To maintain or not, that is the question

Publicly funded health care in Europe stands at a crossroads. The future sustainability of free and equal access to health care for all citizens is challenged by the high costs of new drugs, rising incidence of many cancers and ageing populations. Regulatory authorities in some countries, exemplified by the British National Institute for Health and Care Excellence (National Institute for Health and Care Excellence 2014), have taken action by demanding reasonable balance between costs of new drugs and effects measured by qualityadjusted life years (QALY). Generally, treatments exceeding 31 000–47 000 USD per QALY are not considered cost-effective (National Institute for Health and Care Excellence 2014). In other countries, like Denmark, prioritization in general has no political support and the excessive costs of new drugs are now leading to staggering budget overruns, which threatens to undermine the most basic patient care at our hospitals. Therefore, we cannot maintain our current practice but need to evaluate costs and effects. Currently, regulatory approval of new anticancer drugs is often based on positive results in clinical trials with progression-free survival (PFS) being the primary end-point. However, PFS may be an inappropriate surrogate end-point for overall survival and quality of life in chronic cancer diseases. The use of anti-CD20 antibody (rituximab) maintenance after first line immunochemotherapy in a rare disease, such as follicular lymphoma (FL) is certainly not alone to blame for the current situation, but it is an illustrative example of our problem. The PRIMA (Primary Rituximab and Maintenance) study was a pivotal trial in FL (Salles et al, 2011). Previously untreated patients in complete or partial remission after immunochemotherapy were assigned to receive rituximab maintenance therapy (375 mg/m every 8 weeks) for 2 years or observation. Patients randomized to rituximab maintenance arm experienced significantly longer remissions as compared to the patients in the observation arm (3-year PFS 74 9% vs. 57 6%, P < 0 0001). The time to initiation of the next anti-lymphoma treatment was prolonged for patients receiving rituximab maintenance, but overall survival is still equivalent at 6 years follow-up (Salles et al, 2013). Finally, rituximab maintenance did not increase well-being for the patients. Nevertheless, rituximab maintenance is now widely recommended for FL patients responding to first line immunochemotherapy (Dreyling et al, 2014). The disproportionate relationship between cost and potential benefit of rituximab maintenance emerges when the increase in time to next chemotherapy is estimated on individual patient level. Using the area between the Kaplan–Meier curves, the time to next chemotherapy was prolonged by an average of only 2 8 months [95% confidence interval (CI) 1 0–4 6] in the first 48 months of follow-up. The confidence intervals were obtained by a perturbation resampling method based on data reconstructed from the Kaplan–Meier curves (Guyot et al, 2012; Tian et al, 2014). Rituximab maintenance increased the PFS by an average of 5 5 months (95% CI 3 6–7 5) during the first 48 months, but PFS events included asymptomatic lymph node growth detected by routine imaging. We acknowledge that the inclusion of computerized tomography (CT)-ascertained progressions increases the reproducibility of PFS in clinical trial. Outside clinical trials, however, asymptomatic lymph node growth often goes unnoticed and the PFS improvement may be less obvious in daily clinical practice. We also calculated the costs of rituximab maintenance therapy in Denmark using the Danish DRG (Diagnosis Related Group) tariffs for health care services and the price of fixed-dose subcutaneous rituximab (1400 mg every 8 weeks for 2 years). The cost of this practice over routine follow-up is 25301 USD. We acknowledge that this calculated cost does not represent a complete cost-effectiveness analysis, but we still question the existence of a reasonable balance between costs and effects. A randomized clinical trial in low-tumour burden FL compared extended rituximab with rituximab re-treatment at the time of progression (RESORT) (Kahl et al, 2014). Re-treatment provided the same disease control as continuous treatment while using less rituximab. Would protocoled single-agent rituximab at progression have been equally effective in delaying time to next chemotherapy in the PRIMA trial? Obviating the need for chemotherapy has been a main argument for rituximab maintenance, even in patients with asymptomatic low-tumour burden FL (Ardeshna et al, 2014). Rituximab is well tolerated with few grade 3-4 toxicities and infrequent adverse events (Salles et al, 2011; Ardeshna et al, 2014). However, even rare cases of serious adverse events are relevant for treatments where overall survival and quality of life is not improved (Salles et al, 2011). What do we actually know about the long-term side effects of constant B-cell depletion for years in patients whose survival sometimes exceed 15 years? correspondence