ABSTRACT

Oxaliplatin-induced peripheral neuropathy (OIPN) is a common side effect in patients receiving chemotherapy for colorectal cancer (CRC) and it remains the most frequent dose-limiting toxicity, affecting especially quality of life (QoL) of patients. The best known pathogenetic mechanisms is the production of reactive oxygen species (ROS) and their negative activity at the axonal level. Consequently, medical research focused on the hypothesis that antioxidant substances may be efficacious in preventing OIPN. The purpose of our work is to report the experience of the PLANET trial (Oxaliplatin Neurotoxicity Prevention Trial) and provide a constructive discussion on one of the oncological toxicities still today little controlled by medical therapies.
The PLANET trial was a monocentric, prospective, randomized, placebo-controlled, double blind, phase II clinical study designed to investigate if the association of vitamin E and super oxide dismutase (SOD) is able to prevent OIPN in colorectal cancer patients receiving oxaliplatin-based chemotherapy regimens. Primary endpoint was the assessment of OIPN incidence and severity in the two treatment arms. Secondary endpoints were the correlation between the OIPN and the oxaliplatin dose in terms of symptoms intensity, type of neuropathy and quality of life; finally the OIPN duration along the follow-up checks. 47 patients with CRC, operated or in advance stage, candidates for oxaliplatin- based chemotherapy, were enrolled from January 2014 to October 2015 in our Center and randomized into the two groups, the experimental arm (24 patients) and the placebo arm (23 patients). The study included an analysis of at least 18 months, 6 of treatment and 12 of follow-up. In the global cohort analyzed, 32.5% of patients reported development of paresthesias during chemotherapy treatment, with an increase of symptoms intensity in cycles progression of active treatment and a reduction during follow-up. After 12 months of follow-up, 50% of participants experienced complete relief of paresthesias while 50% had persistent symptoms. But the most important finding was the lack of statistical differences between the two arms in terms of neuropathy incidence, toxicity and variations in QoL.
OIPN represents a still poorly understood oncological toxicity. In addition to oxidative stress, there are other pathogenetic mechanisms, partly clear and partly unknown. Scientific research is trying to better study them and to develop efficacious treatment strategies against this toxicity. Over the years there have been many attempts to use various drugs but with unsatisfactory results. Our PLANET experience leads us to conclude that the association of vitamin E and SOD has not proved efficacious in preventing the OIPN. The main reasons are due to the smallness  of the sample analyzed and the pathogenetic complexity of the phenomenon in which oxidative stress represents, according to medical literature, only a part of the mechanisms responsible for the OIPN. The positive note is that the treatment has a good tolerance. OIPN remains an open chapter of oncology for which more information is needed in order to identify an efficacious treatment strategy. The prevention of this toxicity would allow a better management of platinum-based chemotherapy and an improvement in the quality of life of patients.

IMPACT STATEMENT
With our work, mainly addressed to oncologist colleagues dealing with gastrointestinal malignancies, we wish to provide our monocentric experience on one of the still unresolved chemotherapy toxicities.