Considerations Related to the Patient

Half of the patients with ovarian cancer are over 60 years of age. Patient fragility evaluation is thus critical for treatment strategy.This topic remains under active investigation and criteria of patient fragility have not yet been validated. Age, however, is not the only factor to consider in elderly patients. Other potential factors include co-morbidities, performance status, patient autonomy and depression status.

Treatment-related toxicities increase with the number of treatment lines and should be carefully evaluated before initiating a new line of treatment. Neurotoxicity is of particular concern in patients with ovarian cancer in relapse. It is a long-lasting sequel from taxane and/or cisplatin therapy and is a frequent factor limiting the reintroduction of these drugs. Prior occurrence of severe haematotoxicity, and particularly thrombopenia,may restrict the use of major drugs such as carboplatin, topotecan or gemcitabine. Patients may have experienced prior severe hypersensitivity reactions to platinumderivatives, taxane or pegylated liposomal doxorubicin. Despite specific protocol to prevent or to manage these hypersensitivity reactions, the use of one or several of these agents may have to be dropped during the course of patient evolution.

Because the cure rate of patients with ovarian cancer relapse is low, patient preference is a major determinant of their quality–of–life and should be considered with attention. Major patient concerns about chemotherapy include losing their hair (alopecia), treatment convenience (number of infusions taken at the clinic) and tiredness. All these factors may affect patient work, home duties, social activities, partner/family relationships and ultimately their quality–of–life.When possible, treatment choice should consider particular patient wish.

Moreover, although the global aims of treatment of patients with relapsing ovarian cancer is to prolong survival, together with symptom palliation and an emphasis on patient quality–of–life, considerations must be taken into account for patients who are platinum-resistant compared to platinum-sensitive patients. For platinum-resistant patients a key focus should be symptom palliation and quality-of-life, whilst for platinum-sensitive patients, survival prolongation is the most important aim of treatment.

Timing of Treatment

A symptomatic relapse justifies start of treatment without delay. Ascites and/or pleural effusion may need drainage prior to initiating chemotherapy treatment to relieve severe related symptoms.

The most debated question remains the timing of treatment in patients with an asymptomatic increase of the tumour marker CA125, without detectable lesions on clinical or radiological exams. Whether treatment should be delayed until appearance of symptoms or initiated solely on the increase in CA125 level to prevent symptom occurrence remains controversial. However, this is being addressed in an on-going randomized trial. The kinetics of the CA125 increase, as well as the patient’s inclination for treatment, should help in the decision.

Treatment Modality in Patients with Platinum-sensitive Relapse

Patients with ovarian cancer who experience a durable response to platinum combination have a high probability of responding to platinum retreatment.^17,19–24
In this setting, non-platinum single agent therapy yields response rates (20–45%) inferior to platinumbased regimens (40–90%). An Italian prospective randomized study compared paclitaxel with the three-drug regimen of cyclophosphamide, doxorubicin and cisplatin in 97 patients with a platinum-free interval over 12 months. Despite the small size of this trial, there was a significantly higher response rate, a longer time to progression and a longer survival time for the platinumbased combination. ²⁵

An important outstanding question is whether combination chemotherapy could produce better results than single-agent platinum therapy in patients with recurrent platinum-sensitive ovarian cancer. This question has been addressed by the ICON4 and OVAR 2.2 trials.These were two parallel randomized trials comparing a minimum of six cycles of conventional platinum-based chemotherapy (Plat) versus paclitaxel plus Plat (Pac-Plat) in 802 patients with relapsed ovarian cancer.²⁶ A treatment-free interval of more than six months was required. After randomization, 71% of the patients in the conventional platinum arm received carboplatin alone as treatment.

At a median follow-up of 42 months, the hazard ratio (HR) for progression-free survival (PFS) was 0.76 (p=0.0004), favouring Pac-Plat. The HR for survival was 0.82 (p=0.02), corresponding to an absolute difference in two-year survival of 7% (57% versus 50%) and median survival of five months (29 versus 24 months), favouring the Pac-Plat combination. The results suggest that Pac-Plat improves survival and PFS in patients with ‘platinum-sensitive disease’ relapsed ovarian cancer compared to conventional platinum regimen. However, the improved survival was accompanied by increased neurologic toxicity (20% versus 1%) and alopecia (86% versus 25%), both of which we would like to avoid in patients in relapse.

The GCIG trial was too designed to determine whether platinum-based combination should be used at first relapse in patient previously treated with platinum-based chemotherapy.²⁷ This randomized trial compared the combination of carboplatin and gemcitabine versus single-agent carboplatin in 356 patients with a treatment-free interval of more than six months. The combination regimen produced a significantly longer progression-free survival compared to the single-agent carboplatin control arm (8.6 months versus 5.8 months) with an HR of 0.72 (95% CI, 0.50–0.90 months) (p=0.003).The trial was not powered for overall survival. Alopecia and neurotoxicity rates were low in both arms, but haematologic toxicities were significantly more common with combination therapy.

Based on the results of these randomized trials, there is enough evidence to conclude that platinum-based combination chemotherapy is superior to singleagent carboplatin in patients with recurrent platinum-sensitive ovarian cancer. However, there is still a need for carboplatin-based combinations, which may offer the best outcome, while minimizing toxicity and preserving quality–of–life.

More recent phase II studies have also shown activity for other combination regimens, including the combination of carboplatin and pegylated liposomal doxorubicin.²⁷ Although the population enrolled in this large phase II trial of 105 patients is slightly different from those enrolled in ICON4/OVAR 2.2 and GCIG, progression-free and overall survival are similar for carboplatin plus pegylated liposomal doxorubicin and platinum plus paclitaxel. Haematologic and non-haematologic toxicity was low, with less than 15% of patients experiencing grade 2 alopecia, grade 2 or 3 infection, mucositis, hand–foot syndrome (HFS) or neuropathy. These encouraging results have prompted the GCIG to launch a randomized trial comparing the efficacy and tolerability of carboplatin combined either with pegylated liposomal doxorubicin or paclitaxel in patients with ovarian cancer in late relapse (more than six months).