Oncotarget: Folinic acid in colorectal cancer: esquire or fellow knight?

Oncotarget published "Folinic acid in colorectal cancer: esquire or fellow knight? Real-world results from a mono institutional, retrospective study" which reported that the stock of therapeutic weapons available in metastatic colorectal cancer has been progressively grown over the years, with improving both survival and patients' clinical outcome: notwithstanding advances in the knowledge of mCRC biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs have been for 30 years the mainstay of chemotherapy protocols for this malignancy.

5-Fluorouracil seems to act differently depending on administration method: elastomer-mediated continuous infusion better inhibits Thymidylate Synthase, an enzyme playing a pivotal role in DNA synthetic pathway.

TS overexpression is an acknowledged poor prognosis predicting factor.

The simultaneous combination of 5FU and folinate salt synergistically strengthens fluorouracil cytotoxic effect.

In their experience, levofolinate and 5FU together in continuous infusion prolong progression free survival of patients suffering from mCRC, moreover decreasing death risk and showing a clear clinical benefit for patients, irrespective of RAS mutational status, primitive tumor side and metastases surgery.

Showing a clear clinical benefit for patients, irrespective of RAS mutational status, primitive tumor side and metastases surgery

Dr. Francesco Jacopo Romano from The Antonio Cardarelli Hospital, Oncology Unit in Naples Italy said, "Notwithstanding advances in the knowledge of metastatic colorectal cancer (mCRC) biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs are currently the mainstay of chemotherapy protocols for this malignancy."

5FU seems to act differently depending on administration method: quick bolus mainly increases incorporation of 5FU in RNA, even yielding a more severe hematological and gastrointestinal toxicity than continuous infusion, whereas elastomer-mediated continuous infusion long inhibits Thymidylate Synthase.

Modulation of 5FU activity has been studied for several years, with the aim to enhance antineoplastic effect by combining bolus and continuous infusion administration to maximize 5FU antitumor efficacy.

Therefore, therapeutic strategies combining bolus and continuous infusion have been made to better exploit both genotoxic effects of fluoropyrimidines incorporation and TS inhibition, with extending infusion time to 48 hours and adding folinic acid.

Usually, 5FU bolus is administered at the middle of a 2-hours folinic acid infusion.

Figure 6: No difference was found in univariate OS analysis for folinic salt use - 37,7 vs 33,4 months - p value 0,151 - maybe due to therapy switch over of a large number of patients who underwent NaLF-based therapy in second line after first-line CaLF-based therapy, partially disguising the overall survival difference between the two groups.

This retrospective, single-center observational study is the first with the aim of evaluating differences between these administration modalities: in particular, the authors wondered if co-administration of 5FU and folinic acid in continuous infusion was as effective as the classic sequential administration, or even more effective in terms of progression free- and overall survival, especially considering the aforementioned preclinical data.

The Romano Research Team concluded in their Oncotarget Research Paper that increased survival for patients undergoing NaLF based therapy could be the consequence of a greater and more effective TS inhibition.

A plausible reason for ALL RAS absence of significance on OS multivariate compared to univariate analysis can be found in extremely wide expression of TS in colon cancer cells.

Indeed, on one hand they have an oncogene addiction toward EGFR pathways in ALL RAS wild type cells, but on the other hand we know that TS is essential for non-oncogenic pathways of cancer cells regardless of EGFR or RAS activation.

Noteworthy, there are coincidentally more RAS mutated patients in NaLF group than the CaLF counterpart.

Finally, they highlight the therapy switch over of a large number of patients who underwent NaLF-based therapy in the second line after first-line CaLF-based therapy, partially disguising the overall survival difference between the two groups.

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DOI - https://doi.org/10.18632/oncotarget.27872

Full text - https://www.oncotarget.com/article/27872/text/

Correspondence to - Francesco Jacopo Romano - francesco_jacopo@libero.it

Keywords - colorectal cancer, folinic acid, sodium levofolinate, thymidylate synthase, non oncogene addiction

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