A life-extending advance in treatment of ovarian cancer
Surgical cytoreduction followed by intravenous plus intraperitoneal chemotherapy is likely to become the standard of care for stage III ovarian cancer
A 55-year-old woman presents with a complaint of a mild increase in abdominal girth. She reports no weight loss or other constitutional symptoms. A pelvic exam demonstrates a 4-cm nontender mobile right adnexal mass. An ultrasound shows a complex 5-cm right adnexal mass with an internal nodule that demonstrates blood flow and fluid in the cul-de-sac. CA-125 is 120 U/mL.
If she proves to have stage III ovarian cancer, what are the optimal treatment interventions?
Ovarian cancer causes more deaths than any other gynecologic malignancy. In American women, the lifetime risk of ovarian cancer is approximately 1.5%.1
Survival after typical treatment
Stage III ovarian cancer is typically treated with surgical cytoreduction of the tumor and intravenous therapy with taxane and latinum-based chemotherapy. Using this treatment approach, stage III ovarian cancer has been associated with a median survival of approximately 37 months in women with residual tumor larger than 1 cm after cytoreductive surgery and 49 months in women with residual tumor of less than 1 cm.2
Survival after combination treatment
Data published January 5, 2006, indicate that a combination of optimal cytoreductive surgery with both intravenous and intraperitoneal chemotherapy significantly improves the survival of women with stage III ovarian cancer.3 In this exceptionally well-designed and executed study, 415 ligible patients with stage III ovarian cancer who had undergone optimal cytoreductive surgery (defined as residual tumor nodules <1 cm in diameter) were randomized to receive 6 treatment cycles of either standard therapy with intravenous paclitaxel plus cisplatin or experimental therapy with intravenous paclitaxel plus intraperitoneal cisplatin plus paclitaxel for 6 treatment cycles. The median survival was 50 months in the standard therapy intravenous group compared to 66 months in the experimental intravenous plus intraperitoneal therapy group (P<.03). In the subgroup of women who underwent a “second look” operation at the end of their chemotherapy, 41% in the intravenous chemotherapy group and 57% in the combined intravenous plus intraperitoneal chemotherapy group had a complete pathological response.
Longest life expectancy. The Gynecologic Oncology Group (GOG) has never previously reported a treatment of stage III ovarian cancer that had this large a beneficial effect on life expectancy. The results of this study, plus 2 previous clinical trials,4,5 indicate that combined intravenous plus intraperitoneal chemotherapy will quickly become an important option for women with stage III ovarian cancer.
Side effects more serious
Unfortunately, the marked increase in life expectancy with combined intravenous plus intraperitoneal therapy was associated with significantly more serious side effects than conventional therapy. Women treated with combined intravenous plus intraperitoneal chemotherapy had significantly more serious complications with leukopenia, thrombocytopenia, abdominal pain, and toxic events involving the gastrointestinal, metabolic, and neurological systems. The combined intravenous plus intraperitoneal therapy was so toxic that only 42% of the women in this group were able to complete the 6 cycles of the assigned chemotherapy. In contrast, 83% of the women in the standard therapy group completed 6 cycles of chemotherapy.
It is hoped that ongoing trials with new agents, such as intraperitoneal carboplatin, may find a reduction in side effects associated with intraperitoneal cisplatin. In preliminary studies, intraperitoneal carboplatin has been associated with fewer side effects, such as less abdominal pain, than cisplatin.6
Preop detection of high risk to avert multiple operations
The new treatment protocol requires 2 critical steps: (1) optimal cytoreduction of the ovarian cancer, and (2) placement of an intraperitoneal catheter. To minimize the number of patients with stage III ovarian cancer who need multiple surgeries to achieve these 2 critical steps, as many patients as possible need to be identified preoperatively. Preoperative identification of women at high risk of stage III ovarian cancer will allow gynecologic oncologists with expertise in both cytoreduction of ovarian cancer and intraperitoneal chemotherapy to become involved as early as possible in the patient’s care.
Modalities that may help to identify preoperatively those patients with an adnexal mass most likely to have ovarian cancer might include measurement of CA-125 in menopausal women2 and preoperative ultrasound7 or CT imaging of the abdomen and pelvis. If a patient with stage III ovarian cancer is operated on in a facility that cannot reliably provide optimal cytoreduction nor an intraperitoneal catheter, then the patient may need to undergo a second operation in order to benefit from the new treatment protocol.
It is likely that surgical cytoreduction followed by intravenous plus intraperitoneal chemotherapy will become the standard of care for stage III ovarian cancer. To best translate these research findings into practice, ObGyns will need to identify as many patients as possible preoperatively who might have advanced ovarian cancer, so that they can undergo optimal tumor resection and placement of an intraperitoneal catheter in a single operation.
1. Hartge P, Whittemore AS, Itnyre J, McGowan L, Cramer D. Rates and risks of ovarian cancer in subgroups of white women in the United States. The Collaborative Ovarian Cancer Group. Obstet Gynecol. 1994;84:760-764.
2. Cannistra SA. Cancer of the ovary. N Engl J Med. 2004;351:2519-2529.
3. Armstrong DK, Bundy B, Wenzel L, et al, for the Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.
4. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-1955.
5. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-1007.
6. Fujiwara K, Sakuragi N, Suzuki S, et al. First line intraperitoneal carboplatin-based chemotherapy for 165 patients with epithelial ovarian carcinoma: results of long-term follow-up. Gynecol Oncol. 2003;90:637-643.
7. Kinkel K, Hricak H, Lu Y, Tsuda K, Filly RA. US characterization of ovarian masses: a meta-analysis. Radiology. 2000;217:803-811.