Epithelial ovarian cancer is the most lethal, malignant gynecological tumor. Each year, 230,000 women worldwide are diagnosed with ovarian cancer and 150,000 die from the disease. Ovarian cancer is the seventh most common cancer diagnosis among women worldwide. Unfortunately, there is no ideal screening test for early ovarian cancer; most patients are usually asymptomatic or present with only nonspecific symptoms at the time of diagnosis.[3,4] Thus, approximately 75% of ovarian cancer patients are diagnosed at an advanced stage of disease. Palliative treatment for advanced ovarian cancer begins at diagnosis with the goal of prolonging survival, delaying disease progression, alleviating disease-related symptoms, and improving quality-of-life. The standard treatment for advanced ovarian cancer is optimal cytoreductive surgery, followed by platinum-based chemotherapy.[6,7] Combination therapy with carboplatin-paclitaxel is the most widely used treatment for advanced ovarian cancer, associated with a response rate of approximately 65%, progression-free survival (PFS) of 16 to 21 months, and overall survival (OS) of 32 to 57 months.[8–10] Although ovarian cancer responds well to chemotherapy, recurrence develops in most patients regardless of robust response to frontline treatment.[1,11,12] Therefore, research is needed concerning new combination chemotherapies for advanced or recurrent ovarian cancer.
Of the various anticancer drugs, vinorelbine is a semisynthetic vinca alkaloid. The mechanism of action is similar to the mechanisms of other vinca alkaloids; vinorelbine exerts a cytotoxic effect by inhibiting the reversible binding of microtubules to tubulin, triggering mitotic spindle lysis and stopping cell division. Because vinorelbine is active against mitotic microtubules but less active against axonal microtubules, it is less toxic than vincristine and vinblastine but equally effective. Several phase I and II clinical trials have confirmed that vinorelbine exhibits a response rate equivalent to the response rates of other anticancer drugs when used to treat advanced ovarian cancer.[13,16–19] Burger et al investigated vinorelbine in 38 patients with recurrent or persistent epithelial ovarian cancer. Eleven (29%) objective response were observed, associated with median duration of response of 19 weeks. Based on these studies, vinorelbine monotherapy is recommended by the National Comprehensive Cancer Network as a treatment option for platinum-resistant or platinum-sensitive, advanced ovarian cancer. Cisplatin is a platinum-based drug that is used alone or in combination with gemcitabine or paclitaxel to treat platinum-sensitive, advanced ovarian cancer.[20–22] Both cisplatin and vinorelbine are potentially effective against advanced ovarian cancer, but few studies have investigated a combination of cisplatin and vinorelbine. For other cancers, combination cisplatin and vinorelbine palliative chemotherapy has been widely used.[23–26] Given this background, we evaluated the clinical benefits afforded to patients with advanced ovarian cancer through receipt of combination cisplatin and vinorelbine as second- or higher-line palliative chemotherapy.
We collected and reviewed the medical records of 1352 patients diagnosed with ovarian cancer at Chungnam National University Hospital, Daejeon, Republic of Korea between January 2004 and March 2021. Among them, 104 patients with missing data and 1054 patients diagnosed with stage I to III ovarian cancer were excluded. We identified 194 patients with advanced or recurrent ovarian cancer, of whom 162 patients were excluded according to the exclusion criteria detailed below. As a result, 32 patients with advanced or recurrent ovarian cancer who received cisplatin plus vinorelbine as second- or higher-line chemotherapy were enrolled (Fig. 1). We included patients ≥18 years of age with histologically or cytologically confirmed epithelial ovarian cancer. The other inclusion criteria were the presence of at least 1 measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors (version 1.1) criteria, an Eastern Cooperative Oncology Group performance score ≤ 2, previous systemic treatment with at least 1 palliative chemotherapy regimen, an absolute neutrophil count ≥ 1500/mL, a platelet count ≥ 100,000/mL, a serum creatinine (Cr) level ≤ 1.5-fold the institutional upper limit of normal, a serum bilirubin level ≤ 1.5-fold the upper limit of normal, or an alkaline phosphatase level ≤ 2.5-fold the upper limit of normal. We excluded patients with other malignancies that had developed within the previous 5 years, patients who had not undergone cytoreductive surgery, patients who required hospital admission to control active bleeding or central nervous system disease; and patients with active infections that required systemic therapy at study initiation. Other exclusion criteria included significant cardiovascular disease (e.g., uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure, or uncontrolled arrhythmia), pregnancy or nursing status, or any major surgical procedure within the past 30 days. This study was approved by the Institutional Review Board of Chungnam National University Hospital.
All patients were treated with cisplatin (60 mg/m2 on day 1) and vinorelbine (25 mg/m2 on days 1 and 8); the cycles were repeated at 21-day intervals. The cycles were delayed if the absolute neutrophil count was <1500/mL and/or the platelet count was <100,000/mL on the proposed day of treatment. All patients received prophylactic medication to counter chemotherapy-induced nausea/vomiting. Granulocyte colony-stimulating factor was administered to patients with absolute neutrophil count levels <500/mL and to patients with febrile neutropenia. Chemotherapy was continued until disease progression, the development of unacceptable toxicity, or patient refusal (maximum of 6 cycles).
2.3. Response and toxicity assessments
Response evaluations were performed via clinical assessment and imaging after every second or third cycle (in the absence of overt progression). The treatment response was classified as complete response (CR), partial response (PR), stable disease, or progressive disease, according to the Response Evaluation Criteria in Solid Tumors criteria (version 1.1); toxicity was assessed based on the Common Terminology Criteria for Adverse Events (version 5.0).
2.4. Statistical analysis
Basic descriptive statistics were collected, including medians with ranges. Differences between groups were examined for statistical significance using the chi-squared test for categorical variables. PFS was defined as the time between the first administration of chemotherapy and the date of tumor progression. OS was defined as the time between the first administration of chemotherapy and the date of last contact or death. PFS and OS were estimated using the Kaplan–Meier method with the log-rank test. A P value < .05 was considered statistically significant. SPSS statistical software for Windows (version 25.0; SPSS Inc., Chicago, IL) was used for all statistical analyses.
3.1. Patient population
Thirty-two patients with advanced or recurrent ovarian cancer were treated with cisplatin and vinorelbine as second- or higher-line chemotherapy. The median patient age was 52 years (range, 31–77 years). The histological subtypes were: serous carcinoma (n = 26), transitional cell carcinoma (n = 1), clear cell carcinoma (n = 2), and other (n = 3). All patients had been treated with platinum-based cytotoxic chemotherapy prior to the study. Platinum susceptibility was defined based on evaluations performed over 6 months from completion of platinum-based adjuvant chemotherapy to disease progression. Patients with disease progression after 6 months were classified as platinum-sensitive; patients with progression before 6 months were classified as platinum-resistant. Eleven (34.4%) patients exhibited platinum resistance; 21 (65.6%) patients exhibited platinum sensitivity (Table 1).
Table 1 -
|Age (yr; median, range)
| Serous carcinoma
| Transitional cell carcinoma
| Clear cell carcinoma
|ECOG performance status
|No. prior regimens
ECOG = Eastern Cooperative Oncology Group.
3.2. Tumor responses
No CR was observed; PRs were noted in 6 (18.8%) patients. Stable disease was recorded in 18 (56.3%) patients and progressive disease was recorded in 8 (25.0%) patients. The objective response rate (ORR) was 18.8% and the disease control rate was 75.0% (Table 2). There were significantly more responders in the platinum-sensitive group than in the platinum-resistant group (P = .035). The disease control rate was also better in the platinum-sensitive group (90.5% vs 54.6%; P = .032) (Table 3).
Table 2 -
Best response to combination of cisplatin and vinorelbine
(n = 32).
CR = complete response, DCR = disease control rate, ORR = objective response rate, PD = progressive disease, PR = partial response, SD = stable disease.
Table 3 -
Best response to combination of cisplatin and vinorelbine
according to platinum sensitivity (n = 32).
||Platinum-sensitive, no. (%)
||Platinum-resistant, no. (%)
CR = complete response, DCR = disease control rate, ORR = objective response rate, PD = progressive disease, PR = partial response, SD = stable disease.
3.3. Survival outcomes
For all patients, the median PFS was 4.13 months (95% confidence interval [CI], 2.4–5.8 months) (Fig. 2); the median OS was 56.9 months (95% CI, 50–63.7 months) (Fig. 3). The median PFS was not significantly longer in the platinum-sensitive group than in the platinum-resistant group (5.3 vs 3.8 months; P = .339) (Fig. 4), but the median OS was significantly longer in the platinum-sensitive group (69.6 vs 24 months; P < .001) (Fig. 5).
3.4. Safety profiles
In total, 138 cycles of cisplatin and vinorelbine treatment were administered (median, 4.3 cycles/patient; range, 1–6 cycles/patient). All patients reported hematological toxicities. The neutropenia rates were 100% (all grades) and 56.25% (grades 3–4). The thrombocytopenia rates were 31.2% (all grades) and 6.2% (grades 3–4). The anemia rates were 93.7% (all grades) and 9.3% (grades 3–4). Febrile neutropenia occurred in 2 (6.2%) patients; we recorded no treatment-related deaths. Nonhematological toxicities (all grades) were accompanied by elevated Cr levels in 3.1% of patients, alanine aminotransferase elevation in 21.8% of patients, and bilirubin elevation in 9.3% of patients. There was no grade 3 to 4 nonhematological toxicity (Table 4).
Table 4 -
Laboratory toxicities (n = 32).
||Any grade, no. (%)
||Grade 3 or 4, no. (%)
| Febrile neutropenia
| ALT elevation
| TB elevation
| Cr elevation
ALT = alanine aminotransferase, Cr = creatinine, TB = total bilirubin.
Ovarian cancer is very sensitive to traditional cytotoxic chemotherapy; overall response rates of approximately 80% have been reported in patients treated with platinum- and paclitaxel-based combination therapies. However, most patients eventually experience tumor progression. The most important factor when choosing chemotherapy to treat recurrent ovarian cancer is the duration of the response to previous platinum-based therapy.[28,29] This is regarded as the treatment-free interval, usually defined as follows: platinum-resistant disease constitutes progression within 6 months of the last platinum-containing therapy, while platinum-sensitive disease constitutes progression after 6 months. Furthermore, patients who relapse within 6 to 12 months are partially sensitive and patients who relapse after 12 months are highly sensitive. In general, a longer treatment-free interval is associated with a longer response to retreatment. In patients with advanced, platinum-sensitive ovarian cancer, the PFS of carboplatin monotherapy is 6 to 9 months; the PFS of platinum-based combination regimens and other drug combinations is approximately 12 months.[32,33] Based on these findings, platinum-sensitive patients are usually treated with a platinum-based combination of cytotoxic agents (i.e., gemcitabine, pegylated liposomal doxorubicin, and/or paclitaxel).[21,22,33,34] The standard treatment for platinum-resistant patients is nonplatinum single-agent chemotherapy (i.e., docetaxel, paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan),[32,35–39] which is associated with a short-lived response rate of approximately 10% to 25%. In general, single-agent anticancer regimens for patients with platinum-resistant ovarian cancer afford limited therapeutic benefits, but combination therapy increases toxicity without improving efficacy. Recently, bevacizumab has been added to the standard chemotherapy regimen for ovarian cancer.[35,40–42] Bevacizumab is a monoclonal antibody against vascular endothelial growth factor, which inhibits the development of new blood vessels and the growth of cancer. The addition of bevacizumab to standard chemotherapy improved the median OS, but the improvement was not statistically significant in the intention-to-treat analysis (median OS, 42.2 months [95% CI, 37.7–46.2] in the chemotherapy-plus-bevacizumab group vs 37.3 months [95% CI, 32.6–39.7] in the chemotherapy group; hazard ratio, 0.829 [95% CI, 0.683–1.005; P = .056]). In terms of other targeted therapies, poly (ADP-ribose) polymerase inhibitors (i.e., niraparib, olaparib, and rucaparib) are the preferred monotherapies for patients with advanced ovarian cancer.[44–46] In niraparib monotherapy for the treatment of late-stage ovarian cancer, 13 (28%) of 47 patients in the primary-efficacy population achieved an overall response (95% CI, 15.6–42.6). Immunotherapy for ovarian cancer has shown limited efficacy. Recently, a phase II study to evaluate the efficacy of pembrolizumab was conducted through the KEYNOTE-158 trial. The 223 patients who participated in the study were advanced noncolorectal solid-cancer patients, including ovarian cancer with high microsatellite instability and mismatch repair-deficient cancers. In the KEYNOTE-158 study, the ORR of pembrolizumab was 34.3% (95% CI, 28.3%–40.8%), and the median OS was 23.5 months (95% CI, 13.5 months–not reached). As a result of this study, in May 2017, pembrolizumab was approved for metastatic high microsatellite instability/mismatch repair-deficient solid tumors, including ovarian cancer, by the Food and Drug Administration. However, further research is needed to improve the efficacy of immunotherapeutic applications for ovarian cancer.
As mentioned earlier, combined cisplatin and vinorelbine therapy is widely used as a palliative and adjuvant treatment for other cancers.[49–52] Vinorelbine is a semisynthetic vinca alkaloid that exerts a cytotoxic effect by selective activity against mitotic microtubules. Relative to vinblastine and vincristine, higher concentrations of vinorelbine are required to affect axonal microtubules; presumably this accounts for the decreased neurotoxicity induced by vinorelbine.[13,53] Vinorelbine has a different mechanism of action and is not cross-resistant with cisplatin. In advanced ovarian cancer, vinorelbine has shown antitumor activity as a single agent. However, no previous study has explored the utility of combination cisplatin and vinorelbine in patients with advanced ovarian cancer. To our knowledge, this is the first study to report the clinical outcomes of combination cisplatin and vinorelbine as second- or higher-line palliative chemotherapy in patients with advanced ovarian cancer. In this study, a combination of cisplatin and vinorelbine demonstrated modest clinical efficacy in patients with advanced ovarian cancer. The ORR (18.8% vs 3%) and median OS (56.9 months vs 10.1 months) in our study compares favorably to those with single agent vinorelbine reported by Rothenberg et al These ORR and OS results are similar to the findings regarding other second- or higher-line chemotherapies in advanced ovarian cancer.[55,56] The treatment outcomes were better in the platinum-sensitive group than in the platinum-resistant group; the ORRs were 42.9% and 9.1% and the median OS values were 69.6 and 24 months, respectively. The median OS values in both the platinum-sensitive and platinum-resistant patients in this study were higher than those in patients treated with vinorelbine alone (69.6 months vs 16 months; 24 months vs 8 months, respectively). While the clinical benefit of vinorelbine in combination with cisplatin over vinorelbine alone in advanced ovarian cancer cannot be proven in the absence of a randomized clinical trial, our data imply a possible benefit and support further research.
Hematological toxicity was apparent in all patients, although it was tolerable; of the patients, 56.2% developed grade 3 or higher neutropenia, 6.2% developed grade 3 or higher thrombocytopenia, and 6.2% developed febrile neutropenia. Most patients were adequately managed via granulocyte colony-stimulating factor treatment and antibiotic administration, as well as supportive care. Patients with advanced ovarian cancer in palliative settings are often retreated with regimens similar to those previously used in the first-line settings, including platinum or taxane alone or in combination. Early retreatment with platinum may limit the possibility of further treatment, considering the increasing risk of hematological toxicity that reduces the quality-of-life. Cisplatin and vinorelbine combination therapy is widely used as an adjuvant therapy for patients with nonsmall cell lung cancer; similar to our findings, such therapy is associated with a favorable safety profile. Most treatment-related adverse events associated with cisplatin and vinorelbine combination therapy for nonsmall-cell lung cancer were reversible hematological toxicities. Considering the favorable toxicity profile, cisplatin and vinorelbine combination therapy may be appropriate for elderly patients with advanced ovarian cancer or for patients with poor performance status.
Our study had several limitations. First, the statistical power was limited by the small number of patients. Second, the retrospective design may have biased the recorded effects and adverse events of combination therapy. Third, because this was a single-center study, the patient population was generally homogeneous. Finally, we lacked data regarding patient-reported outcomes such as quality-of-life. Additional well-designed, controlled prospective studies are needed to validate our findings.
In conclusion, combination cisplatin and vinorelbine second- or higher-line palliative chemotherapy for patients with advanced ovarian cancer may be effective, particularly in platinum-sensitive patients. The combination exhibited a favorable toxicity profile.
Conceptualization: Young Bok Ko, Hyo Jin Lee.
Data curation: Sang Hoon Yeon, Ik-Chan Song.
Funding acquisition: Hyo Jin Lee.
Investigation: Sang Hoon Yeon, Hwan-Jung Yun.
Methodology: Sang Hoon Yeon, Hyewon Ryu.
Supervision: Young Bok Ko, Hyo Jin Lee.
Writing – original draft: Sang Hoon Yeon, Myung-Won Lee, Ik-Chan Song.
Writing – review & editing: Deog-Yeon Jo, Young Bok Ko, Hyo Jin Lee.
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