Oxaliplatin plus leucovorin and 5-fluorouracil (FOLFOX-4) as a salvage chemotherapy in heavily-pretreated platinum-resistant ovarian cancer

Ovarian cancer remains a highly lethal malignancy, representing the sixth leading cause of cancer death in women and the most lethal gynecologic malignancy [1, 2]. The prognosis for advanced ovarian cancer has improved over the last 10 years, especially thanks mainly to the introduction of more personalized therapeutic strategies. However, despite the high response rate to the standard carboplatin-paclitaxel first-line combination, most patients develop recurrent disease, with a median survival ranging from 12 to 24 months. Patients who progress on cisplatin or carboplatin or who relapse within 6 months of the end of treatment show the poorest outcome [2]. Single-agent therapies for platinum-refractory/resistant patients include oral etoposide, taxanes, topotecan, gemcitabine, vinorelbine, liposomal doxorubicin, and oxaliplatin, with response rates of around 15–20% and an overall survival (OS) of less than 12 months [3]. Research is now aiming to improve chemotherapy, identify novel, effective and well-tolerated agents, and overcome platinum resistance.

Cisplatin and carboplatin are the most common platinum compounds used to treat ovarian cancer. Oxaliplatin, a diaminocyclohexane platinum compound, has a different spectrum of activity and toxicity to that of other platinum agents and does not usually show cross-resistance with cisplatin and carboplatin in ovarian cancer [4, 5]. In previous phase II studies, oxaliplatin at a dose of 130 mg/m² every 3 weeks was administered to patients with cisplatin- or carboplatin-refractory/resistant and taxane-pretreated ovarian cancer, obtaining response rates of 4.3–29.0% and a median OS of 9.5–15 months [6–9]. The combination of 5-fluorouracil with leucovorin given as intravenous bolus or continuous infusion has also been used to treat platinum-resistant/recurrent ovarian cancer but has shown limited clinical activity [10–14].

Some in vitro studies indicate a potential synergy between oxaliplatin and 5-fluorouracil/leucovorin [15]. The combination of these drugs (called FOLFOX) represents a standard chemotherapeutic regimen in the management of some advanced tumours [16–18]. Preliminary data on the use of this treatment in recurrent ovarian cancer have not been entirely satisfactory/have not been encouraging [19–22]. In the present study we evaluated the efficacy, in terms of clinical outcome, and toxicity of FOLFOX-4 in platinum-resistant ovarian cancer. In addition, through an exploratory analysis, we compared our results with data from patients treated with topotecan, a drug usually administered alone as salvage chemotherapy in platinum-resistant disease.

Despite relatively high response rates to first-line platinum-based therapies for epithelial ovarian cancer, the majority of patients relapse and a number of treatment-related deaths have also been reported. New-generation chemotherapeutic drugs and biological agents, especially those targeting angiogenesis [26] and the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) [27, 28], have recently been introduced into clinical practice, increasing the number of therapies available for relapsed or refractory disease. Consequently, patients with advanced ovarian cancer often undergo multiple chemotherapy courses in an effort to achieve long-term remission and maintain an acceptable quality of life. The main risk from using an increasing number of therapeutic agents is cumulative toxicity, especially myelotoxicity, which may influence subsequent treatments. Hence the need for new, effective and less toxic therapies in patients with recurrent and persistent disease after failure of chemotherapy.

In the present retrospective monoinstitutional study, we analyzed the results obtained in a population of ovarian cancer patients treated with FOLFOX-4 or standard topotecan monotherapy in terms of clinical impact on outcome and toxicity. The choice of therapy and dosing schedule was at the discretion of the treating physician, as was the possibility of initial dose reduction due to older age and poor performance status. Efficacy and safety were comparable in both regimens, with hematological toxicity the most frequent reason for dose reduction. Treatment discontinuation due to toxicity was rare. Despite dose limiting cumulative neurotoxicity of oxaliplatin-based therapy, only one case presented a grade 4 neurotoxicity, although grade 2 neurotoxicities had a negative impact on the quality of life in a few cases heavily pretreated with taxane- and platinum-based therapies.

In terms of response, our findings were comparable to those of other studies [19–22] on patients with measurable disease. Major limitations of this study were a small number of patients, the retrospective design, and the presence of mismatch of the cohorts related to a lack of randomization. We observed that NLR was the only prognostic factor in our patient cohort, as reported in a recent meta-analysis [29]. However, due to exploratory intent, no multiple testing correction was performed. Although adjustments for multiple comparisons can help control the study-wide false-positive rate, for exploratory analyses it is more important to judge P values cautiously than to try to formally determine their true significance level. Precise adjustment of P values and confidence intervals is often impractical in the context of exploratory research but can be useful for hypothesis-driven research.

Despite all these several limitations of this study, we showed similar treatment outcomes (PFS, OS, and CA-125 response) between FOLFOX-4 and topotecan group. Specifically, there were fewer cases of PD (15 [51.7%] vs.18 [69.3%]) and a similar number of SD (8 [27.6%] vs. 6 [23.1%]) in FOLFOX-4 compared to topotecan patients. FOLFOX-4 could thus represent a potential alternative to standard chemotherapy, with a similar toxicity profile, in this patient setting. However, more recent studies [30] suggested different dose regimes of topotecan characterized by reduced number of side effects and thus this could alter the comparison of toxicities between FOLFOX-4 and topotecan profiles in our study.

The present study did not bring to light any clinical prognostic factors for PFS and OS in either treatment group, probably because of the small sample size and the lack of adequate patient selection. In addition, currently, there are no biomarkers able to improve the selection of patients candidates to FOLFOX-4 combination. Potential predictive biomarkers could derive from the analysis of homologous recombination deficiencies such as BRCA1/2 alterations, especially because they are of particular interest for platinum-based regimens. Therefore, future clinical trials in this disease setting could be supported by genomic and proteomic studies to identify prognostic factors associated with response to fluorouracil. The advances made in genetic and molecular biology could provide a valuable insight into the alterations underlying these types of ovarian cancer, and the relationship between the mechanism of action of fluorouracil and the subsequent downstream molecular pathways activated during tumorigenesis and disease progression.

The retrospective nature of our study and the small sample size do not allow for definitive conclusions to be drawn. However, our results provide further evidence that the FOLFOX-4 regimen may be as effective as standard monotherapies and could be proposed as an appropriate salvage treatment in refractory or resistant ovarian cancer. However, it should be appropriate to consider these heavily-pretreated patients as an ideal group for clinical trials; particularly given the success or emerging data of some newer classes of targeted therapies such as PARP inhibitors, antivascular drugs, dual antibody like molecules, antibody drug conjugates and so randomized multicenter trials comparing the FOLFOX-4 regimen, alone or, particularly, in combination with targeted therapy, are warranted to improve the standard of care in patients with heavily-pretreated disease.