**7. Systemic Chemotherapy Drugs and Approaches to Improving HCC**

The US Food and Drug Administration has approved sorafenib, sunitinib, brivanib, linifanib, sorafenib plus erlotinib, vandetanib, nintedanib, dovitinib, and sorafenib plus doxorubicin for treating HCC. These chemotheraputic drugs act as first-line chemotherapy. Numerous chemotherapeutic drugs have been examined as first-line treatments for patients with advanced HCC. Since its approval, the number of HCC patients receiving treatment with the medicine has increased significantly, irrespective of their tumor stage. Phase 2 findings in patients with advanced metastatic HCC support the use of sorafenib, with the treated group demonstrating a nearly three-month survival advantage over the untreated group. The phase 2 chemotheraputic drugs of brivanib, everolimus, S-1, axitinib, GC33, and tigatuzumab act as valuble drugs for liver cancer. The objective response rate is currently at around 2%, with the majority of the benefit being attributed to the stable disease rate, which was observed in phase 2 and 3 trials to range from 35% to 71%. In the phase 3 study, more than 80% of the participants had previously undergone liver-directed therapy (chemoembolization). Phase 3 chemotheraputic drugs such as lenvatinib, sorafenib plus resminostat, regorafenib, cabozantinib, ramucirumab, and tivantinib (ARQ 197) are promising drugs for HCC [134–136].

Sorafenib is a currently available therapeutic option because the response rate to liver-directed treatment is still around 70%. Sorafenib is a protein kinase inhbiter, including VEGFR, PDGFR, and RAF kinase. When combined with liver-directed therapy, sorafenib was found to show acceptable safety profiles and marginally improved efficacy. The great majority of patients required dose delays and/or reductions [137].

Less persuasive are the most recent phase 3 findings examining sorafenib's advantages in the adjuvant situation following embolization [138]. Sorafenib has not been researched in the neoadjuvant situation before either liver-directed therapy, resection, or transplant. This adds potential periprocedural or postoperative problems that could jeopardize the successful administration of therapy, the life of the patient, or the graft, according to the lessons learnt from the use of various antiangiogenic substances in the neoadjuvanttherapy. For instance, with catheter-based procedures, arterial pruning brought on by antiangiogenic drugs may have an effect on how the small micron particle is delivered into the tumor bed.

There are a number of reasons to refrain from administering sorafenib prior to surgery when liver transplantation is involved. Due to nutritional deficiencies, transplant patients are frequently at a higher baseline risk of wound-healing complications; arterial complications are devastating and frequently fatal, and the nearly 70% stable disease rate seen in phase 3 trials may conceal the underlying metastatic disease, which could make a transplant inappropriate. In other cancer subtypes, antiangiogenic medications and radiation have been successfully combined. Therefore, research examining the combination of stereotactic body radiation therapy plus sorafenib or internal radiation (yttrium-90) plus sorafenib appear appropriate, and information on these combination regimens should become available over the next several years.
