© 2006 European Society for Medical Oncology
editorial |
The cost of life: should it matter to doctors?
Director, Medical Oncology 1, Istituto Nazionale Tumori, Via Vneenzian 1, 20133 – Milano, Italy
(E-mail: luca.gianni{at}istitutotumori.mi.it)
Is there a tag-price on patients' life? Would such a price be any business of doctors? The rapidly evolving success of the adjuvant use of the HER-2 directed monoclonal antibody trastuzumab and an article appearing in today's issue of Annals of Oncology [1
] raise the above and many more issues.
With rare unison the interim analyses of four large-scale independent prospective studies (NSABP-B31, NCCTG-N9831, HERA and BCIRG-006) have reported in the past few months that adjuvant trastuzumab either given with or after chemotherapy, and administered either weekly or three-weekly reduces the risk of early recurrence by almost 50% even at less than 2 years of follow up [2–4]. Decades of clinical research to improve the outcome of women who incur breast cancer have hardly if ever witnessed such a success story before.
In urging caution and a cool-headedness before embracing adjuvant trastuzumab as standard of care in the absence of dependable and mature survival data [5], some have chastised the ever more common habit of embarking on large randomized clinical trials, and stop them early for benefit based on precarious and biased interim analyses [5, 6]. None of these issues appears directly applicable to the adjuvant trastuzumab trials [7]. The magnitude of the benefit afforded by trastuzumab was largely unexpected, but the consistency of results across different studies lends strength to the reliability of the observations while underscoring the fact that the knowledgeable statisticians of all studies were fed pessimistic and wrong forecasts of the potential impact of the monoclonal antibody when calculating the size of the trials.
The important point is that the progression-free survival sustained by adjuvant trastuzumab will inevitably transform into a survival benefit [7]. This is already the case in the combined analysis of the NASBP and NCCTG studies in which the use of trastuzumab has already been associated with a statistically significant reduction of 33% of the risk of death at three years of follow-up [2]. As for the other studies, most recurrences avoided by adjuvant trastuzumab were distant metastases [3, 4]. Given that metastatic disease is almost always incurable, there is no doubt that adjuvant trastuzumab has saved, is saving and will save lives. But at what cost?
The article in this issue of Annals of Oncology provides an insight into the assessment of the monetary cost of lives saved by adjuvant trastuzumab [1]. Taking advantage of the direct participation of their hospital to the BCIRG 006 trial, Neyt and collaborators calculated all costs of the application of either one of the two experimental therapies of the study, namely AC 
TH (doxorubicin and cyclophosphamide for 4 cycles followed by docetaxel for 4 cycles and trastuzumab for 1 year), and TCH (docetaxel and carboplatin for 6 cycles and concurrent trastuzumab to be maintained for 1 year) and compared such costs with those of the commonly used FEC regimen [1]. Interestingly, the cost of the medications of the BCIRG-006 therapies was about 13 times higher than that of FEC, and not surprisingly the cost of trastuzumab at the current tag-price accounted for more than 75% of that cost [1]. The interim analysis of the BCIRG-06 was publicly released for the first time months later than the article of Nyet et al. was submitted [1, 4], and it does not show any significant survival advantage so far [4]. One may therefore wonder how could anybody conduct a reliable analysis of the monetary worth of each life saved by adjuvant trastuzumab if the survival results were not yet available. However, the approach used by Neyt et al. did not need real survival data, but only a dependable estimate of costs (including those associated with incurred toxicity) and some arbitrary assumption, such as the stage and the age of the patients considered [1]. It is arguable that those assumptions limited the analysis to women older than 50 years with stage III breast cancer [1], because the choice lowers the estimated overall economic impact of implementing the new therapy in everyday practice. Some may also argue against the choice of the comparator regimen, or may point to the fact that costs per patient would be different and (somewhat) lower if adjuvant trastuzumab were given every three weeks as in the HERA trial [1, 3]. However, all these issues minimally detract from the value of the study which aims at calculating the incremental cost-effectiveness of using adjuvant trastuzumab by compounding the higher immediate costs with the longer-term improvements in time to disease progression and percentage of cancer not becoming metastatic. In other words, one can use the framework of the study and apply all desired changes to best fit the estimate to the preferred therapeutic approach, dialing-in an extension to stage II cases; the use of taxanes in the comparator therapy; the elimination of a lower age limit; the adoption of the three-weekly instead of the weekly schedule; or the impact of chronic cardiac toxicity [8]. What matters in the study is illustrated by the graph of the hypothetical improvement that would be needed to meet any given level of incremental cost-effectiveness. The graph shows with numbers what is conceptually obvious to most: if effectiveness is low and the incremental cost-effectiveness is too high, a lower and more acceptable level can always be reached by changing the price of drugs. In contrast, high efficacy may tolerate costly drugs without sky-rocketing cost-effectiveness [1].
Is the economic impact of prescribing adjuvant trastuzumab relevant to the daily decision-making responsibilities of medical oncologists? In principle economic analyses of how much the life of an "average" patient would cost to society upon the introduction of new and more expensive standards of therapy should not affect the choice of the best therapy by doctors, who are simply bound to take into account the worth of the individual life of the patient seeking their knowledge, experience, advice and prescriptions. Economic considerations should only matter to policy makers, leaving doctors to their role of being advocates of their patients' rights. However, resources cannot forever match the rising cost of new treatments, and this practical limit is challenging doctors with new dilemmas [9].
In the case of adjuvant trastuzumab the economic aspect is less than an immediate challenge for doctors and patients due to the attention of policy makers in many countries. As an example, in a striking display of administrative timeliness most European countries have already found a way of granting access to adjuvant trastuzumab to women with HER2-positive breast cancer, even though the actual registration process of such use of the drug is still far from at an end. European governments should be commended for their readiness and sensitivity to the patients' rights, but such a favorable outcome should not make doctors think that this is or will be the rule. Considerations of deontology notwithstanding, doctors will have to accept that the rising cost of new drugs cannot forever be discounted as "their" (policy makers') problem. The temptation of policy makers could be the simplistic one of delegating doctors the role of diligent vigilantes of the pharmacy's budget according to iniquitous criteria such as "first come first served". How else can doctors face this new reality? The medical community offered a unique display of enthusiasm and determination when partnering with the pharmaceutical industry and adhering to the four protocols of adjuvant trastuzumab that brought us here. The study by Neyt and collaborators shows that cutting the tag-price of drugs is one solution, but also that costs can be curbed in many different ways [1]. One is that of optimizing trastuzumab treatment. The drug's dose, schedule and length of administration were empirically selected to offer the chance of maximum drug exposure when the nonlinearity of trastuzumab's disposition and its very long half-life were not yet recognized: a shorter duration of treatment, a longer interval between doses, or the proven efficacy of smaller individual doses would all have a major impact on costs. In addition, the mechanisms associated with the likelihood of responding to trastuzumab are still far from being elucidated, but tailoring trastuzumab treatment to the individual needs of the patients may represent another outstanding opportunity for doing great science while restricting the indication for and the costs of the new therapy in a rational way. In pursuing these or similar scientific goals medical oncologists could partner with and find financial support from governments. This is not wishful thinking but a distinct reality that is best exemplified by the recently reported FinHER trial [10]. Supported by the government of Finland, the report of the trial took by surprise the audience at the last San Antonio Breast Cancer Symposium when it showed that a short course of 9 weeks of adjuvant trastuzumab in combination with either docetaxel or vinorelbine afforded a progression-free benefit of the same order of magnitude of that seen with the year-long trastuzumab therapy used in all other adjuvant trials [2–4, 10]. The question of duration of trastuzumab treatment is still open and also waits for the results of the 2-year treatment arm of the HERA trial [3] that is based on the consideration that a more prolonged therapy could better match the risk of recurrence that continues for years [11]. However, were the FinHer results independently confirmed in another trial, the implications would be dual: an immediate major economical saving for the health care system, and a clear demonstration that doctors may curb the rising cost of new therapies, if they are independently supported for optimizing treatments, as good doctors and good clinical scientists are expected to do.
disclosure
Dr. Gianni is member of the Executive Committee of the HERA trial; he has received honoraria for participation to advisory board meetings for Roche and for Genentech in the past 2 years; he has received honoraria for participation to Roche-sponsored satellite symposia in the past 2 years.
References
1. Nyet M, Albrecht J, Cocquyt V. An Economic evaluation of Herceptin® in adjuvant setting: the Breast Cancer Research Group 006 trial. Ann Oncol 2006; 17: 381–390.
2. EH Romond, EA Perez and J Bryant et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673–1684.
3. MJ Piccart-Gebhart, M Procter and B Leyland-Jones et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353: 1659–1672.
4. Slamon D, Eiermann W, Robert N et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by Docetaxel (AC T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 94: Suppl 1: S1, 2005
5. The Lancet, Herceptin and early breast cancer: a time for caution. Lancet 2005; 366: 1673.[CrossRef][Web of Science][Medline]
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7. Smith IE. Trastuzumab for early breast cancer. Lancet. 2006; 367: 107.[Web of Science][Medline]
8. E Tan-Chiu, G Yothers and R Romond et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005; 23: 7811–7819.
9. Schrag D. The price tag on progress–chemotherapy for colorectal cancer. N Engl J Med. 2004; 351: 317–9
10. Joensuu H, Kellokumpu-Lehtinen P-L, Bono P et al. Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Blanco G, Isola J: Trastuzumab in combination with docetaxel or vinorelbine as adjuvant treatment of breast cancer: the FinHer Trial. Breast Cancer Res Treat 94, Suppl 2005; 1: S5
11. Early Breast Cancer Trialists Collaborative Group (EBCTCG), 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.[CrossRef][Web of Science][Medline]
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