More on sunitinib 2 weeks on/1 week off schedule: the Rainbow analysis
Authors: U. Basso, M. Maruzzo
Journal: Annals of Oncology (2015)

We read with great interest the recent Rainbow study by Bracarda et al. [1.Bracarda S. Iacovelli R. Boni L. et al.Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis.Ann Oncol. 2015; 26: 2107-2113Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. This is the largest retrospective analysis published so far focusing on the alternative schedule of sunitinib administered 2 weeks on/1 week off (2/1) to 208 patients who had developed significant adverse events with the standard schedule of 4 weeks followed by a pause of 2 weeks (4/2). As the authors pointed out, safety was the primary objective of this analysis, and the 2/1 schedule demonstrated a reduced incidence of overall grade 3–4 toxicities (8.2%) compared with the first period of 4/1 schedule administered to the same patients (45.7%) as well as to the overall incidence of grade 3–4 toxicities registered in a French control group (29.4%). Apart from the limitations already raised by the authors and the comments previously expressed by Iacovelli et al. [2.Iacovelli R. Verri E. Cossu Rocca M. et al.Sunitinib 2 weeks on, 1 off: strengths and weaknesses.Ann Oncol. 2015; 26: 1512-1513Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar], we would add the following considerations:•The 2/1 schedule was applied to patients who had already received a median of 4.3 months of the standard 4/2 schedule, who had likely undergone the first radiological restaging. The same happened in other similar studies with the 2/1 schedule [3.Kalra S. Rini B.I. Jonasch E. Alternate sunitinib schedules in patients with metastatic renal cell carcinoma.Ann Oncol. 2015; 26: 1300-1304Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. This means that refractory patients (21% in registrative studies [4.Motzer R.J. Hutson T.E. Tomczak P. et al.Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.N Engl J Med. 2007; 356: 115-124Crossref PubMed Scopus (5070) Google Scholar]) have not been switched to the 2/1 schedule, as well as those who had unacceptable toxicities or dropped out for treatment-unrelated reasons. This fact clearly represents a strong selection bias and may explain, at least in part, the striking improved median progression-free (PFS) and overall survival (OS) of the 2/1 cohort. It would be useful to know the reasons for which 41 patients of the total 4/2 group were not switched to the 2/1 schedule, and how fared those patients who were able to continue the 4/2 sunitinib schedule afterward.•The second cohort of 41 patients starting 2/1 sunitinib on the basis of ‘non-optimal general conditions’ according to the local treating oncologists shows only a moderate and unsignificant increase of poor risk features compared with the first cohort, such as median age, ECOG PS of 2 or more, bone or CNS involvement. Indeed, they had a PFS of 10.4 months and a 36-month survival rate of 39.4%, very close to the 9.7 months and 39.5% of the unselected French cohort. In fact, patients with unfavorable clinical conditions may be expected to be given temsirolimus or alternative tyrosine kinase inhibitors such as sorafenib and more recently pazopanib, which are perceived as less toxic than sunitinib. This second group does not appear to us a significantly disadvantaged cohort, and the higher toxicity of 2/1 sunitinib administered since the first cycle (26.8% versus 8.2%) may reflect the absence of the selection bias applied to the first cohort. As the authors correctly point out in the discussion, there are still not enough data to justify the start of 2/1 sunitinib upfront.•Eighty-two of 188 patients starting sunitinib at 50 mg/daily were not able to maintain the full dose of sunitinib even after switching (43.6%), as a demonstration that the 2/1 schedule may still frequently require dose reductions to ameliorate tolerability.•Registration of toxicity by physicians may not intercept the actual incidence and severity of treatment toxicities, as we have recently learnt from the PISCES trial in which patient-reported outcomes were assessed and compared with toxicities of sunitinib and pazopanib reported by doctors [5.Escudier B. Porta C. Bono P. et al.Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study.J Clin Oncol. 2014; 32: 1412-1418Crossref PubMed Scopus (328) Google Scholar]. This may be particularly true when the physician claims that a modification of treatment will improve tolerability (observer bias). In conclusion, we compliment the authors for carrying out and reporting strengths and limits of the Rainbow analysis, which adds further information on feasibility and tolerability of the 2/1 schedule of sunitinib administered to patients who cannot tolerate the standard 4/1 schedule [3.Kalra S. Rini B.I. Jonasch E. Alternate sunitinib schedules in patients with metastatic renal cell carcinoma.Ann Oncol. 2015; 26: 1300-1304Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. We agree with them that a randomized, controlled trial is warranted, for which both the standard 4/2 sunitinib or the continuous pazopanib could be suitable control arms. The authors have declared no conflicts of interest.