Evidence-based Oncology
Volume 1 • Number 3 • September 2000
Copyright © 2000 Harcourt Brace & Company Ltd.





  _____


95


Cost-effectiveness analysis

  _____


Pamidronate associated with high incremental costs per adverse event avoided
in patients with metastatic breast cancer


Hillner BE, Weeks JC, Desch CE, Smith TJ. Pamidronate in prevention of bone
complications in metastatic breast cancer: a cost-effectiveness analysis. J
Clin Oncol 2000; 18: 72-79

QUESTION

Is pamidronate a cost-effective treatment for reducing bony complications in
patients with metastatic breast cancer who have known osteolytic lesions?

DESIGN

A post-hoc evaluation of the cost-effectiveness of pamidronate.

SETTING

Data from two randomized trials (Aredia Breast Cancer Study Group Protocols
18 and 19) that evaluated pamidronate 90 mg administered intravenously every
month vs placebo were analyzed. Each protocol was an international,
multicenter, randomized, double-blind, parallel trial of women with
metastatic breast cancer with one or more osteolytic lesions at least 1 cm
in diameter. All women received systemic therapy. The trials differed only
in the initial systemic therapy administered (hormonal or chemotherapy).
Primary end-point of the trials was skeletal-related events (SREs), an
aggregate of all bony complications. Median age was approximately 57 years.
Approximately 60% of women had bony involvement as their sole site of
metastates, and approximately 65% had an Eastern Cooperative Oncology Group
performance score of 0 or 1. Both trials clearly showed that pamidronate was
effective in reducing SREs.

PATIENTS

A hypothetical group of women meeting the entry criteria for the two trials.

INTERVENTIONS

Total SREs, including surgery for pathologic fracture, radiation for
fracture or pain control, conservatively treated pathologic fracture, spinal
cord compression, or hypercalcemia, were taken directly from the trials.
Using a societal perspective, direct health-care costs were assigned to each
SRE. Each group's monthly survival was equal and was projected to decline
using observed median survivals. The cost of pamidronate reflected the
average wholesale price of the drug plus infusion. The value or disutility
of an adverse event per month was evaluated using a zero value (events
avoided) or an assigned value (range, 0.2-0.8).

MAIN OUTCOME MEASURES

The analysis considered end-points of all adverse events as well as assigned
quality-of-life values for non-fatal complications. Over a 24-month time
horizon, the study projected direct health-care costs, cost per adverse
event avoided. The model's primary end-points were cost per quality-adjusted
life year (QALY).

MAIN RESULTS

The cost of pamidronate therapy exceeded the cost savings from prevented
adverse events. The difference between the treated and placebo groups was
larger with hormonal systemic therapy than with chemotherapy (additional
$7685 compared with $3968 per woman). The projected net cost per SRE avoided
was $3940 with chemotherapy and $9390 with hormonal
  _____


96

therapy. The cost-effectiveness ratios were $108,200 with chemotherapy and
$305,300 with hormonal therapy per quality-adjusted year ( Table 1
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11536915
&sid=52257413/N/200115/#T0095001>  ).
TABLE 1 -- Evidence Table 1 *
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11536915
&sid=52257413/N/200115/#T0095001.001>


Costs per QALY ($)
Costs per SRE avoided ($)
Base case
108,200
3940
Analytic strategy


   Combined analysis of both trials
175,200
5860
   Symptomatic events only (costs and quality of life for asymptomatic
fractures excluded)
134,700
3480
   Exclude hypercalcemia
187,900
5200
Costs


   If 50% decrease in cost of pamidronate ($378)
Dominant strategy
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11536915
&sid=52257413/N/200115/#T0095001.002>

   If decreased to $618
50,000

   If decreased to $484
Equivalent cost

   High range of costs for each adverse event
Dominant strategy
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11536915
&sid=52257413/N/200115/#T0095001.002>

If no refusals of therapy and pamidronate continued until death
122,200

Quality of life/utility values


   If the duration of assigned quality of life decrease with each
symptomatic adverse event is doubled
77,300

   If monthly quality of life with pamidronate is decreased from 1.00 to
0.995 (20% reduction for 1 day)
134,100

*For the stated purpose of increasing clarity, only the results of changes
in the chemotherapy group were presented by the authors in the sensitivity
analysis. However, data under 'Analytic strategy' were pooled from both
studies.
Lower costs and higher quality-adjusted survival with pamidronate.
  _____





CONCLUSION

Although pamidronate is effective in preventing a feared, common adverse
outcome in metastatic breast cancer, its use is associated with high
incremental costs per adverse event avoided. The analysis is most sensitive
to the costs of pamidronate and pathologic fractures that were asymptomatic
or treated conservatively.

  _____

Sources of funding: Supported in part by a Faculty Research Award from the
American Cancer Society
  _____

Correspondence to: B.E. Hillner, Virginia Commonwealth University, Box
980170, Richmond, BA 23298-0170 (e-mail: [log in to unmask]).

Martine Extermann MD

H. Lee Moffitt Cancer Center University of South Florida, Tampa, FL, USA




Commentary

Pamidronate has been demonstrated in three studies to reduce complications
from bone metastates in patients with metastatic breast cancer. As a result,
pamidronate is widely used for treating such patients. In their article,
Hillner et al explore the cost-effectiveness of this approach from an
American societal perspective and conclude that this is a costly approach,
mostly sensitive to the cost of pamidronate. This is a well-designed
cost-effectiveness analysis, with clearly stated sources and assumptions.
Under a wide range of hypotheses pamidronate, given in an American setting,
has a marginal cost-effectiveness above that commonly accepted as
cost-effective. The authors use hypothetical patients with a profile similar
to those enrolled in two randomized studies. Their cost calculation is based
on a database from their institution and Medicare data. This is weaker
evidence than a direct prospective cost-effectiveness analysis integrated
into the study. However, if carefully conducted, this type of approach can
provide good cost-effectiveness assessments.
Can these results be transferred to other countries? Not without validation.
A Canadian cost utility analysis using similar data concluded that in the
Canadian health system, the marginal cost-effectiveness of pamidronate was
Can$ 18,700 (about US$ 12,700) per QALY gained over 1 year for
chemotherapy-treated patients.[ 1
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11536915
&sid=52257413/N/200115/#R0096001> ] This is markedly different from the
results of Hillner et al and falls well within the range of interventions
considered as cost-effective. It is interesting to note that the cost of
pamidronate administration was US$ 406, including infusion costs, compared
to US$ 621 wholesale price for the drug alone in the study of Hillner et al
reflecting major international pricing variations. In another country with a
high cost of living, Switzerland, the authorized retail price for the drug
is US$ 328.[ 2
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11536915
&sid=52257413/N/200115/#R0096002> ] The Canadian insurance system is
state-controlled, the Swiss system is private with state control against
medication overpricing, and the American system is private and state without
medication price control. As the authors themselves conclude,
cost-effectiveness considerations alone are unlikely to modify the clinical
use of pamidronate in metastatic breast cancer: pathological fractures are
viewed by both patients and physicians as a distressing event that needs to
be avoided as much as possible. Pamidronate being presently the only
FDA-approved biphosphonate in this indication, we will probably have to wait
for future approval of competing biphosphonates such as clodronate,
alendronate or zolendronate before cost considerations bear weight and can
be used as a leverage. The example of the Canadian and Swiss prices of
pamidronate suggests that there may be large room for maneuver.

Literature cited


1. Dranitsaris G, Hsu T. Cost utility analysis of prophylactic pamidronate
for the prevention of skeletal related events in patients with advanced
breast cancer. Support Care Cancer 1999; 7: 271-279   Abstract
<http://home.mdconsult.com/das/journal/view/N/10925193?PAGE=1&Source=CL,HS,M
I&ANCHOR=abs>

2. Compendium Suisse des Medicaments, Documed SA ED, 2000; 21: 165. CHF
546.65. Exchange rates 3/23/00.
Level and quality of evidence: At this time the journal is not formally
evaluating the quality of economic analysis due to the lack of acceptable
published rank of evidence in this category.

Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.