medwireNews: A post-hoc analysis of the PRADO trial points to an association between pretreatment emotional distress (ED) and poor response to neoadjuvant immune checkpoint blockade (ICB) therapy in people with stage III melanoma.
“Although the importance of screening and psychosocial care for cancer patients has long been recognized, our findings suggest yet another reason: if it is confirmed in an independent cohort that ED before treatment negatively affects the effectiveness of ICB, this would be an additional reason to systematically screen for ED in patients and evaluate (non)pharmacological interventions that could potentially improve patient outcomes after neoadjuvant ICB,” say the researchers.
They explain that “[r]ecently, more comprehensive views on optimizing ICB therapies have raised the importance of exploring the complexity of ICB responses in relation to environmental, behavioral and psychological factors such as dietary habits, physical activity and psychological distress.”
The team adds that “[e]merging evidence from preclinical studies suggests that ED negatively affects tumor progression and antitumor immune responses, mediated by β-adrenergic or glucocorticoid signaling resulting from the sympathetic nervous system or hypothalamic-pituitary-adrenal axis activation.”
Lonneke van de Poll-Franse (Netherlands Cancer Institute, Amsterdam) and colleagues therefore analyzed data from the phase 2 PRADO trial of neoadjuvant nivolumab plus ipilimumab in patients with stage IIIB–IIID melanoma to address this question.
A total of 88 participants completed the health-related quality of life EORTC QLQ-C30 questionnaire at baseline, and the major pathologic response (MPR) rate was significantly lower among the 28 with ED than the 60 without ED, at 46% versus 65%.
Patients with ED also had significantly reduced 2-year rates of relapse-free survival and distant metastasis-free survival compared with their counterparts without ED, at 74% versus 91% and 78% versus 95%, respectively.
Multivariable analysis confirmed these associations in a subgroup of 64 patients. Specifically, the adjusted odds ratio of achieving an MPR was 0.20 for participants with versus without ED, while the adjusted hazard ratios for relapse and distant metastasis were a respective 3.81 and 4.38.
The investigators say in Nature Medicine that the analysis “is limited by its relatively small sample size and the absence of an independent confirmation cohort,” and therefore, the findings “can only be seen as hypothesis-generating.”
They continue: “Nevertheless, our observation is in line with animal experiments indicating a role for adrenergic signaling in regulating the antitumor immune response, a retrospective analysis in a similar early-stage melanoma cohort treated with adjuvant ICB and a phase 1 prospective trial evaluating propranolol with ICB.
“Therefore, if confirmed in another large cohort like the NADINA trial, these data could be the rationale for testing adrenergic receptor blockade and/or psychological interventions in stage III melanoma patients with ED treated with neoadjuvant ICB.”
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