Analysis of Efficacy, Safety, and Prognostic Factors of mFOLFOX6 Regimen Combined with Cetuximab and Simvastatin in the Treatment of K-RAS Mutant Colorectal Cancer

Abstract

Colorectal cancer (CRC) is one of the most common malignant tumors with high morbidity and mortality. The early symptoms are latent, and most patients are in the middle or late stage when they are diagnosed. The best opportunity for surgery has been lost, and surgical resection has failed to achieve good results. In clinical practice, targeted therapy or chemotherapy is usually the main treatment. The mFOLFOX6 regimen is a standardized regimen for the treatment of advanced CRC. The main drugs in this regimen are oxaliplatin and 5-fluorouracil (5-FU). Patients with advanced CRC combined with standard chemotherapy regimens can achieve a higher resection rate of liver metastases in unresectable patients, which can achieve significant survival improvement. Therefore, in this study, oxaliplatin + calcium folinate + 5-Fu + mFOLFOX6 regimen was combined with cetuximab and simvastatin to treat CRC patients, and the clinical efficacy and prognosis were analyzed, as well as the prognostic factors. The results showed that the addition of simvastatin on the basis of conventional mFOLFOX6 regimen combined with cetuximab chemotherapy could effectively improve the efficacy, reduce the total incidence of adverse reactions, improve the overall survival rate, and prolong the overall survival time of patients. Pathological grade and peritoneal metastasis were the factors affecting the mean survival time of CRC patients.

Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy

“…In addition, colorectal cancer patients who were taking statins prior to neoadjuvant chemotherapy had significantly lower median American Joint Committee on Cancer (AJCC) grades compared to those not taking statins, indicating that patients with lower AJCC grades had significantly better OS, DFS, cancer-specific mortality and local recurrence [ 45 ]. Moreover, the addition of simvastatin to mFOLFOX6 + cetuximab was shown to increase the efficacy of FOLFOX6 + cetuximab, reduce the incidence of side effects, including peripheral neuropathy, and prolong OS of KRAS-mutated colorectal cancer patients [ 46 ]. These observations indicate that statins may improve the prognosis and QOL of colorectal cancer patients treated with neoadjuvant or adjuvant chemotherapy and surgery; however, there are negative observations that need to be validated in future studies.…”

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

“…There is a retrospective study comparing bevacizumab plus capecitabine, with capecitabine monotherapy for KRAS-mutant metastatic CRC showing that combination therapy was better tolerated, and also contributing a longer PFS (9.0 months vs. 7.2 months, p < 0.05) [ 82 ]. Another study found that conventional mFOLFOX6 chemotherapy combined with cetuximab for KRAS-mutant CRC patients showed was shown to improve efficacy, reduce the overall incidence of adverse events (AEs), improve OS, and extend overall patient survival when adding simvastatin [ 83 ]. A phase 1 study of binimetinib (MEK inhibitor) plus carboplatin and pemetrexed chemotherapy for stage-IV non-squamous NSCLC showed that the ORR of patients with KRAS/NRAS mutations was 62.5%, while wild-type patients had an ORR of 25% [ 84 ].…”

A phase 1 study of simvastatin in combination with topotecan and cyclophosphamide in pediatric patients with relapsed and/or refractory solid and CNS tumors

“…Multiple clinical trials testing fixed doses of simvastatin, most commonly 40 mg daily (range 10−80 mg), in combination with chemotherapy, have been performed in adults with advanced solid tumors 17–25 . While these trials have broadly shown mixed results, nearly all of the randomized controlled trials have failed to show a benefit with the addition of simvastatin 17,19,20,24,25 .…”

“…Multiple clinical trials testing fixed doses of simvastatin, most commonly 40 mg daily (range 10−80 mg), in combination with chemother-apy, have been performed in adults with advanced solid tumors. [17][18][19][20][21][22][23][24][25] While these trials have broadly shown mixed results, nearly all of the randomized controlled trials have failed to show a benefit with the addition of simvastatin. 17,19,20,24,25 Investigators from these trials hypothesized that the lack of clinical efficacy may have been due to the lower dosing of simvastatin that was insufficient to achieve serum concentrations needed to control tumor cell proliferation.…”