Download Gain, but what, how much and at what cost?

letters to the editor
Annals of Oncology
Gain, but what, how much and at
what cost?
One of my radiotherapy colleagues asked me in how much
benefit the addition of bevacizumab to interferon in patients
with metastatic renal cell cancer resulted, and after answering,
he looked at me with scepticism. When another colleague asked
me to review some criteria for anticancer treatments, I could
hardly find references that cited the effectiveness on which
anticancer drugs are registered. And when I went to a lecture on
cost-effectiveness or efficiency of cancer drugs, I knew the
oncology community will face a hard time to formulate good
criteria for the benefits that a drug should give to be registered
but more importantly to be reimbursed for every patient.
When looking at cancer treatment, two main aims can be
defined: cure of the patient (curative treatment) or improving
the quality of life (palliative treatment).
Several treatments have a proven effect in adjuvant setting to
increase overall survival of the targeted patient population. The
survival benefit can be defined in different endpoints, such as
improvement of the absolute or relative percentage of patients
alive without disease after a certain time span (e.g. 5-year
survival rate) or in time gained (e.g. median survival in years).
A surrogate endpoint that has been used to register anticancer
drugs in this setting is disease-free survival.
The absolute gain to approve and accept an anticancer drug
varies. For patients with early breast cancer, an absolute
improvement in 10-year survival of 10.9% for node positive
and 5.6% for node negative with tamoxifen seems acceptable
for everybody [1]. Also, the benefit of the aromatase inhibitor
letrozole in disease-free survival, the endpoint of the study, of
4.6% seemed good enough for registration of this drug in
adjuvant setting, while the overall survival benefit of 0.4% at
4 years should give rise to some questions [2]. Similar
observations can be made for other adjuvant treatments in
other tumour types.
So what is the benefit an adjuvant treatment should give in
overall survival at, for instance, 5 years: 5%, 2%, or 0.5%. And
what about the surrogate endpoint disease-free survival: 10%,
4%; or 1%. Some things to consider.
1562 | letters to the editor
Volume 21 | No. 7 | July 2010
letters to the editor
Annals of Oncology
Even more difficult is to make this exercise for palliative
treatments. Several endpoints have been used to register a drug:
response rate, progression-free survival, overall survival and
quality of life, such as pain control, cosmesis, xerostomia, or
skeletal-related events [3, 4].
A response rate of 20% has been traditionally accepted to
consider a drug as active in cancer treatment. However, with
the newer drugs, response is no longer a criterion for activity
and clinical benefit (complete response + partial response +
stable disease) has been introduced. When considering renal
cell cancer, a benefit of bevacizumab in combination with
interferon when compared with interferon alone of around
3 months in disease-free survival was sufficient to register this
drug. Also, the addition of cetuximab to cisplatin plus
5-fluorouracil in patients with recurrent or metastatic head and
neck cancer was approved based on an overall survival benefit
of just below 3 months [6] and the registration of docetaxel–
prednisone compared with mitoxantrone–prednisone in
castration-resistant prostate cancer (CRPC) of between 2 and
3 months [7]. The last combination was the previous standard
in patients with CRPC based on a palliative response defined as
a 2-point decrease in pain assessed by a 6-point pain scale of
17% [8].
So there seems to be no firm criteria for the benefit
a treatment should provide to be recognized as an effective
treatment. A suggestion is given in Table 1.
And in comes the cost we as a society are willing to pay for
a certain benefit. Different societies have provided
different values to treatments making that some drugs
are not reimbursed in certain countries, while patients in other
countries can get that specific treatment.
For the gain in 1 year of life, societies are willing to spent
between €30 000 and €50 000, but for other endpoint such as
quality of life, no criteria have been defined.
Fortunately, efficiency of anticancer drugs with cost/value is
the responsibilities of politicians. However, we as oncologists
should be able to define the benefit that we expect of an
anticancer treatment to be effective.
Dirk Schrijvers*
Department of Medical Oncology, AZ Jan Palfijn, Merksem, Belgium
(*E-mail: [email protected])
references
1. Clarke MJ. WITHDRAWN: tamoxifen for early breast cancer. Cochrane Database
Syst Rev 2008; (4): CD000486.
2. Goss PE, Ingle JN, Martino S et al. Randomized trial of letrozole following
tamoxifen as extended adjuvant therapy in receptor-positive breast cancer:
updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005; 97(17):
1262–1271.
3. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug
Administration approval of oncology drugs. J Clin Oncol 2003; 21(7): 1404–1411.
4. Sridhara R, Johnson JR, Justice R et al. Review of oncology and hematology
drug product approvals at the US Food and Drug Administration between
July 2005 and December 2007. J Natl Cancer Inst 2010; 102(4):
230–243.
5. Escudier B, Pluzanska A, Koralewski P et al. AVOREN Trial investigators.
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell
carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370(9605):
2103–2111.
6. Vermorken JB, Mesia R, Rivera F et al. Platinum-based chemotherapy
plus cetuximab in head and neck cancer. N Engl J Med 2008; 359(11):
1116–1127.
7. Berthold DR, Pond GR, Soban F et al. Docetaxel plus prednisone or mitoxantrone
plus prednisone for advanced prostate cancer: updated survival in the TAX 327
study. J Clin Oncol 2008; 26(2): 242–245.
8. Tannock IF, Osoba D, Stockler MR et al. Chemotherapy with mitoxantrone plus
prednisone or prednisone alone for symptomatic hormone-resistant prostate
cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;
14(6): 1756–1764.
doi:10.1093/annonc/mdq274
Table 1. Suggested efficacy criteria for anticancer drugs
Setting
Endpoint
Benefit
Gain
Curative
5-year survival
Major
Moderate
Minor
Major
Moderate
Minor
Major
Moderate
Minor
Major
Moderate
Minor
Major
Moderate
Minor
Major
Moderate
Minor
>5%
2%–5%
>0%–2%
>5%
2%–5%
>0%–2%
>20%
>10%–20%
>0%–10%
>20%
>10%–20%
>0%–10%
>3 months
>1–3 months
>0–1 months
>20%
>10%–20%
>0%–10%
Disease-free survival
Palliative
Response rate
Clinical benefit
Progression-free survival
Quality of life
Volume 21 | No. 7 | July 2010
letters to the editor | 1563