European Journal of Cancer (2014) 50, 2171– 2172

A v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

ScienceDirect

journa l homepag e : www.e j cancer . com

Letter to the Editor

Decreased toxicity with 2 weeks on and 1 week off scheduleof sunitinib in metastatic renal cell carcinoma:Is it a mirage or an oasis?

http://dx.doi.org/10.1016/j.ejca.2014.05.014

0959-8049/� 2014 Elsevier Ltd. All rights reserved.

⇑ Tel.: +1 210 450 5947; fax: +1 210 294 4551.E-mail address: Malikl@uthscsa.edu

Laeeq Malik ⇑

Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio,

TX, USA

To the editor:

In their recent study, Y.G. Najjar and colleagues [1]shared their clinical experience of a new sunitinib sche-dule 2 weeks of treatment/1 week off (schedule 2/1) atThe Cleveland Clinic. The authors should be commendedfor their efforts in exploring new ways to minimise suniti-nib related adverse effects. Patients entering the study hadto have initially received sunitinib using schedule 4 weeksof treatment/2 weeks off (schedule 4/2), but subsequentlychanged to schedule 2/1 due to toxicity reasons. Treat-ment of 30 patients with schedule 2/1 was reported tohave significantly decreased toxicity and similar medianoverall treatment duration. Y.G. Najjar and colleaguesinterpreted their data positively and generated a hypoth-esis that schedule 2/1 has significantly decreased toxicityand should be explored further. This analysis providesmore data and complements the findings of similarstudies that sunitinib schedule 2/1 boasts a better safetyprofile [2].

In this single institutional, retrospective analysis,patients were identified from the database maintainedand shared by treating physicians. However, these dataneed to be analysed carefully and no real conclusionsshould be drawn about the toxicity of schedule 2/1and actual effectiveness compared to the standard

dosing schedule. Methodological issues are a significantconcern in obtaining and interpreting toxicity data inthis analysis. Because of the nature of this work, thereexist no standardised time points to assess toxicity.Patients were selectively switched over to 2/1 scheduleat different time points and the heterogeneous proce-dures for data collection seem rather flimsy. The assess-ment of toxicity in retrospective studies is alwaysdifficult and unlikely to be completely captured bydiscrete assessments of specific health dimensions in iso-lation. Furthermore, only 17.6% of the total renal cellcancer patients (N = 170) were treated with the schedule2/1. It will be interesting to know about the toxicityinformation for the 16 patients (53.3%) who were previ-ously dose-reduced relative to the schedule 2/1. As theauthors noted that in advanced renal cancer the clinicaloutcome is related to drug exposure (AUC). We do nothave pharmacokinetic or pharmacodynamic data of thisschedule 2/1. The median overall treatment durationwith the schedule 2/1 suggests better tolerance, but doesnot provide any information about the efficacy. We willlike to point out that previous experience in advancedrenal cell cancer has shown that the alternate dosingschedules of sunitinib may not provide the same levelof efficacy as the standard schedule 4/2 [3].

The effects of sunitinib using schedule 4/2 on qual-ity of life (QOL) are emerging as an important issuein modern oncology. As a matter of fact, some recent

2172 L. Malik / European Journal of Cancer 50 (2014) 2171–2172

trials have used this as a control arm to study theeffect of new agents on QOL [4]. It can be difficultto understand how meaningful toxic effects (whetherassessed by clinicians or patients) are to patients’ over-all QOL. We have to yet establish a relationshipbetween the presence and severity of the most com-monly observed toxic effects and the correspondingQOL. Although efficacy remains the primary goal oftreatment, we do need treatment schedules that areassociated with improved safety and better QOL,and build on the small steps that have been made inthis area. Patients prefer a new treatment or schedulefor a variety of reasons, primarily a better overallQOL. Nonetheless, this study reported by Y.G. Najjarand colleagues may herald a new frontier in optimis-ing therapeutic decision-making in advanced renalcancer. Future research that (1) involves randomisedcross-over design evaluating patient preference forschedule 4/2 or schedule 2/1 and the influence ofhealth-related quality of life and safety factors ontheir preference (2) involves pharmacokinetic work(3) uses progression free survival as primary end-pointand (4) is adequately powered will further elucidate

the value of schedule 2/1 in management of patientswith advanced renal cancer.

Conflict of interest statement

None declared.

References

[1] Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week offschedule of sunitinib is associated with decreased toxicity inmetastatic renal cell carcinoma. Eur J Cancer 2014;50(6):1084–9.

[2] Kondo T, Takagi T, Kobayashi H, et al. Superior tolerability ofaltered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma – comparison tostandard dosing schedule of 4-weeks-on and 2-weeks-off. Jpn J ClinOncol 2014;44(3):270–7.

[3] Motzer RJ, Hutson TE, Olsen MR, et al. Randomized phase IItrial of sunitinib on an intermittent versus continuous dosingschedule as first-line therapy for advanced renal cell carcinoma. JClin Oncol 2012;30(12):1371–7.

[4] Escudier B, Porta C, Bono P, et al. Randomized, controlled,double-blind, cross-over trial assessing treatment preference forpazopanib versus sunitinib in patients with metastatic renal cellcarcinoma: PISCES study. J Clin Oncol 2014. http://dx.doi.org/10.1200/JCO.2013.50.8267.