Uncertainties in timing
James Fleck & Gustavo De Agostin: Anticancerweb 08(04), 2019
Global data published in 2018 by the International Agency for Research on Cancer (IARC) indicate that ovarian cancer ranks third in incidence (ASR = 6.6) and second in mortality (ASR = 3.9) among gynecological malignancies. Data relevance is underestimated by high incidence and mortality of cervical cancer in developing and underdeveloped countries. In USA, ovarian cancer is the leading cause of death among gynecological malignancies (14,000/year). The high mortality rate is due to inefficiency in screening. A low predictive value of positive test for CA-125 + pelvic US leads to unnecessary invasive diagnostic interventions. Only 25% of cases are diagnosed in the early stages. Regardless of the stage, surgery continues to play a central role in the treatment of ovarian carcinoma.
In the 20th century, primary cytoreductive surgery was considered the standard treatment for advanced ovarian carcinoma. Larger tumors have proportionally less blood vessels and a greater expression of hypoxia and necrosis, leading to a lower proliferative compartment. Smaller tumors, with a central blood perfusion have a higher proliferative index, favoring kinetics of cytotoxic chemotherapy. In 1995, a study conducted by the European Organization for Research and Treatment of Cancer (EORTC) showed a survival benefit with interval cytoreductive surgery. Patients with advanced ovarian carcinoma were treated with three cycles of chemotherapy after primary cytoreductive surgery failure in achieving optimal resection (meaning residual disease less than 1cm). Later, in 2004, the Gynecologic Oncology Group (GOG) presented a trial that showed no difference in overall survival and progression-free survival among patients who underwent a second cytoreductive surgery followed by chemotherapy or chemotherapy alone. However, the study required maximum surgical effort in the first approach. In addition, the chemotherapy treatment was different from that performed in the EORTC study. Despite the controversy, a second cytoreductive surgery was progressively abandoned. More recently, the use of neoadjuvant chemotherapy as an alternative to primary cytoreductive surgery has been evaluated. In 2010, a prospective randomized trial conducted by EORTC and the National Cancer Institute of Canada (NCIC) was published in the New England Journal of Medicine evaluating the best timing for cytoreductive surgery in patients with ovarian cancer stages IIIC and IV. The control arm consisted of primary cytoreductive surgery followed by six cycles of platinum-based chemotherapy. In the test arm patients received three cycles of platinum-based neoadjuvant chemotherapy followed by interval cytoreductive surgery after objective response plus three additional cycles of chemotherapy. The primary outcome was median overall survival (m-OS). The result showed non-inferiority with a m-OS = 29 months in the control arm and a m-OS = 30 months in the test arm (HR = 0.98 P = 0.01). Limiting factors were the participation of multiple surgical teams and the use of different regimens of chemotherapy. Two other subsequent smaller trials also showed no difference in overall survival and progression-free survival between patients undergoing primary cytoreductive surgery or neoadjuvant chemotherapy followed by interval surgery.
In 2019, there is still no consensus on the criteria for indication of neoadjuvant chemotherapy in patients with advanced ovarian carcinoma. While 82% of members of the Society of Gynecologic Oncologist believe there is no evidence for the administration of neoadjuvant chemotherapy, 70% of the members of the European Society of Gynecological Oncology (ESGO) admit that current evidence favours its recommendation. The expression of comorbidities, poor performance status or apparently unresectable disease at initial presentation may favor the indication of neoadjuvant chemotherapy. However, lack of unanimity is likely to persist for a long period of time, and the future development of more efficient screening tests associated with new intelligent drugs may make the question of advanced ovarian cancer surgical timing irrelevant.
References:
Van Der Burg, Maria EL et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer, New England Journal of Medicine, 332:10, 629-634, 1995
Rose, Peter G. et al. Secondary surgical cytoreduction for advanced ovarian carcinoma, New England Journal of Medicine, 351:24, 2489-2497, 2004
Vergote, Ignace et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer, New England Journal of Medicine, 363:10, 943-953, 2010
Photo by Jeanne Rouillard on Unsplash
The logic behind "Neoadjuvant therapy" is that a medication will be given before the surgery so that the tumor can reduce its size, resulting in a smaller mass, which logically will make it easier to resect. In a study, Melamed et al., 2018 reported that in regions of the United States (eg, New England) that rapidly increased the use of neoadjuvant chemotherapy for stage IIIC or IV epithelial ovarian cancer from 2011 to 2012, all-cause mortality through 3 years post-diagnosis dropped significantly in this patient population (hazard ratio [HR], 0.81). In contrast, regions where use of neoadjuvant chemotherapy remained unchanged (eg, the south Atlantic) saw no improvement in mortality (HR, 1.02). Therefore, according to the previous study, adoption of NACT for advanced epithelial ovarian cancer in New England and east south central regions led to a sizable reduction in mortality within three years after diagnosis. The study was observational, so more evidence is needed to evaluate the impact of this technique and the confirmation of its importance in the scenario of advanced ovarian cancer.
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