Marcello Guaglio, MD
Staff Surgeon
Fondazione IRCCS Istituto Nazionale dei Tumori - Milan - Peritoneal Surface Malignancies Unit
Milan, Lombardia, Italy
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Peritoneal metastases (PM) from colorectal carcinoma (CRC) are still related to bad prognosis and poor survival, in spite of the improvements brought by cytoreductive (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC).
Moreover, recent randomized clinical trial showed controversies about HIPEC efficacy employing oxaliplatin.
To improve HIPEC efficacy, a representative in vitro CRCPM model is required. Patient derived cancer organoids (PDO) provide the opportunity to use more specific and relevant human cancer models in a comprehensive bench-to-bedside strategy.
We established a preclinical platform based on CRCPM-PDO to rationalize HIPEC protocols, to develop patient-tailored HIPEC regimens and to predict therapeutic responses in a personalized manner based on drug sensitivity tests.
Methods: To mimic HIPEC, standard of care drugs (i.e. oxaliplatin, cisplatin, mitomycin-c and doxorubicin) were used in different combinations to treat PDOs at concentrations and temperature usually attained in the peritoneal cavity during HIPEC procedures for CRCPMs. Cell viability was evaluated after chemotherapy (CT) interventions and the dose-response curves obtained were fitted to the luminescent signal intensities and the half-maximal inhibitory concentrations (IC50) were determined. Western blot analyses were conducted to determine the main biochemical changes after the CT interventions.
Results:
The two schemes with a better response at clinically relevant concentrations included mytomicine-c alone or combined with cisplatin.
Even, oxaliplatin showed a relative efficacy only when administered at low concentration dose (“Wake Forest” scheme) for long perfusion time (120 min).
Conclusions: Our experiments show PDOs are reliable and useful in vitro models to evaluate HIPEC regimens at individual-patient level, and to develop more effective treatment strategies for CRSPM.
Lastly, our PDO models are consistent to recent randomized clinical trial, in which oxaliplatin did not seem to be the best choice for HIPEC in CRCPM, especially when administered according to Elias scheme (high concentration, short perfusion time).