Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?

INTRODUCTION: The increasing knowledge of the genomic landscape of hepatocellular carcinoma (HCC) and the development of molecular targeted therapies are a promising background for increasing the number of effective drugs for HCC patients. In recent years, many new drugs have been tested as an alternative to sorafenib or after sorafenib failure. AREAS COVERED: In this review, our aim is to describe the randomized trials recently conducted in HCC patients, in order to understand the main reasons potentially related to the failures of many drugs. In addition, we briefly describe the main ongoing trials, that could potentially change the scenario of HCC treatment in the next years. Expert commentary: Heterogeneity of study populations, lack of understanding of critical drivers of tumor progression, risk of liver toxicity associated with experimental agents, flaws in trial design and marginal antitumoral potency can be considered the main reasons for failure of phase III clinical trials in HCC. Most ongoing trials are conducted without any molecular selection criteria, although many drugs could be probably better tested in a molecularly selected population. The knowledge of potential predictive factors for drug efficacy in patients with advanced HCC could improve the chance of obtaining positive results in clinical trials.

A case of long-term survival after repeated response to oxaliplatin-based chemotherapy and repeated thermoablation of liver metastases from colorectal cancer. Should we introduce the concept of oxaliplatin-resistant tumors?

BACKGROUND: The management of advanced colorectal cancer patients differs among cancer centers. International guidelines recommend offering all the recognized active regimens in order to obtain survival advantage, but little information is given about the sequence and combination in which such regimens should be administered. CASE REPORT: We report the case of a man with multiple liver metastasis from colorectal cancer followed for more than 78 months at our Institution. Repeated response to the same oxaliplatin, 5-fluorouracil and folinic acid chemotherapy schedule was achieved, and repeated radiofrequency ablation of liver metastases was performed until progression of lung and brain disease at 50 and 72 months, respectively, after the diagnosis of advanced disease. Although the tumor became oxaliplatin and chemo-resistant after the onset of extra-hepatic disease, a more aggressive chemotherapy regimen, including a doublet with a biological, halted tumor growth. CONCLUSIONS: The patient survived for more than 78 months without experiencing a major impact on his quality of life. This case reflects the importance of following tumor biology in the therapeutic decision-making process, reintroducing oxaliplatin whenever possible, and adopting a more aggressive strategy when the tumor becomes oxaliplatin-resistant.

Pharmacoeconomic comparison between chronochemotherapy and FOLFOX regimen in the treatment of patients with metastatic colorectal cancer: a cost-minimization study.

AIMS AND BACKGROUND: The addition of oxaliplatin to the widely employed De Gramont schedule (FOLFOX regimen) in patients with metastatic colorectal cancer improved their outcome with a moderate toxicity pattern. The adaptation of the delivery rate of 5-fluorouracil, leucovorin and oxaliplatin to circadian rhythms (chronotherapy) resulted in a very high drug tolerability with clinical results at least comparable to those achieved with the FOLFOX regimen. However, chronomodulated infusion seemed to be more expensive, requiring dedicated electronic pumps and several disposable materials. The present study aimed to compare the direct costs of the two regimens and to determine whether chronotherapy was effectively more expensive than the FOLFOX regimen. STUDY DESIGN: The direct costs of drug delivery devices derived from various publicly available sources and of toxicity management as extrapolated from two published studies considering comparable patient subsets were added and compared. RESULTS: Pump, central venous system and disposable materials for a single chronotherapy cycle were Euro 193 or Euro 212 according to whether the pumps were bought or rented, compared to Euro 58 for the FOLFOX regimen. Toxicity management costs were Euro 144 vs Euro 288 for the two schemes, respectively. Globally, a single course of chronotherapy cost Euro 337 or Euro 356, whereas a single FOLFOX cycle cost Euro 346. CONCLUSIONS: Direct costs for a single chronotherapy cycle appeared to be comparable to a single course of the FOLFOX regimen. In fact, the major material cost of chronochemotherapy devices was balanced by a better tolerability profile. The overall improvement in quality of life with chronochemotherapy affecting indirect costs, such as reduction of work, and intangible costs is worthy of further pharmacoeconomic attention.