Maintenance Chemotherapy in Patients with Platinum-Sensitive Relapsed Epithelial Ovarian Cancer after Second-Line Chemotherapy

(1) Background: Our aim was to evaluate the efficacy and adverse effects of maintenance chemotherapy in platinum-sensitive recurrent epithelial ovarian cancer after second-line chemotherapy. (2) Methods: A total of 72 patients from a single institute who had been diagnosed with platinum-sensitive recurrent ovarian cancer and had experienced either complete or partial response after six cycles of second-line chemotherapy were divided into a standard group (n = 31) with six cycles or a maintenance group (n = 41) with more than six cycles. We then compared patient characteristics and survival outcomes between these two groups. (3) Results: In all patients, after primary management for the first recurrence, the maintenance group showed worse survival outcomes. Patients who had not undergone either surgery or radiotherapy were divided into complete response and partial response groups after six cycles of chemotherapy. In patients with partial response, maintenance chemotherapy led to a significant improvement in PFS (median, 3.6 vs. 6.7 months, p = 0.007), but no significant change in in OS. The median cycle number of maintenance chemotherapy was four. (4) Conclusions: Maintenance chemotherapy may still play an important role in patients with platinum-sensitive recurrent ovarian cancer, particularly in selected patient groups.


Introduction
Epithelial ovarian cancer (EOC) has been one of the leading causes of death in women worldwide over the past decade, with over 314,000 women being diagnosed in the year 2020 alone, and approximately 207,000 of them dying, making it the second most common cause of death from gynecologic cancers [1].In Taiwan, an incidence rate of 6.36 per 100,000 women in 2020 was documented, with a steady increase since the 1990s at an annual percentage change of 1.5% during the period 1995 to 2014 [2].Ovarian cancer is also one of the most common causes of death in women, with a standardized mortality This is a retrospective cohort study with data taken from a tertiary medical center in Taichung City, Taiwan.The study protocol was approved by our Institutional Review Board (IRB) (Number: CE21233B).
We identified patients who had experienced their first relapse of epithelial ovarian cancer (EOC) in a decade between the years 2011 and 2021 (n = 134, Figure 1), with or without having undergone secondary cytoreduction surgery or radiation therapy.We excluded patients who had not received either a primary debulking operation or first-line standard adjuvant therapy at our medical center (n = 10), as well as patients with platinum-resistant disease (n = 16) as a recurrent disease less than 6 months from their last first-line chemotherapy session.Patients who opted for maintenance therapy involving PARP inhibitors or immunotherapy (n = 7) were excluded, however, those treated with bevacizumab were included.In addition, patients who declined standard chemotherapy treatment or were lost during follow-up (n = 15), patients who experienced disease progression before their 6th cycle of second-line chemotherapy (n = 6), and patients who were currently under chemotherapy before the evaluation of their 6th cycle of second-line chemotherapy as of the end date of this study on 2 May 2021 (n = 8) were also excluded.
response range was defined as disease progression, which was 70 IU/mL at our institution.The primary outcome of this study was progression-free survival (PFS) and overall survival (OS) as a secondary endpoint in terms of maintenance therapy.To explore the role of maintenance chemotherapy, PFS was defined as the interval from the date of the sixth cycle of second-line chemotherapy to the date of disease progression or patient mortality.OS was defined as the interval from the date of the sixth cycle of second-line chemotherapy to the date of mortality.

Statistical Analysis
Differences in baseline characteristics between the two treatment groups were compared using the Mann-Whitney U test and chi-square test for continuous and categorical variables, respectively.The Kaplan-Meier method was used to generate survival curves for OS and PFS, while Cox proportional hazard analysis was performed to determine the association of maintenance chemotherapy treatment with OS and PFS after adjustments for relevant variables.Subgroup analysis was conducted to determine whether a significant variation existed in the aforementioned association.All statistical analyses were A total of 72 patients who had exhibited either complete or partial response after six cycles of second-line chemotherapy, based on the images from their CT scan and the incorporated criteria of RECIST 1.1 and CA-125 agreed by the Gynecological Cancer Intergroup (GCIG), were included in the study.The patients were then divided into two groups according to the number of cycles they received, which included both a standard group (6 cycles) and a maintenance group (more than 6 cycles).Patients who underwent secondary cytoreduction surgery were evaluated first in multidisciplinary team meetings and needed to fulfill the following criteria: single or countable tumor lesions that were resectable, minimal ascites, and no distant metastases seen on PET or CT scans.
The status of disease progression and survival was confirmed by the date of 2 May 2021.Either an increase in the volume of tumors, the presence of new lesions or more ascites on abdominal CT scans, or an elevation in CA-125 over twice the upper limit of the response range was defined as disease progression, which was 70 IU/mL at our institution.The primary outcome of this study was progression-free survival (PFS) and overall survival (OS) as a secondary endpoint in terms of maintenance therapy.To explore the role of maintenance chemotherapy, PFS was defined as the interval from the date of the sixth cycle of second-line chemotherapy to the date of disease progression or patient mortality.OS was defined as the interval from the date of the sixth cycle of second-line chemotherapy to the date of mortality.

Statistical Analysis
Differences in baseline characteristics between the two treatment groups were compared using the Mann-Whitney U test and chi-square test for continuous and categorical variables, respectively.The Kaplan-Meier method was used to generate survival curves for OS and PFS, while Cox proportional hazard analysis was performed to determine the association of maintenance chemotherapy treatment with OS and PFS after adjustments for relevant variables.Subgroup analysis was conducted to determine whether a significant variation existed in the aforementioned association.All statistical analyses were performed using the Statistical Package for Social Sciences (IBM SPSS version 22.0; International Business Machines Corp, Armonk, NY, USA) with a p value of <0.05 considered as being statistically significant.

Results
Overall, 72 patients were included in this analysis: 41 in the maintenance group (>6 cycles) and 31 in the standard group (6 cycles).To better evaluate the effect of maintenance chemotherapy, we compared patients in groups with secondary cytoreduction surgery or chemotherapy alone.We found that only in the subgroup of patients who did not receive secondary cytoreduction surgery and had partial response after six cycles did they present a significant improvement in progression-free survival (PFS).However, we carried out a thorough analysis of every group in the attempt to explore which subgroup of patients would benefit most from the maintenance chemotherapy.

Analysis of All Patients (n = 72)
Table 1 presents the clinicopathologic characteristics of all patients.No differences in patient age, histologic type, tumor grade, FIGO stage, or primary treatment strategy (chemotherapy regimens) were observed between the maintenance and standard groups.Most of the patients had been diagnosed with serous ovarian cancer (58/72, 80.5%) at the advanced stage (59/72, 81.9% stage III-IV) during initial diagnosis.Nearly all of the patients underwent optimal debulking surgery (64/72, 88.8%), with 17 of them (17/72, 23.6%) receiving neoadjuvant chemotherapy.All of the patients were treated with a combination of paclitaxel and carboplatin as first-line adjuvant chemotherapy.The platinum-free interval (PFI) on average was significantly longer in the standard group than that seen in the maintenance group (median, 19.4 vs. 13.9 months, p = 0.038).Additionally, there was a significantly higher level of serum CA-125 in the maintenance group at first recurrence (median, 181.5 vs. 68.1 IU/mL; p = 0.005).In all patients (n = 72), median progression-free survival (PFS) was 15.3 months, while overall survival (OS) was 52.1 months.After the first recurrence, 26 (36.1%) patients underwent secondary cytoreductive surgery, with complete gross resection (R0) achieved in all of them.Two patients who had received radiotherapy were identified with localized recurrence but could not be resected completely, one of whom was diagnosed with brain metastases and the other with paraaortic lymphadenopathy, before the initiation of second-line chemotherapy.There were 44 patients (44/72, 61.1%) who underwent second-line salvage chemotherapy only.After primary management for first recurrence, the maintenance group showed worse outcomes in progression-free survival (Figure 2) (median, 12.5 vs. 19.1 months; p = 0.206) and significantly shorter overall survival (Figure 3) (median, 35.7 vs. 73.9months; p = 0.031).

Analysis of Patients Who Did Not Undergo Surgery or Radiotherapy (n = 44)
Table 4 demonstrates that no differences in patient age, histologic type, tumor grade, FIGO stage, or primary treatment strategy were observed between the maintenance and standard groups.Unlike the results seen in all patients, the PFI was of no significance between the two groups (median, 12.1 vs. 11.3 months, p = 0.481).There was, however, a significantly higher level of serum CA-125 at first recurrence in the maintenance group (median, 250.0 vs. 75.7 IU/mL; p = 0.033).During and after platinum doublet chemotherapy, the number of patients who received bevacizumab as maintenance therapy showed no significance (50.0% vs. 44.1%;p = 1.00).After primary management for the first recurrence, the maintenance group showed a poorer performance in PFS (Figure 4) (median, 5 vs. 12 months; p = 0.449) and OS (Figure 5) (median, 35.7 vs. 67.6 months; p = 0.634).Multivariate analyses, after adjusting for variables such as complete response after six cycles of chemotherapy and PFI, revealed that maintenance chemotherapy did not have an impact on either PFS (HR, 0.95; 95%CI, 0.43-2.07;p = 0.893) or OS (HR, 1.16; 95%CI, 0.37-3.62;p = 0.799) (Tables 5 and 6).For PFS, a PFI ≥12 months was identified as the only favorable prognostic factor (HR, 0.18; 95%CI, 0.06-0.48;p = 0.001).To better understand the role of maintenance chemotherapy, we focused on the patients who had not undergone surgery or radiotherapy and divided them more specifically into complete response and partial response groups after six cycles of second-line chemotherapy.

Progression-Free Survival (without Surgery)
In patients with partial response, maintenance chemotherapy led to a significant improvement in PFS (Figure 6) (median, 3.6 vs. 6.7 months, p = 0.007), but showed no significance in OS (Figure 7).The median cycle number of maintenance chemotherapy was 4 (range from 1-16).

Adverse Effects in All Patients
According to the criteria of CTCAE 5.0, adverse effects such as anemia, neutropenia, thrombocytopenia, liver toxicities, and renal toxicities were identified as both mild (grade 1-2) and severe (grade 3-4).Differences were only observed in mild anemia between the groups (51.6% vs. 75.6%,p = 0.034).The other adverse effects were of no significant difference between the two groups in terms of severity (Table 7).

Adverse Effects in All Patients
According to the criteria of CTCAE 5.0, adverse effects such as anemia, neutropenia, thrombocytopenia, liver toxicities, and renal toxicities were identified as both mild (grade 1-2) and severe (grade 3-4).Differences were only observed in mild anemia between the groups (51.6% vs. 75.6%,p = 0.034).The other adverse effects were of no significant difference between the two groups in terms of severity (Table 7).

Discussion
In our study, we evaluated maintenance chemotherapy in all patients diagnosed with platinum-sensitive recurrent ovarian cancer.In comparison to the standard chemotherapy group, the maintenance group presented a worse trend in progression-free survival (median, 12.5 vs. 19.1 months; p = 0.206) and significantly shorter overall survival (median, 35.7 vs. 73.9months; p = 0.031).Since patients diagnosed with less extensive recurrent disease are more prone to receiving either secondary cytoreduction surgery or radiotherapy, a better outcome in these patients would be expected, therefore they would then receive only six cycles of adjuvant chemotherapy.All patients in the standard group showed a longer PFI and a significantly lower serum level of CA-125 at first recurrence.However, when it came to patients with a partial response after six cycles of second-line chemotherapy who had received only chemotherapy after recurrence (n = 21), maintenance chemotherapy led to a significant improvement in PFS (Figure 6) (median, 3.6 vs. 6.7 months, p = 0.007).
The essence of maintenance therapy lies in the prolonging of the platinum-free interval (PFI), which correlates to better survival outcomes and favorable use in platinum-based chemotherapy regimens.Maintenance chemotherapy has been studied with a single agent of paclitaxel, pegylated liposomal doxorubicin combined with carboplatin, or paclitaxel with carboplatin in first-line adjuvant therapy [8,10,12].Here, mixed results were found, as some showed improvement in PFS, although no significant improvement was seen in OS among those studies.As for other maintenance agents, bevacizumab in first-line maintenance therapy only offered a benefit in PFS to patients with advanced-stage disease [19,20].In patients with BRCA mutations or homologous recombination deficiency (HRD), PARP inhibitors provided a significant improvement in PFS [21,22].
Regarding the recurrent setting, many studies have focused on patients with platinumsensitive disease, with pegylated liposomal doxorubicin showing promising results [23,24], though there remains a lack of larger randomized trials.As long as the toxicities are tolerable, we expect survival benefits, particularly in patients with partial or complete response.Bevacizumab works as a maintenance agent according to the OCEANS study and GOG-0213 study, both of which showed there was an improvement in PFS and OS for patients with platinum-sensitive recurrence [5,25].PARP inhibitors can also be candidates for maintenance therapy in platinum-sensitive recurrence [6].Maintenance chemotherapy still plays an important role, particularly in patients without BRCA mutations or homologous recombination deficiency (HRD), as well as patients in countries whose NHI does not cover the cost of the agents as mentioned above due to financial issues and the currently limited evidence among these populations [7].
Upon reviewing previous studies [24,[26][27][28][29], controversies remain regarding the role of maintenance chemotherapy in patients with platinum-sensitive recurrent ovarian cancer.What we learned from previous studies validated the availability of platinum-based doublet chemotherapy regimens, which included platinum plus paclitaxel [18], platinum plus gemcitabine [30], and platinum plus pegylated liposomal doxorubicin [16].The adequate cycle number in second-line chemotherapy has yet to be determined due to the lack of convincing results in the aforementioned studies, which suggested no survival benefits after six cycles, particularly in patients with complete response [8,11,31].
A recent retrospective study from Korea [31] analyzed the use of extended chemotherapy in patients who experienced platinum-sensitive recurrence after primary management with a residual tumor ≥0.5 cm (on CT scans) after six cycles of second-line, platinum-based chemotherapy.Under the same circumstance without secondary cytoreduction surgery, the characteristics of their patients were closely similar to our patients with partial response after six cycles of chemotherapy.In our study, there was significantly better PFS in the maintenance group (median, 6.7 vs. 3.6 months; p = 0.007).Compared to the data resulting from the Korean study, our results showed significantly worse PFS in the extended group (median, 13.9 vs. 14.8 months; p = 0.036).However, in the Korean study, patients without surgery who received extended cycles of chemotherapy were inferior to the standard group in several factors: fewer patients achieved R0 (41.2% vs. 56.7%)after primary debulking surgery, the platinum-free interval was shorter (median, 11.0 vs. 12.7 months), and fewer patients received any maintenance therapy (11.8% vs. 32.8%).Even under multivariate analysis, all the above factors may still play a part in the reasons behind worse outcomes in the extended group.Additionally, the evaluations of CT scans in the Korean study showed no clear evidence of any response after second-line chemotherapy, which also raised the concern of whether smaller lesions would be neglected in CT scans.In conclusion, the reasons that no compatible results were found in the Korean study may lie not only in the fundamental inferior patient characteristics seen in the extended group but also in the incomplete evaluation of chemotherapy response in patients, some of whom may be identified as either platinum-resistant or experiencing progression of disease after six cycles of second-line chemotherapy.
Nevertheless, several limitations do exist in our study.First and foremost, the sample size of our study population was small, particularly concerning those patients who had not undergone secondary cytoreduction surgery or radiation (n = 44), which was our main focus here.Therefore, there exists the possibility of selection bias and statistical issues.When we focused on patients with partial response (n = 22), there were only 3 in the standard group and 19 in the maintenance group.Secondly, even though we performed multivariate analyses for identifying possible confounders and subgroup analyses such as PFI and secondary cytoreduction surgery, the heterogeneity of the whole study population was never resolved, thus possibly requiring further prospective RCTs.Notwithstanding, we used standardized criteria for selecting our patients with complete response and partial response to chemotherapy to identify the role of maintenance chemotherapy, which is seldom described in previous studies on the same topic.The results we came up with have helped shed light on the promising direction that maintenance chemotherapy will take in platinum-sensitive recurrent ovarian cancer.

Conclusions
To sum up, even though we initiated our study with the attempt to prove maintenance chemotherapy could provide survival benefits in epithelial ovarian patients with platinum-sensitive recurrence, there was no significant improvement in the whole cohort.Nonetheless, in a subgroup of patients who did not undergo secondary cytoreduction surgery and experienced partial response after six cycles of chemotherapy, maintenance chemotherapy could significantly improve PFS.Maintenance target therapy and biological therapy have been thriving in the recurrent setting in recent years.However, maintenance chemotherapy still could play an important role due to the financial considerations in

Figure 3 .
Figure 3. Overall survival in all patients.

Figure 3 .
Figure 3. Overall survival in all patients.

Figure 5 .
Figure 5. Overall survival in patients without surgery.

Figure 4 .
Figure 4. Progression-free survival in patients without surgery.

Figure 5 .
Figure 5. Overall survival in patients without surgery.

Figure 5 .
Figure 5. Overall survival in patients without surgery.

Figure 7 .
Figure 7. Overall survival in patients without surgery who had a partial response after 6 cycles of chemotherapy.

Figure 7 .
Figure 7. Overall survival in patients without surgery who had a partial response after 6 cycles of chemotherapy.

Table 1 .
The clinicopathologic characteristics of all patients.

Table 2 .
Multivariate analyses for PFS in all patients.

Table 3 .
Multivariate analyses for OS in all patients.

Table 4 .
The clinicopathologic characteristics of patients without surgery.

Table 5 .
Multivariate analyses for PFS in patients without surgery.

Table 5 .
Multivariate analyses for PFS in patients without surgery.

Table 5 .
Multivariate analyses for PFS in patients without surgery.

Table 6 .
Multivariate analyses for OS in patients without surgery.
Figure 6.Progression-free survival in patients without surgery who had a partial response after 6 cycles of chemotherapy.Figure 6. Progression-free survival in patients without surgery who had a partial response after 6 cycles of chemotherapy.J. Clin.Med.2024, 13, x FOR PEER REVIEW 13 of 17Overall Survival (without Surgery)-PR

Table 7 .
Adverse effects in all patients.