Favorable response to combination therapy with bevacizumab and chemotherapy in first-line treatment of advanced ovarian cancer
Dr. Kenneth Wing-Sum Li
Department of Clinical Oncology
Queen Elizabeth Hospital
Presentation and history
A 50-year-old female presented in June 2013 with stage IV ovarian cancer with peritoneal and pleural metastases. In May 2013, she had presented with abdominal distension and shortness of breath. Chest X-ray showed bilateral pleural effusion and CT scan revealed a right ovarian tumor with peritoneal metastases and marked ascites. Pleurocentesis confirmed the presence of malignant cells.
She underwent staging laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and bilateral pelvic lymph node dissection. Unfortunately, only suboptimal debulking was achieved, leaving gross residual disease over the pouch of Douglas and miliary tumor deposits over the subdiaphragmatic surface. Pathology revealed poorly differentiated serous carcinoma arising from the right ovary, with involvement of the left ovary, serosal surfaces of the fallopian tubes and uterus, omentum and the left paracolic gutter. Three out of 15 left pelvic lymph nodes and four out of 19 right pelvic lymph nodes were involved. Peritoneal cytology showed malignant cells. The patient recovered well from surgery.
Postoperative cancer antigen (CA)-125 was 1,618 U/mL. Postoperative CT scan showed bilateral pleural effusion, discrete nodules up to 1.5 cm in diameter along the gastrocolic ligament, generalized increased strandings throughout the peritoneal lining and lymphoceles in the pelvic cavity.
The patient received one cycle of Paclitaxel (175 mg/m2 over 180 minutes) and Carboplatin (area under the curve = 5) 3 weeks postsurgery. Bevacizumab (15 mg/kg) was added onto cycle 2 and onwards, allowing an interval of 4 to 6 weeks from surgery as per the protocol observed in the Gynecologic Oncology Group (GOG) 0218 study.3 Bevacizumab was suspended during chemotherapy cycles 3 and 4 due to grade 3 hypertension. It was later resumed after her blood pressure was controlled with antihypertensive treatment. Maintenance therapy with Bevazicumab was initiated after cycle 6. Thus far, she has received eight more cycles of maintenance Bevacizumab with no adverse effects.
A favorable treatment response was observed in our patient. CA 125 normalized after three treatment cycles. CT scan after cycle 5 showed resolution of pleural effusion (Figure 1) and a decrease in the extent of peritoneal strandings. The latest CT scan after cycle 13 showed a marked reduction in the size of nodules along the gastrocolic ligament (Figure 2).
According to the latest statistics from the Hong Kong Cancer Registry, the incidence of ovarian cancer has risen steadily over the past 10 years. In 2011, ovarian cancer was the sixth most common female cancer and the seventh leading cause of mortality, the highest ranked of all gynecological cancers.1 Due to the vagueness of the presenting symptoms which could easily be neglected, patients often present at an advanced stage.
The outcome of stage IIIC and IV ovarian cancer patients with suboptimal debulking after surgery is poor. In a study analyzing the outcome of patients based on the extent of debulking, the median progression-free survival (PFS) was only 13.7 months and 11.5 months for stage IIIC and IV patients with residual tumors >10 mm, respectively, while the median overall survival (OS) was 30.7 months and 23.9 months, respectively. In contrast, the median PFS in stage IIIC patients and median OS in stage IIIC and IV patients with no residual tumors were more than doubled.2
In recent years, there has been a breakthrough in the treatment of advanced ovarian cancer. Two phase III randomized controlled trials showed that the addition of Bevacizumab to chemotherapy could prolong the median PFS of these patients.3,4 In the ICON7 study (International Collaboration on Ovarian Neoplasms 7), there was a significant improvement in the rate of complete or partial response, from 48 to 67 percent. In patients at high risk of progression, the ICON7 study even demonstrated a significant improvement in median OS, from 28.8 to 36.6 months.4
The improvement in outcome has been achieved at the expense of increased toxicity. Hypertension of grade 2 or higher was observed in 18 to 23 percent of patients in the Bevacizumab maintenance arm vs 2.0 to 7.2 percent in the chemotherapy-alone arm. Other side effects included gastrointestinal perforation, grade 3 or higher proteinuria, and thromboembolism; these were within expectation based on the known toxicity profile of Bevazicumab, and patients’ quality of life was not affected.3,4 As for our patient, she suffered from grade 3 hypertension which led to interruption of Bevacizumab during the induction phase. However, her blood pressure was controlled with antihypertensives and, thus, Bevacizumab was resumed in subsequent treatment cycles and continued uneventfully in the maintenance phase.
In both studies, the PFS curves started to converge after completion of the maintenance phase of Bevacizumab. This may suggest a role for maintenance therapy with Bevacizumab until progression, especially in patients at high risk of progression. In the OCEANS study (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease), the PFS curves of the two treatment groups did not converge when Bevacizumab was continued until disease progression in platinum-sensitive recurrent disease.5 Therefore, further clinical trials looking into more prolonged administration of maintenance Bevacizumab are warranted.
1. Hong Kong Cancer Registry: http://www3.ha.org.hk/cancereg/.
2. Cancer 2009;115:1234-1244.
3. N Engl J Med 2011;365:2473-2483.
4. N Engl J Med 2011;365:2484-2496.
5. J Clin Oncol 2012;30:2039-2045.
Figure 1. Complete resolution of pleural effusion (a) at baseline, and (b) after 13 cycles of chemotherapy and intermittent Bevacizumab
Figure 2. Serial decrease in the size of nodule along the gastrocolic ligament at (a) baseline and (b) after 13 cycles of chemotherapy and intermittent Bevacizumab (arrows)
This special report is made possible through an unrestricted educational grant from the industry and first appeared in MIMS Oncology.