The past and future of ‘reported outcomes’ in studies on chemotherapy neuropathy
Authors: A.S. Beutler, N. Majithia, C.L. Loprinzi
Journal: Annals of Oncology (2017)

The manuscript by Park et al. in this issue ofAnnals of Oncology [1.Park S.B. Kwok J.B. Asher R. et al.Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial.Ann Oncol. 2017; 28: 2733-2740Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar] reports on potential clinical and genetic prognostic factors of chemotherapy-induced peripheral neuropathy (CIPN). Predicting CIPN in individual patients, before symptoms manifest, is a critical goal that has not been achieved in the field. Even at the cohort level (a lesser challenge) available CIPN studies tend to disagree, regarding which predictors (genetic and otherwise) are significant. Therefore, additional clinical data are critically needed. We congratulate Park et al. on achieving this step: to put ICON7, a large, high-quality clinical trial, onto the 'map' of CIPN research. Park et al. also report genetic analyses. Of the single nucleotide polymorphisms (SNPs) tested, none was significantly associated with CIPN when tested alone. A combined end point that the authors call 'additive polymorphisms' found that SNPs in the genesMAPTandGSK3B were associated with clinician- and patient-reported CIPN, respectively. (Of note, Park et al. appear to use the term 'additive' here not to refer to the use of a standard additive model combining the genotype information of two alleles but instead to a sum score of alleles across multiple loci per gene.) It remains somewhat unclear to the reader, whether this analysis was developed post hoc, how many score-versus-phenotype comparisons were allowed, and how the multiple testing problem was approached. The potential of ICON7 for a future comprehensive genetic analysis is strong. While the present study reports a carefully planned first step in regard to genetic testing that was supported by a biological rationale (for the selection of the small number of SNPs tested), the authors (or their collaborators) may be working already on more comprehensive analyses, such as genome-wide association study (GWAS) arrays and/or exome- or genome sequencing, which will allow re-testing of all genetic variants claimed previously (by other studies) to be associated with CIPN and some responsible unbiased discovery. Results from such work would be welcomed. In the present manuscript, Park et al. emphasize a comparison of clinician reported outcomes (CROs) and patient reported outcomes (PROs), a distinction that takes a generation of researchers back in time. When one of the authors of this editorial started his career about three decades ago, clinical trials were designed to have CROs as the primary end point. Over time, however, it became apparent that physicians tend to underreport symptoms experienced by patients [2.Stephens R.J. Hopwood P. Girling D.J. Machin D. et al.Randomized trials with quality of life endpoints: are doctors' ratings of patients' physical symptoms interchangeable with patients' self-ratings?.Qual Life Res. 1997; 6: 225-236Crossref PubMed Google Scholar]. Trials, published many years to decades ago, showed that PROs identified a higher incidence and severity of treatment-related toxicities, than did CROs, for example, for symptoms such as oral mucositis [3.Mahood D.J. Dose A.M. Loprinzi C.L. et al.Inhibition of fluorouracil-induced stomatitis by oral cryotherapy.J Clin Oncol. 1991; 9: 449-452Crossref PubMed Scopus (239) Google Scholar] and chemotherapy-induced nausea [4.Grunberg S.M. Deuson R.R. Mavros P. et al.Incidence of chemotherapy-induced nausea and emesis after modern antiemetics.Cancer. 2004; 100: 2261-2268Crossref PubMed Scopus (380) Google Scholar]. The clinical use of PROs have recently been linked to improved quality of life measures [5.Basch E. Deal A.M. Kris M.G. et al.Symptom monitoring with patient-reported outcomes during routine cancer treatment: a randomized controlled trial.J Clin Oncol. 2016; 34: 557-565Crossref PubMed Scopus (1247) Google Scholar] and even overall survival improvements [6.Basch E. Deal A.M. Dueck A.C. et al.Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment.JAMA. 2017; 318: 197-198Crossref PubMed Scopus (1071) Google Scholar]. The superiority of PROs have been extended to the field of CIPN [7.Shimozuma K. Ohasi Y. Takeuchi A. et al.Feasibility and validity of the patient neurotoxicity questionnaire during taxane chemotherapy in a phase III randomized trial in patients with breast cancer: N-SAS BC 02.Support Care Cancer. 2009; 17: 1483-1491Crossref PubMed Scopus (119) Google Scholar,8.Le-Rademacher J. Kanwar R. Seisler D. et al.Patient-reported (EORTC QLQ-CIPN20) versus physician-reported (CTCAE) quantification of oxaliplatin- and paclitaxel/carboplatin-induced peripheral neuropathy in NCCTG/Alliance clinical trials.Support Care Cancer. 2017; Crossref PubMed Scopus (42) Google Scholar], where, for instance, a recent genetics study (using massively parallel 'nextgen' whole exome sequencing) selected patients for analysis solely on the basis of PROs [9.Beutler A.S. Kulkarni A.A. Kanwar R. et al.Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy.Ann Neurol. 2014; 76: 727-737Crossref PubMed Scopus (62) Google Scholar]. While we might argue that the absence of a diagnostic gold standard for CIPN has kept the field from settling the PRO versus CRO issue in a statistically compelling way, a shortcoming that Park et al. did not remedy either, PROs have won most arguments and are now supported by majority consensus, while CROs have, largely, been relegated to the past. What, however, is thefuture of 'reported outcomes' in CIPN and, for clinical oncology symptom control research, more broadly? New ideas tend to emerge in very dynamic subcultures of society before their adoption into the field of medicine. Considering this premise, we could, for instance, understand the dismissal of CROs, in favor of PROs, as part of the cultural shift from medical paternalism to the patient-as-a-partner philosophy that changed medicine in the wake of the 1970s liberalization of Western cultures: CROs represented paternalism, while PROs better represented a new generation of physicians who strived for more patient autonomy. What is the social trend ofour time, the 2010s, that will (and should) affect 'reported outcomes' in CIPN research? In short, it is the widespread availability of data in society and our ability (or that of our now-trainees) to access and analyze it with ever better sophistication. The future generation of researchers will be well versed in 'big data' analysis and personally empowered by fluency in writing program code as thelingua franca of the exploring human mind. Which 'Reported Outcome' will match the expectations of this coming generation? Let's just call them 'hashtag RO,' or #RO. #ROs are just that: all the bits of outcome data in a machine-readable format with annotations that are friendly to human researchers, so that they can decipher them easily. #RO will replace the currently all-too-common practice of using 'Hidden (orhideous) Reported Outcomes' (HROs). HROs are data that are incompletely documented and hide behind a curtain of interpretation (often following the narrative bias of a particular field). The genomic data sharing policy instituted by NIH shows how some parts of the scientific enterprise already lead the way in #RO. The symptom control field is poised to join #RO. Let us consider the enclosed study by Park et al. as an example of how #ROs might be helpful. Some readers might be puzzled for instance, whether the comparison between CROs and PROs as presented by the authors was affected by a systematic bias, because CROs were reportedly used in ICON7 to alter therapy decisions, while PROs were not: patients with high CROs (but normal PROs) had their chemotherapy dose reduced, while patients with high PROs (but normal CROs) continued with the same chemotherapy timing and dose. If this occurred only in few patients (which the reader cannot know), the impact is probably small, but if it occurred frequently, it might explain the relative lack of high CRO scores compared with the relative abundance of high PRO scores, which is a key argument by Park et al. #ROs, if available, would provide a straightforward answer to any reader interested in clarifying this issue. Today, most studies in the oncology symptom control field, even those that are most expertly planned and executed, represent incremental progress. Great value may result from data sharing with a broader group of colleagues in the field. While a single study may, on its own, neither be paradigm shifting nor a final answer to a long-standing challenge, the potential for insight may exponentially increase when a growing number of studies can be interpreted together, which can be achieved through #ROs. The current crop of CIPN studies may serve as an example because (nearly) all of them collect similar clinical and PRO data and many have (or will), in addition, carry out well-established genotyping methods such as GWAS or exome or genome sequencing, but most still lack #RO. Let's not wait until a future generation explains why HROs were obsolete in the year 2017. Rather, lets support authors by defining criteria for publication that allow investigators to succeed in their careers by helping the entire field to prosper. National Institute of Nursing Research (NINR) of the National Institutes of Health (NIH) (R01NR15259).