Adjuvant anti-VEGF therapy in an elderly patient with metastatic ovarian cancer
Dr. Karen K.L. Chan
Clinical Associate Professor
Department of Obstetrics & Gynecology
The University of Hong Kong
Presentation and clinical history
A 69-year-old Japanese woman presented with shortness of breath in late 2012. She had a history of carcinoma of the breast with left mastectomy done in 2010 and was put on Tamoxifen. She otherwise had good past health.
Physical examination was unremarkable apart from dullness over the right lower zone of the chest with decreased air entry and some fullness in the right adnexa. Chest X-ray showed right pleural effusion. Pleural tapping showed metastatic adenocarcinoma. Immunohistochemistry (IHC) staining was positive for cytokeratin-7 (CK-7), paired box 8 (PAX-8) and cancer antigen 125 (CA 125) and negative for thyroid transcription factor-1 (TTF-1), CDX-2, breast cancer antigen-2 (BRST-2), and estrogen receptor (ER) and progesterone receptor (PR).
Subsequent PET-CT showed hypermetabolic subcentimeter subpleural nodules in the lungs and matted mesenteric nodules in the lower anterior abdomen at midline and in the right lower quadrant. (Figure 1) There was a right adnexal mass (4.2 x 2.8 x 3.2 cm) abutting the uterus (SUVmax 4.0), an enlarged precaval node (1.1 x 1 x 1.4 cm), and a small amount of ascites in the pouch of Douglas. (Figure 2) The uterus was atrophic. The patient’s tumor marker CA 125 was 61 U/mL.
Figure 1. Matted mesenteric nodules (SUVmax 2.9) in the lower anterior abdomen at midline
Figure 2. Right adnexal mass (4.2 x 2.8 x 3.2 cm, SUVmax 4.0) abutting the uterus
Laparotomy was performed. Intraoperatively, a right ovarian tumor measuring 4 x 3 x 2 cm adherent to the back of the uterus was found. The peritoneum was grossly thickened and a 3 cm peritoneal tumor plaque was adherent to the ascending colon. Miliary deposits were seen in the sigmoid, small bowel and subdiaphragmatic surfaces. Total abdominal hysterectomy, bilateral salpingo-oophrectomy, omentectomy and debulking were done. There were residual military deposits on the bowels, peritoneal and diaphragmatic surfaces. The pathology report showed high-grade serous adenocarcinoma involving the right ovary, right parametrium, subserosal myometrium, omentum and subumbilical soft tissue. The final diagnosis was stage 4 carcinoma of the ovary according to the International Federation of Gynecology and Obstetrics (FIGO) classification.
She recovered well from the operation. About 3 weeks post operation, she was started on 3-weekly Carboplatin (AUC=6) and Paclitaxel 175 mg/m2. Bevacizumab 15 mg/kg was started from cycle two onwards. She tolerated the treatment well apart from one episode of grade 4 neutropenia during chemotherapy, but she managed to continue treatment without any dose reductions. Her tumor marker rose to 319 U/mL immediately post operation but returned to normal levels after the 2nd cycle of chemotherapy. She completed her six cycles of Carboplatin and Paclitaxel together with five cycles of Bevacizumab in April 2013. PET-CT showed no residual disease and the pleural effusion resolved. She continued to receive maintenance Bevacizumab every 3 weeks, and she remained disease free when last seen in August 2013.
Ovarian cancer is the 6th most common female cancer in Hong Kong, but it has the highest fatality amongst all gynecological cancers.1 Symptoms are vague and currently there is no effective screening program. Many women, like this patient, present late. Cytology of the pleural fluid showed metastatic adenocarcinoma. In view of her recent history of carcinoma of the breast, the picture could be compatible with recurrence. However, IHC staining was overall more suggestive of a gynecological origin. She underwent primary debulking surgery and the operative findings confirmed extensive disease, with residual miliary disease after surgery. Three-weekly Carboplatin in combination with Paclitaxel has been the standard adjuvant chemotherapy. Recently, addition of Bevacizumab has been shown to improve progression-free survival in women with advanced ovarian cancer in two large phase III randomized trials, resulting in the inclusion of Bevacizumab in US National Comprehensive Cancer Network (NCCN) guidelines for treatment of advanced ovarian cancer.2,3
Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) pathway, which has been shown to play an important role in the spread of ovarian cancer.4 It binds and inactivates VEGF, thus inhibiting cell activation and proliferation. In the first randomized trial (GOG-0218), 1,873 patients with newly diagnosed stage III (including those with residual disease >1 cm or <1 cm) or IV epithelial ovarian cancer were randomly assigned to six cycles of Carboplatin/Paclitaxel, or Carboplatin/Paclitaxel with concurrent Bevacizumab (15 mg/kg), or Carboplatin/Paclitaxel with concurrent Bevacizumab followed by up to 22 cycles of maintenance Bevacizumab.2 In the second randomized trial (International Collaboration on Ovarian Neoplasms 7 [ICON7]), 1,528 patients with high-risk early disease or advanced disease were randomized to receive Carboplatin/Paclitaxel with or without concurrent and maintenance Bevacizumab (7.5 mg/kg, half the dose used in GOG-0218) for 18 cycles.3 GOG-0218 showed that Bevacizumab maintenance led to an extension of progression-free survival (PFS) by 3.8 months (median PFS, 14.1 vs 10.3 months; p< 0.001), and similar results were seen in the highest risk subgroup in the ICON7 trial where a 3.6-month PFS improvement was shown (18.1 vs 14.5 months; p=0.002). Although a 4-month PFS advantage appears small, it does translate into a 30-40 percent prolongation of median survival in this group of patients with poor prognosis.
Generally, Bevacizumab is well tolerated. Due to its different mechanism of action, it has a different set of toxicities vs standard chemotherapy. The main toxicities are hypertension, headache, proteinuria and mucosal bleeding.5 Usually, these are mild and can be easily managed. More serious effects such as bowel perforations have been reported in those with tumors involving bowel walls, but the reported rates were <3 percent in the recent randomized trials. Bevacizumab also affects surgical and wound healing, so it was started at cycle 2 in our patient rather than too soon after the operation.
Quality of life (QoL) studies from these large randomized trials have also been reported.6,7 In ICON7, QoL scores in the Bevacizumab maintenance group were significantly lower than in the standard treatment group.6 In GOG-0218, where women not receiving Bevacizumab were still required to return 3 weekly for their placebo treatment, QoL scores were lower during chemotherapy but no prolonged effects were seen during the maintenance phase.7 Taking the results from these two trials together, it appeared that Bevacizumab has minimal negative impact on QoL from its side effects, but overall OoL may be affected by the need for frequent hospital visits for maintenance therapy.
In summary, in this lady with advanced ovarian cancer, addition of Bevacizumab to chemotherapy and Bevacizumab maintenance therapy may improve PFS. She had tolerated the treatment well and did not experience any significant side effects from Bevacizumab.
1. Hong Kong Cancer Registry; http://www3.ha.org.hk/cancereg/.
2. N Engl J Med 2011;365:2473-2483.
3. N Engl J Med 2011;365:2484-2496.
4. Eur J Cancer 2011;47(Suppl 3):S116-S130.
5. Gynecol Oncol 2010;117:497-504.
6. Lancet Oncol 2013;14:236-243.
7. Gynecol Oncol 2013;128:573-578.
This special report is made possible through an unrestricted educational grant from the industry and first appeared in MIMS Oncology.