PERSPECTIVE: Challenging preoperative α-blockade in phaeochromocytoma surgery: beyond tradition, towards ‘safer surgery’

The rarity of phaeochromocytomas has left a gap in evidence supporting existing guideline recommendations for preoperative α-blockade dose-escalation. While this pre-treatment aims to reduce cardiovascular complications, recent studies question its efficacy. The systematic review of Schimmack et al. (1) revealed no beneficial efficacy compared to no α-blockade and highlighted potential harm, including prolonged postoperative hypotension. The updated meta-analysis of Wang et al. (2) confirmed Schimmack’s conclusions, describing their findings as ‘a critical appraisal against the adherence to a dogmatic preparation paradigm, which is cumbersome, expensive and without evident benefits’.

Despite these outcomes, randomized-controlled trials (RCTs) are warranted before considering omitting preoperative α-blockade dose-escalation. However, besides practical challenges of conducting RCTs for rare diseases like phaeochromocytomas, there is also a lack of consensus on optimal study design for assessing perioperative outcomes, as evident in the current heterogeneity in research designs.

To determine this ideal RCT design, we conducted an online survey to gather opinions from specialists involved in phaeochromocytoma management in the Netherlands on preferred study designs, outcome measures and patient eligibility criteria.

The responses from 23 physicians (including eight surgeons, seven endocrinologists and seven anaesthesiologists) from eight centres (response rate of 71.9%) demonstrated the diverse opinions within the specialist community (Table 1). The most heterogeneous responses were regarding preferred primary endpoint; 43% (10/23) favoured surrogate endpoints, with the PRESCRIPT study’s haemodynamic instability (HDI) score (3) as most preferred endpoint. The remaining respondents argued that such metrics may lack clinical relevance and proposed the clinical outcomes of cardiovascular events and perioperative complications as more appropriate to assess the entire process – Dr Wang’s study (2) further debated the significance of intraoperative HDI as outcome due to a lack of data establishing a clear association with perioperative complications; intraoperative HDI is still common despite adequate α-blockade pre-treatment but rarely associated with significant cardiovascular events (2, 4, 5). This underscores the importance of utilizing clinical outcome measures into future RCTs and not focussing on HDI as primary endpoint.

Furthermore, while hypertension consistently emerged as primary perioperative concern, significant variations in prioritization existed across different disciplines; 100% of endocrinologists prioritized hypertension, compared to 75% of surgeons and 57% of anaesthesiologists. This group perceived hypertension as a more hazardous and less manageable perioperative threat than hypotension. However, 22% (5/23) of the respondents who indicated hypotension as their primary concern stated that prolonged severe hypertension preceding diagnosis contributes to existing morbidity, making it less likely to manifest suddenly during surgery. In contrary, abrupt hypotension may be more detrimental, often requiring post-anaesthesia care unit intervention with haemodynamic support.

In terms of study design, 39% (9/23) favoured a non-inferiority RCT, while 35% (8/23) preferred a mixed-design RCT with non-inferiority for primary endpoints and superiority for secondary outcomes. Regarding patient eligibility, 65% (15/23) favoured excluding certain patients, with the most consensuses on excluding patients in phaeochromocytoma crisis (74%), patients with cardiac decompensation (78%) and those with a tumour size ≥6 cm (24%).

A limitation of our survey is the focus on Dutch specialists, which may affect generalizability. However, the equal inclusion of the different disciplines strengthens our findings’ robustness. The diverse perspectives regarding study design and perioperative threats, alongside the predominant monodisciplinary focus of current guidelines led by endocrinologists, emphasize the necessity of a multidisciplinary approach in future research, particularly when conducting RCTs.

In conclusion, recent studies highlight the evolving understanding of phaeochromocytoma management. More research, preferably RCTs, is needed to improve treatment strategies and patient outcomes. Our survey suggests a non-inferiority-designed RCT that only excludes patients with severe comorbidities and incorporates clinical outcome measures as most suitable design. We hope our findings contribute to this ongoing discussion and assist in shaping future RCT frameworks.