The Utilization of the Rand Appropriateness Method (RAM) and International Expert Opinion in the Development of Risk Stratification and Decision Model for Prophylaxis and Treatment of Tumor Lysis Syndrome (TLS).
Authors: Cairo Mitchell S. , Kahan James P. , Cornelis Marleen , Coiffier Bertrand 
Published: October 2019

Abstract
Objectives: To develop risk assessment of TLS utilizing a validated risk assessment tool and TLS management guidelines from an international expert panel.
Methods: TLS risk scoring was based on odds ratio evaluations of a list of 63 patient characteristics and cancers (mainly lymphoma and leukaemia) with known TLS risk. A 3 level risk scoring system was constructed: low, moderate and high TLS risk. The RAND Appropriateness Method (RAM) was used to systematically investigate the opinions of an expert panel (4 paediatric oncologists and 7 adult haematologists) on the appropriateness of both prophylaxis and treatment for 92 different patient scenarios. To evaluate prophylaxis, each case was defined by the unique combination of the TLS risk score and other diagnostic characteristics relevant in prophylactic choice. Treatment was evaluated in clinical scenarios where TLS is already present (defined as three abnormal laboratory values are present from the following list of parameters: uricemia, phosphatemia, kalemia, calcemia, urine output volume). All parameters used were explicitly and empirically defined. The panel members rated the appropriateness of all patient scenarios according to the RAM methodology using a 9-point rating system. Subsequently, all appropriateness ratings were validated using a holistic set of 36 clinical cases. Prophylactic and treatment strategies evaluated were the same, and include: none, hydration or diuretics, rasburicase, allopurinol, allopurinol together with alkalisation. Decision tree (CART analysis) was used to study the relationship between diagnostic characteristics and panel outcomes.
Results: The odds ratios from 63 patient characteristics and cancers were rated by all experts and allowed a detailed evaluation of TLS risks and ranked from 1 for a normal person younger than 60 years to the highest of 8.61 for B-cell Mature Burkitt’s cell leukaemia with high tumor burden. The appropriateness analysis showed overall disagreement of 12% in prophylaxis, 17% in treatment; these instances call for further research. Absence of prophylaxis or treatment and allopurinol with alkalinisation were generally rated inappropriate. Hydration or diuretics were largely rated appropriate. In treatment, Rasburicase was generally rated more appropriate then allopurinol alone. In prophylaxis, Rasburicase showed a better choice than allopurinol alone in case of higher risk and several risk factors. Allopurinol alone showed a more favourable choice than rasburicase in several cases of low to moderate risk patients such as low to moderate patients with hyperuricemia, normal phosphatemia: mean of median rating respectively 6.2 ±1.0 vs. 4.4 ± 1.8 and with normal uricemia, respectively 4.2 ±1.1 vs. 2.0 ± 1.2.
Conclusions : Overall agreement existed regarding the early use of prophylaxis as soon as a patient risk is identified. Hydration or diuretics should be used in all cases where prophylaxis or treatment are recommended, whether or not medication is used. Rasburicase is rated by the panel as the best choice for TLS in prophylaxis for patients at risk and in treatment for patients with hyperuricemia, hyperphosphatemia and hyperkalemia. This model allowed evaluating the development of a practical risk stratification method and prophylactic and treatment recommendations.