Introduction

Hepatocellular carcinoma (HCC) is a global health problem, as it is the sixth most common cancer in the world and the third leading cause of cancer-related death. The incidence of HCC shows wide geographical variation, with the European countries having an incidence of about 3 out of 100,000, while the incidence in other parts of the world reaches 15 out of 100,000; such variation closely follows the geographical distribution of viral hepatitis B (HBV) and hepatitis C (HCV), the most important causes of chronic liver disease and HCC [1].

Many patients with HCC present with disease that is not suitable for any potentially curative therapy (e.g., resection, transplantation, or radiofrequency ablation) due to either the high burden of liver disease, extra-hepatic spread, or poor background liver function related to cirrhosis. Such patients are candidates for palliative transarterial or systemic therapies.

Sorafenib is the only systemic therapy to demonstrate modest survival benefit over supportive care in the context of randomised controlled trials [2, 3]. This benefit has been re demonstrated in many other smaller phase II studies and retrospective analyses [4–9]. However, the modest benefit achieved with sorafenib is achieved mainly by prolonging tumour stabilisation. On the contrary, many cytotoxic chemotherapeutics have achieved a range of tumour responses, but so far without convincing survival benefits in smaller phase II studies, indicating that these agents may also have a role in advanced HCC, provided correct placement in combination strategies with sorafenib as well as other systemic agents [10]. In this commentary, we will review the data regarding the recent interest in the use of oxaliplatin-based regimens for advanced HCC.

Clinical Experience with Oxaliplatin-based Regimens for Advanced HCC

Oxaliplatin-based regimens have been extensively investigated for advanced hepatocellular carcinoma patients, both in Western and Eastern patient populations. Initially, Yen and co-workers conducted a phase II study of single-agent oxaliplatin in patients with unresectable metastatic or recurrent hepatocellular carcinoma. However, it failed to meet the a priori criterion for promise in this trial [11]. Accordingly, a number of different oxaliplatin-based regimens have been investigated. The most commonly tested combination was Gemcitabine and oxaliplatin (GEMOX) chemotherapy, both as a first line as well as second line treatment option. Zanaan and co-workers evaluated Gemox as a first line option; it demonstrated manageable toxicity and encouraging tumour responses [12]. Additionally, Louafi and colleagues evaluated GEMOX as a first line treatment in HCC patients in another prospective phase II study. Again, it seemed to be well tolerated and active in advanced HCC, especially in patients with underlying non-alcoholic liver disease [13]. Moreover, Patrikidou and co-workers have evaluated GEMOX chemotherapy as a second line option after failure of anti-angiogenic therapies. GEMOX showed clinical activity with an acceptable toxicity profile in this setting also [14]. Building on the above data, combinations of GEMOX with targeted therapies have been explored; Asnacios and colleagues evaluated GEMOX combined with cetuximab in patients with advanced hepatocellular carcinoma in a prospective multicenter phase II study. This combination appears to be active and to have manageable toxicity [15]. Next to this, Zhu and co-workers conducted a phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. Such a combination has shown a high 6-month PFS with tolerable toxicity and, thus, is worthy of further consideration [16]. Additionally, Assenat and colleagues evaluated GEMOX plus sorafenib in a randomised phase II study. They found that this combination was feasible in HCC and the trial met its primary endpoint (4-mo PFS ≥ 50%); ORR, median PFS, and OS were encouraging. Exploratory analyses are underway to identify subgroups of patients likely to derive the most benefit from this combination [17•].

Likewise, the combination of oxaliplatin with fluoropyrimidines has been explored in advanced hepatocellular carcinoma with encouraging results; Boige and co-workers conducted a multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma (FFCD 03-03 trial). This regimen showed modest anti-tumour activity with tolerable toxicities in patients with advanced HCC [18]. Additionally, Qin and colleagues conducted a phase III study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia; although the study did not meet its primary end point of improved OS, the trend toward improved OS with FOLFOX4, along with increased PFS and RR, suggests that this regimen may confer some benefit to Asian patients [10]. Building on the above GEMOX experience, combination targeted therapies with oxaliplatin/fluoropyrimidine regimens have been explored. Sun and co-workers conducted a phase II trial of bevacizumab, capecitabine, and oxaliplatin in advanced HCC. The combination appeared effective and safe, with encouraging results [19•]. Moreover, Yau and co-workers evaluated the combination of sorafenib, capecitabine, and oxaliplatin (SECOX) in a phase II study in Asian patients with advanced hepatocellular carcinoma. They found that the SECOX regime has promising activity and safety in Asian patients with advanced HCC [20••]. A randomized study of sorafenib monotherapy vs. SECOX was launched in 2010; however it has been withdrawn prior to enrollment [21].

The above literature review clearly illustrates the potential validity of oxaliplatin-based regimens as a systemic therapy for advanced HCC and provides a strong basis for combining antiangiogenic therapies like bevacizumab or sorafenib with oxaliplatin-based regimens.

Ongoing Studies

According to clinicaltrials.gov records, two ongoing studies are evaluating different oxaliplatin-based regimens in HCC. The first of them is at Massachusetts General Hospital and the second of them is at The University of Hong Kong (See Table 1). The results of these studies are awaited to further guide our think tank with regards to the proper use of oxaliplatin-based regimens in HCC.

Table 1 Ongoing Studies Evaluating Oxaliplatin-based Regimens in HCC
Full size table

Conclusions

Despite the numerous studies evaluating various systemic therapies in HCC, very few have provided convincing results. We believe that the key to improve the outcomes lies in the search for appropriate biomarkers to help select the appropriate personalized therapy for each patient; in that regard, oxalplatin is no exception.