Since the advent of polyadenosine bisphosphate ribose polymerase (PARP) inhibitors, their maintenance therapy has attracted much attention as a new standard treatment for ovarian cancer and has become an important part of the overall management model of ovarian cancer. With its good efficacy and safety, PARP inhibitors have become the first-line maintenance therapy for patients with ovarian cancer. So, how to choose first-line maintenance drugs for patients with high-grade serous adenocarcinoma of both ovaries in stage III .c? Can nilapaline maintenance therapy be initiated when other PARP inhibitors are poorly tolerated? How well is it tolerated in patients with nilapally maintenance therapy? How is the patient's condition monitored during maintenance therapy? This case will share the experience of nilapally in first-line maintenance therapy applied to patients with advanced BRCA-positive ovarian cancer who are intolerant to Olaparelli.
Professor He Chenyun
Affiliated Cancer Hospital of Nantong University
Master, Deputy Chief Physician, Associate Professor
He has been engaged in gynecological tumor work for more than 10 years, and has accumulated rich clinical experience in the diagnosis and treatment of gynecological tumors, especially in the early diagnosis and early treatment of gynecological tumors.
01 Case review
Basic information
Patient, female, 53 years old.
Treatment progression
✔ Stage 1: initial cytokinesis (PDS) + postoperative chemotherapy
The patient was treated to the local hospital for "bloating for three months and the discovery of pelvic masses for a week.". Considering the possibility of ovarian cancer, the large omental mass > 2 cm. PDS (whole uterus + double appendage + large omentum + pelvic abdominal tumor resection + partial rectal resection + anastomosis) was performed on December 16, 2019.
Postoperative pathology: double ovarian high-grade serous adenocarcinoma with vascular carcinoma embolus, cancerous tissue extensively involving bilateral ovarian surface and uterine serous surface, omentum seeing cancer nodules, cancerous tissue from the intestinal serous surface infiltrated into the intestinal muscular layer with vascular carcinoma embolism.
Final diagnosis after surgery: high-grade serous adenocarcinoma of both ovaries stage III.c.
After the operation, when the local hospital gave "paclitaxel + carboplatin" chemotherapy, the "paclitaxel" allergy appeared and the chemotherapy was stopped and transferred to our hospital. Ct scan + enhancement of the neck, chest, and whole abdomen shows slightly thickening of the vaginal stump, slightly more presacral structure, and postoperative changes may occur; intrahepatic hypodermic foci, considering cysts; left adrenal gland is slightly thicker, with several small lymph nodes in the abdominal cavity, posterior peritoneum, and bilateral iliac vessels; several small nodules in both lungs, which may be inflammatory; a small lymph node shadow is seen in the anterior mediastinum. Replace the "paclitaxel liposome + carboplatin" regime for 6 courses of chemotherapy. Last chemotherapy: May 18, 2020. During chemotherapy, blood CA125 levels gradually return to normal and HE4 fluctuates within the normal range (Figure 1).
Figure 1 Changes in tumor markers during chemotherapy
✔ Stage 2: first-line maintenance therapy with PARP inhibitors
The patient underwent postoperative genetic testing and found a total of 3 clear pathogenic mutations in the BRCA gene. On June 7, 2020 (20 days after chemotherapy), the patient began oral oral olapally 300 mg bid maintenance therapy, and had severe gastrointestinal reactions such as nausea and vomiting and stomach pain, which affected eating and life, and underwent antiemetic, rehydration and other treatments, and the symptoms improved slightly after a period of time. There was still a pronounced gastrointestinal reaction after reducing the dose, and the patient refused to continue the medication and discontinued olapalide (olapally treatment lasted 1.5 months). Switch to maintenance therapy with nilapali 200 mg qd starting on July 24, 2020. During maintenance therapy, blood CA125 and HE4 levels fluctuated within the normal range (Figure 2), and leukocytes, hemoglobin, and platelets fluctuated within the normal range (Figure 3). No signs of tumor recurrence were seen in PET-CT on July 9, 2021 (Figure 4). On October 29, 2021, ultrasound B suggested pelvic effusion; no obvious mass lesions were seen in the spleen, pancreas, and no obvious embolism in bilateral internal jugular veins, bilateral subclavian veins, bilateral femoral veins, and bilateral popliteal veins.
Fig. 2 Changes in blood CA125 and HE4 levels during maintenance therapy
Fig. 3 Changes in the level of white blood cells, hemoglobin, and platelets during maintenance therapy
Figure 4 PET-CT situation on July 9, 2021
Summary of cases
In this case, the patient was treated with "abdominal distension for three months, pelvic mass was found for one week", considered the possibility of ovarian cancer, underwent PDS surgery, and the postoperative pathological diagnosis was biovarian high-grade serous adenocarcinoma IIIc stage. During the "paclitaxel + carboplatin" chemotherapy, the "paclitaxel" allergy stopped chemotherapy and transferred to our hospital, and the "paclitaxel liposome + carboplatin" chemotherapy was replaced for 6 cycles. BRCA genetic testing revealed 3 definitive pathogenic mutations. After olapally 300 mg bid maintenance therapy, due to the occurrence of severe gastrointestinal reactions, and the gastrointestinal reactions are still obvious after reducing the dose, it was decisively changed to nilapali 200 mg qd maintenance therapy, which has been more than 1 year. During the follow-up period, the relevant hematologic indicators fluctuated within the normal range, no obvious abnormalities were found on imaging examinations, and the patient's disease control was stable and the drug tolerability was good.
03 Expert reviews
Professor He Aiqin
Chief physician, master tutor, discipline leader
Director of the Department of Gynecology and Oncology, Affiliated Cancer Hospital of Nantong University
Member of the Gynecologic Oncology Committee of the Chinese Anti-Cancer Association
Member of the Brachytherapy Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Gynecologic Tumor Professional Committee of Jiangsu Anti-Cancer Association
Member of the Gynecologic Tumor Professional Committee of Jiangsu Medical Association
Member of the Gynecologic Oncology Group of the Obstetrics and Gynecology Branch of Jiangsu Medical Association
Chairman of the Gynecologic Oncology Professional Committee of Nantong Anti-Cancer Association
Vice Chairman of obstetrics and gynecology branch of Nantong Medical Association
Vice Chairman of obstetrics and gynecology branch of Nantong Medical Doctor Association
Expert reviews
Advanced ovarian cancer is the most fatal gynecologic tumor, and first-line standard treatment regimens based on debulking and platinum-containing chemotherapy can achieve remission in 70% to 80% of patients. Paclitaxel plus carboplatin remains the standard and preferred regimen for first-line chemotherapy for epithelial ovarian cancer, and albumin-binding paclitaxel may be substituted for patients with solution-based paclitaxel-soluble allergy[1]. The patient in this case was diagnosed with ovarian cancer in the local hospital, and after PDS surgery and first-line chemotherapy of paclitaxel + carboplatin, an allergic reaction of paclitaxel appeared, so he was transferred to our hospital and replaced by paclitaxel liposome + carboplatin regimen chemotherapy for 6 cycles. If the genetic test shows a positive BRCA, how should the patient choose a first-line maintenance treatment plan?
Maintenance therapy is an important part of the management of ovarian cancer treatment, and the advent of PARP inhibitors has reshaped the maintenance treatment model for ovarian cancer, significantly delaying patient recurrence and prolonging progression-free survival (PFS) and overall survival (OS). The NCCN guidelines recommend that for newly diagnosed stage II to IV. high-grade serous carcinoma, G2/3 ovarian endometrioid carcinoma, or BRCA1/2 mutated clear cell carcinoma and carcinosarcoma, there may be benefits of complete remission (CR) or partial remission (PR) after surgery and platinum-based first-line therapy [2]. Some gastrointestinal adverse events may occur during the use of PARP inhibitors, and adverse events of grade 1 to 2 are more common.
The PRIMA study is a phase III randomized controlled study of comparing nirapali with placebo maintenance therapy after first-line platinum-containing chemotherapy for advanced ovarian epithelial cancer has been remission. In the overall population, the Nilapali group had a 38% lower risk of disease progression or death than the placebo group (median PFS 13.8 months versus 8.2 months; HR 0.62, 95% Cl 0.50 to 0.76). Different benefits were observed in different subgroup analyses of biomarkers, with the NILAPALI group having a 60% lower risk of disease progression or death than the placebo group in BRCA-positive patients (HR 0.40, 95% Cl 0.27-0.62). At the same time, the study confirmed the safety of the long-term application of nilapali. This study supports the use of nilapa as a first-line maintenance therapy for all ovarian epithelial cancers, even in patients without BRCA mutations or HRD-negative [3]. Based on the results of the PRIMA study, the NCCN guidelines recommend nilapalli monotherapy for first-line maintenance therapy for the entire population of ovarian cancer [2].
In this case, the patient was intolerant of the first-line maintenance therapy regimen of olaparil 300 mg bid, and there were no adverse reactions after switching to the 200 mg qd regimen of nilapali. The cause may be related to the different metabolic pathways of the two, with olapally metabolized primarily by the CYP3A4/5 enzyme and nilapali metabolized primarily by carboxylate enzymes (CEs). Nilapali first-line maintenance therapy has been more than a year now, and follow-up imaging tests and blood indicators have indicated a stable state. For this patient, it is recommended to continue to closely monitor the blood count, liver and kidney function, and blood pressure, to continue to pay attention to the patient's tolerance to the drug, and if necessary, to adjust the appropriate dose according to adverse reactions.
In this case, a BRCA-positive patient with advanced ovarian cancer who was intolerant to other PARP inhibitors was replaced by nilapagli first-line maintenance therapy, and the tolerance was good, achieving a stable state for more than 1 year. The choice of first-line maintenance regimen needs to be considered in conjunction with approved indications, degree of benefit, safety and convenience. It is hoped that the patient's experience in this case can provide thinking and inspiration for the clinical diagnosis and treatment of ovarian cancer, so as to bring more survival benefits to a wider range of patients with advanced ovarian cancer.
bibliography
Gynecologic Oncology Committee of Chinese Anti-Cancer Association. Guidelines for the Diagnosis and Treatment of Ovarian Malignant Tumors (Fourth Edition)[J].Chinese Journal of Practical Gynecology and Obstetrics.2018,34(7):739-749.
[2] NCCN Guidelines®. Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2021. available at www.nccn.org.
[3] Gonzalez-Martin A,Pothuri B,Vergote I,et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med.2019;381(25):2391–2402.