To optimize the use of PLD and avoid unnecessary toxicity effects, predicting responses is of crucial importance[17, 18]. To the best of our knowledge, limited clinical trial studies have investigated the factors for predicting PLD monotherapy activity in recurrent ovarian cancers. Our findings might have important implications for the future management of patients on PLD therapy.
First, we found that a previous response status to first-line platinum-based chemotherapy was a predictive factor of the objective response, which is in line with previous studies[19–21].
Second, and most importantly, we analyzed the predictive role of CA125 levels at baseline and the changes in CA125 after the first cycle of PLD in patients with relative non-platinum-sensitive relapse. We found that a low CA125 level at baseline and a CA125 decrease after the first cycle were predictive factors for a better objective response. Previous studies showed that an early decline predicted an improved prognosis [22], however, the patients were limited to those with platinum-sensitive relapse. For patients with non-platinum- sensitive relapse, there are limited data. Therefore, it remains uncertain whether CA125 levels or variation can be utilized to predict the efficacy in the non-platinum- sensitive setting. The findings of this study showed that CA125 levels may provide important predictive information about the PLD efficacy in patients with non-platinum- sensitive relapse. The efficacy may be more satisfactory for patients with a baseline CA125 ≤ 200 U/mL or a CA125 decrease after the first cycle than for other patients. And this was true for the patients in whom efficacy were evaluated by the GCIG criteria or the RECIST. Since this was a preliminary analysis and the sample size of patients enrolled was not enough, if the number of patients enrolled increased, the difference may become significant statistically. On the other hand, even for the patients who achieved objective response, a portion of these patients had a CA125 increase from the baseline after each cycle. The highest proportion was 40.5% which occurred after the first cycle, subsequently, the proportion decreased. This trend is consistent with that observed in a previous study [23]. While bevacizumab might influence CA-125 levels by altering the regulation of MUC16 expression[24], the reason why this transient increase in CA125 occurred during the early treatment of PLD needs to be investigated.
The choice of second-line chemotherapy depends on several factors such as platinum-free interval, persistent side-effects after prior treatments, toxic profiles of future therapies and patient preferences[21]. For platinum-resistant/platinum-refractory relapse, sequential single-agent salvage chemotherapy is superior to multiagent chemotherapy which increases toxicity without clear benefits; however, no priority sequence of these single agents is recommended[5]. As previously mentioned, PLD is the most common initial therapy in the real world[6]. In this preliminary analysis, though the total sample size was 67 (less than 78), 20 patients had achieved an objective response. Therefore, PLD could be considered a success and the response rate in platinum-resistant and-refractory group was 29.9%, which is consistent with previous studies that reported response rates were 15%[16], 23.1%[25], 26%[26] or 40.4%[6]. Moreover, the response rate of PLD was similar to that of other single agents: topotecan, 17%[27]-20.5%[28]; gemcitabine, 9.2%[29]-29%[30]; oral etoposide, 26.8%[31]; docetaxel, 22.4%[32] and weekly paclitaxel,13.2%[28]− 25%[33].
The median time interval, from the date of enrollment to the date of changing to other therapies, was 4 months and 8 months for patients with platinum-refractory relapse, platinum-resistant relapse, respectively. In that many patients in our study switched to other anticancer therapies based on the local investigator’s decision, before disease progression, therefore, this time interval, we analyzed, was shorter than progression-free survival (PFS) which was defined from the date of enrollment to the date of disease progression. Even so, the time interval following treatment with PLD, in our research, was comparable to or even longer than the PFS with other single agents in other previous studies: topotecan, 4.7 months[34]; paclitaxel, 3.7 months[34]; gemcitabine, 3.6 months [29]; oral etoposide, 5.7 months[31]; and weekly paclitaxel, 3.49 months [33].
Moreover, for patients in our research with platinum-refractory and-resistant relapse, 80.7% and 32.3% of them had the chance to be retreated with platinum-based chemotherapy, respectively; for these patients, the platinum-free interval could be artificially prolonged to 6 months or more using PLD.
In patients with partially sensitive relapse, two options are available: platinum-based doublets or non-platinum therapy (single-agent or combination)[21]. Whether prolonging the platinum-free interval through with a nonplatinum-based chemotherapy agent could improve overall prognosis is controversial. On one hand, prolonging the platinum-free interval was hypothesized to increase the sensitivity to subsequent retreatment with platinum [3, 11]. Moreover, a vitro study has demonstrated that extending the platinum-free interval in recurrent ovarian cancer can reverse resistance to platinum[35]. On the other hand, in 2017, the MITO 8 study compared the experimental sequence of a non-platinum single agent chemo followed by a platinum based chemotherapy versus the reversed sequence, and demonstrated that the use of non-platinum-based chemotherapy to artificially prolong the platinum-free interval is not effective to improve prognosis [9].
However, the platinum-based therapy is not always the best option. The incidence of hypersensitivity reactions (allergic reactions) of any grade to carboplatin is approximately 12–19%[36]. The rate of hypersensitivity reactions increased with more frequent exposure to carboplatin, it was reported to be 27% in cycle 7 or higher [37]. For more severe or life-threatening reactions, unless the patient is under the guidance of a specialist with desensitization experience, the drug should not be used again [38]. Moreover, approximately 50% of patients re-challenging with platinum-based chemotherapy experienced recurrent hypersensitivity reactions despite premedication [39]. The decision to re-challenge should be based on several clinical factors, including the risks for severe recurrent hypersensitivity reactions and the potential clinical benefits of further treatment[36]. Additionally, adverse effects should be carefully taken into account before considering platinum re-challenge; cumulative myelosuppression, characterized by thrombocytopenia, granulocytopenia and anemia, is the main toxicity associated with carboplatin [12]. At the very least, non-platinum-based chemotherapy allows extra time for the patient to recover from toxic effects of their front-line platinum-based therapy [40]. Moreover, a significant proportion of recurrent ovarian cancer patients are considered “fragile” and therefore not fit to receive further platinum-based chemotherapy treatments due to their poor performance status and/or older age. Therefore, some less toxic options have been suggested for these patients[12]. For patients with partially platinum-sensitive relapse, PLD may not be preferred but may be an option for selected patients with ORR being 47.9% in ITT patients and 56.1% in PP population. Importantly, we want to emphasize that for patients with partially platinum-sensitive relapse, the choice of non-platinum-based chemotherapy should be prudent, and thoughtful evaluations of the disease status, the performance status of the patient, adverse effects of front-line platinum-based chemotherapy and the planned strategy for the follow-up treatment are essential. Above all, enough consent cannot be omitted.
The most common treatment-related AEs included myelosuppression, foot-hand syndrome and mucositis[41]. In this study, grade 3–4 myelosuppression included neutropenia (2.0%), anemia (1.0%) and thrombocytopenia (2.0%). Consistent with previous evidence, the myelosuppression observed in our study was generally mild[42, 43]. Therefore, more patients were able to receive other subsequent treatments. Consequently, PLD has a better impact on overall survival than other single agents [26]. In this study, the rates of grade 3–4 foot-hand syndrome and mucositis were 3.0% and 2.0%, respectively. which is consistent with the previous evidence[42, 43]. In some studies, the rates of foot-hand syndrome and mucositis may be higher than those reported in this study [44, 45], which may be due to a higher dosage of PLD (50 mg/m2). Previous evidence showed that the rate of these adverse effects increased with increasing drug doses and decreasing dose intervals[42]. In line with previous evidence, the incidence of severe adverse effects was very low, remaining lower than the 4% of the patients treated [43]. We believe that the adverse effects of PLD in this study were relatively favorable, even compared with those of oral anticancer therapy agents such as apatinib combined with oral etoposide, which had incidences of 50%, 32%, 29%, and 24% for grade 3 or 4 neutropenia, fatigue, anemia and mucositis, respectively [46], although cross-trial comparisons were difficult.
In addition to the relatively low rate of adverse effects, the QOL did not change significantly during the treatment, and no differences were found in the QOL-C30 scores between baseline and post-chemotherapy. In parallel with the ongoing improvements in cancer treatment options, the effects of treatment on QOL are also important to consider [47]. Especially for recurrent ovarian cancer which is generally incurable, the QOL is highly important[11]. Moreover, the 4-week cycle of PLD was well-accepted and more patient-friendly than the 3-week or 1-week cycle of other agents[7]. All of the above findings may support why PLD was the most common initial agent in the real world for patients with platinum-refractory and platinum-resistant relapse.
In conclusion, for patients with platinum-resistant and refractory patients, the use of PLD may be a favorite choice because of the associated satisfactory efficacy, low frequency of adverse effects and high QOL. Moreover, a lower CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for better efficacy.