The cost of life: should it matter to doctors?

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 P 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 costeffectiveness 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 e d it o ri a l