Although many remarkable achievements have been made in the treatment of ovarian cancer in recent years, second-line and later treatment regimens of platinum-resistant ovarian cancer are still unsatisfactory. In the relevant research on platinum-sensitive recurrent ovarian cancer, chemotherapy plans containing platinum were found to have an ideal curative effect; however, in patients with platinum-resistant recurrent or acquired platinum-resistant disease during first-line chemotherapy, the efficacy of various chemotherapy drugs is not ideal. The overall response rates were as follows: weekly paclitaxel therapy was 20.9%[12], docetaxel was 22.4%[13], gemcitabine chemotherapy was 29%[4], and bevacizumab was 21%[5]. Therefore, prolonging the recurrence time of ovarian cancer and improving the quality of life of patients with ovarian cancer are focuses in the current exploration of ovarian cancer treatment. Drug resistance and treatment for recurrent ovarian cancer are urgent problems that need to be solved.
Pemetrexed disodium is a new multitarget antitumor drug against folic acid that has been approved by the FDA for the treatment of pleural mesothelioma and nonsquamous non-small cell lung cancer[8]. This drug was also studied in the treatment of ovarian cancer. It is gratifying that pemetrexed is also effective in the treatment of platinum-sensitive and platinum-resistant ovarian cancer, and the toxicity is mild[10, 11, 14, 15]. The NCCN guidelines in 2019 recommended this drug for platinum-sensitive and platinum-resistant recurrent ovarian cancer.
The present study confirmed the feasibility, efficacy and safety of pemetrexed in women with epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. Among the 96 patients, 340 cycles of chemotherapy were completed (the median chemotherapy cycle number was 3 cycles), the ORR was 32.29% (31 patients), the overall clinical response rate was 62.5%, and 37.5% (36 patients) patients developed disease progression. There were 28 platinum-sensitive patients and 68 platinum-resistant patients, and the ORRs were 42.86% (12 patients) and 27.94% (19 patients), respectively; the difference was not statistically significant (p = 0.16). In previous studies, Matulonis et al. conducted a phase II clinical study of pemetrexed disodium (500 mg/m2) combined with carboplatin (AUC = 5) chemotherapy in platinum-sensitive recurrent ovarian cancer, with an ORR of 51.1% and no complete response[15]. In another phase II clinical trial[10] of platinum-sensitive recurrent ovarian cancer, 66 patients with platinum-sensitive recurrent ovarian cancer received pemetrexed disodium (500 mg/m2) combined with carboplatin (AUC = 6) chemotherapy. The ORR of chemotherapy was 32.8%. Vergote et al.[11] conducted a phase II, randomized, double-blind trial in which 98 patients with platinum-resistant recurrent ovarian cancer or primary peritoneal cancer were treated with pemetrexed disodium (500 mg/m2 or 900 mg/m2). The ORR of pemetrexed disodium (500 mg/m2) was 9.3%, and the ORR of pemetrexed disodium (900 mg/m2) was 10.4%. Another phase II clinical trial of pemetrexed for the treatment of recurrent or persistent platinum-resistant ovarian cancer or primary peritoneal cancer included 259 cycles of pemetrexed disodium (900 mg/m2) single-drug chemotherapy in 51 patients. The ORR was 21%[14]. Based on these clinical experiences, pemetrexed combined with platinum is effective in the treatment of platinum-sensitive recurrent ovarian cancer, while pemetrexed alone is effective in the treatment of platinum-resistant recurrent ovarian cancer.
Therefore, the application value of pemetrexed in the treatment of epithelial ovarian cancer was confirmed. The median progression-free survival (PFS) of platinum-sensitive patients was 3.5 months (95% CI, 1.75–5.25), while platinum-resistant patients had a PFS of 2.97 months (95% CI, 2.47–3.47), respectively; there was no significant difference between the two groups (p = 0.06). However, the median overall survival (OS) of the two groups was 36 months and 18 months, respectively, and the difference was statistically significant (P = 0.01). For the antitumor effect, pemetrexed disodium has a similar effect in platinum-sensitive and platinum-resistant ovarian cancer, but platinum-sensitive patients seem to have a better long-term prognosis, which may be due to the increased efficacy of platinum in the treatment of platinum-sensitive recurrent ovarian cancer.
The toxic side effects of chemotherapy in 96 patients were mainly myelosuppression, gastrointestinal reactions and hepatotoxicity, all of which were mild reactions. After the appropriate supportive treatment, the side effects improved. The incidence of neutropenia of grade III and above was 6.47%, and the incidence of thrombocytopenia of grade III and above was 1.18%. There were no adverse reactions, such as purpura and gastrointestinal and intracranial hemorrhage, related to thrombocytopenia. Two patients (2.08%) received blood transfusions, 5 patients (5.21%) underwent chemotherapy dose reductions and had chemotherapy cycle prolongation. It can be seen that the side effects of pemetrexed in chemotherapy are tolerable, and the same results can be reflected in previous studies. In a phase I clinical trial conducted by Sehouli et al.[16], only one case of grade IV hepatotoxicity was found in 20 patients, and no grade IV nonhematotoxicity was found. The most common toxicity was grade I in this trial, with one case of grade III nausea and one case of grade 3 anaphylaxis. In another phase II clinical trial conducted by Andrea R. et al.[17], half of these patients had grade III-IV hematologic toxicity, of which neutropenia was the most common and severe. Common nonhematologic toxicities were fatigue and gastrointestinal reactions, which were mainly grade I-II. In conclusion, the side effects of pemetrexed chemotherapy are basically controllable and safe.