Reply to the letter to the editor ‘Reporting of HRQoL results from the PALOMA-2 trial: unfounded conclusions due to highly biased analyses’ by Kaiser et al.
Authors: H.S. Rugo, S. Iyer, C. Huang
Journal: Annals of Oncology (2018)

Kaiser et al. [1.Kaiser T. Köhler M. Wieseler B. Reporting of HRQoL results from the PALOMA-2 trial: Relevant data are still missing.Ann Oncol. 2018; 29: 1877Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar] have provided comments on our recently published article ‘Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial’. However, we have significant concerns about the content of the letter, and believe it misstates the data in order to make a point. We have responded to each concern in detail below. We have clearly specified in the publication that pain item analysis was post hoc. The original scoring manual of FACT-B included item 4 as part of the physical well-being subscale. This was not the case with item 10 in the breast cancer concerns subscale (BCS), which at the time when the study Statistical Analyses Plan (SAP) was developed was not included in the BCS scoring as per the original scoring algorithm provided by the developers, but instead left as an individual item. For this reason, we decided to analyze item 10 of the BCS post hoc as a separate item. The BCS scores and analyses presented in the publication do not include pain item 10, although this pain item is included in the physical well-being subscale in adherence with the scoring algorithm recommended at the time of development of the study SAP. Indeed, the original validation and scoring of the FACT-B and BCS subscale did not include the pain item [2.Brady M.J. Cella D.F. Mo F. et al.Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument.J Clin Oncol. 1997; 15: 974-986Crossref PubMed Scopus (1175) Google Scholar, 3.Eton D.T. Cella D. Yost K.J. et al.A combination of distribution- and anchor-based approaches determined minimally important differences (MIDs) for four endpoints in a breast cancer scale.J Clin Epidemiol. 2004; 57: 898-910Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar]. The time-to-deterioration (TTD) analyses again are specified very clearly as post hoc analyses. The article unambiguously states that the difference between treatment arms was not statistically significant. Hence, unlike what the authors of this letter claim, we have not made any claim of a delay in deterioration of quality of life specifically related to the CDK4/6 inhibitor, nor is this included in our conclusion. The observed positive trend alludes only to the hazard ratio being less than one, but clearly notes that this relationship was not statistically significant. The definition of definitive deterioration (decrease greater than pre-specified threshold with no subsequent increase) in the post hoc TTD analyses have been previously employed in other cancer and breast cancer studies [4.Hamidou Z. Chibaudel B. Hebbar M. et al.Time to definitive health-related quality of life score deterioration in patients with resectable metastatic colorectal cancer treated with FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI: the MIROX randomized phase III Trial.PLoS One. 2016; 11: e0157067Crossref PubMed Scopus (17) Google Scholar, 5.Burris H.A. Lebrun F. Rugo H.S. et al.Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial.Cancer. 2013; 119: 1908-1915Crossref PubMed Scopus (81) Google Scholar], providing some degree of validation to the definition. In the TTD analyses, we compared responders and non-responders, as well as those who did or did not have progressive disease. The conclusions reflect a within and not between treatment arm comparison. We note that the conclusions from these analyses apply to both treatment arms and do not include any conclusion specific to the palbociclib plus letrozole combination. Regarding the comment about including post-progression Health Related Quality of Life (HRQoL) data, in Paloma-2 patients were followed for overall survival (OS) without frequent site visits once they stopped study drugs—a common if not consistent approach to studies with OS as a secondary end point. We actually did attempt to collect data post-progression by protocol amendment, but as expected, there were considerable missing data due to infrequent site visits. Given that patients with metastatic breast cancer in the first-line setting who experience disease progression quickly switch to other therapies, evaluating PROs post-progression would actually be assessing the impact of subsequent treatment, rather than the study drugs. In summary, we believe that the concerns brought up by Kaiser et al. refer to issues not actually included in the article, as we have outlined in detail above. Paloma-2 conduct, data collection and data analysis was funded by Pfizer Inc. (no grant numbers apply).