20: 751–757.
4. Johannessen DC, Engan T, Salle ED et al. Endocrine and clinical effects of
exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in
postmenopausal breast cancer patients: a phase I study. Clin Cancer Res 1997;
3: 1101–1108.
2 | letter to the editor
5. Lønning PE, Bajetta E, Murray R et al. Activity of exemestane in metastatic breast
cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. J Clin
Oncol 2000; 18: 2234–2244.
6. Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S. Effect of tamoxifen on
bone mineral density measured by dual-energy X-ray absorptiometry in
healthy premenopausal and postmenopausal women. J Clin Oncol 1996;
14: 78–84.
7. Perez EA, Josse RG, Pritchard KI et al. Effect of letrozole versus placebo on
bone mineral density in women completing >5 years (yrs) of adjuvant
tamoxifen: ncic ctg ma.17b. Breast Cancer Res Treat 2004; 88 (Suppl 1):
Abstr 404, s36.
8. Lønning PE, Geisler J, Krag LE et al. Effects of exemestane administered for 2
years versus placebo on bone mineral density, bone biomarkers, and plasma
lipids in patients with surgically resected early breast cancer. J Clin Oncol 2005;
23: 5126–5137.
9. Geisler J, Lønning PE. Aromatase inhibitors as adjuvant treatment of breast
cancer. Crit Rev Oncol Hematol 2006; 57: 53–61.
10. Group EBCTC. Effects of chemotherapy and hormonal therapy for early breast
cancer on recurrence and 15-year survival: an overview of the randomised trials.
Lancet 2005; 365: 1687–1717.
11. Nordenskjold B, Rosell J, Rutqvist LE et al. Coronary heart disease mortality after
5 years of adjuvant tamoxifen therapy: Results from a randomized trial. Journal of
the National Cancer Institute 2005; 97: 1609–1610.
12. Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated, equine
estrogen in postmenopausal women with hysterectomy. The women’s
health initiative randomized controlled trial. JAMA 2004; 291:
1701–1712.
doi:10.1093/annonc/mdl170
Annals of Oncology
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