Advisory board comment
In last week’s issue of The New England Journal of Medicine, Willemien van Driel and colleagues from the Netherlands Cancer Institute in Amsterdam reported results from their open-label, phase III randomized clinical trial of interval cytoreduction with and without hyperthermic intraperitoneal chemotherapy (HIPEC) in women with FIGO stage III epithelial ovarian carcinoma.
This work is very interesting because the theory invoked to support the potential efficacy of HIPEC makes sense scientifically. DNA is typically coiled tightly around histone proteins and heat causes proteins to denature or lose their quaternary structure, allowing the DNA double helix to unwind. This increases the DNA surface area that is available to form bulky platinum–DNA adducts, which are difficult to replicate and/or transcribe. The entire tumor nuclear machinery responsible for cancer cell division and aberrant protein expression grinds to a halt. However, an absence of well-designed clinical trials has rendered the field of HIPEC to an esoteric realm, championed by some surgical oncologists as a marketing tool without any strong data to support its implementation in the ovarian cancer armamentarium. Until now.
The strengths of this study from the Netherlands lie in the use of neoadjuvant chemotherapy to level the playing field and to have randomization occur only after the surgical outcome at interval cytoreduction is known.
The limitations suggest that further study will be required before a phase III randomized clinical trial such as this one can be considered to be transformative. It is not clear whether HIPEC alone conferred the reported results or whether it is the use of intraperitoneal chemotherapy following neoadjuvant chemotherapy that wins the day. Additionally, dose-intensification of platinum may also be at play here.
Finally, although median overall survival was clearly significantly improved, this was a secondary endpoint. Using recurrence-free survival (or progression-free survival) as a primary endpoint for front-line therapies in this disease may be problematic. This is because due to the high sensitivity of imaging modalities, many patients may progress radiographically long before they are symptomatic from disease recrudescence.