The use of neoadjuvant chemotherapy for advanced ovarian cancer may not have the negative impact on survival feared by many gynecologic oncologists. In fact, according to a pair of studies that were to have been presented at the Society of Gynecologic Oncology (SGO) 2020 Annual Meeting on Women’s Cancer,1,2 accelerated adoption of neoadjuvant chemotherapy may even be associated with reduced postoperative morbidity and mortality. [Editor’s note: The SGO 2020 Annual Meeting was canceled due to the COVID-19 pandemic, but abstracts and SGO press releases were issued to allow reporting.]
Findings from a time-series analysis of more than 72,000 women treated for advanced epithelial ovarian cancer showed that the use of primary chemotherapy increased from 17.6% in 2004 to 45.1% in 2016. Over the same period, median survival improved by 2.1% per year.
Alexander Melamed, MD, MPH
“These data should help allay concerns that the use of neoadjuvant chemotherapy is leading to a decline in survival, although we cannot infer causality from this analysis,” said Alexander Melamed, MD, MPH, Assistant Professor of Obstetrics & Gynecology at NewYork-Presbyterian/Columbia University Medical Center. “While adoption of neoadjuvant chemotherapy accelerated over a 10-year period, we found no changes of trend in median survival outcomes. Survival rates were rising slowly before and they continued to rise through this period of rapid adoption.”
As Dr. Melamed explained, the effect of neoadjuvant chemotherapy uptake on survival in advanced ovarian cancer has been a subject of debate for nearly 2 decades. Proponents of the traditional approach—primary debulking surgery before initiation of chemotherapy—have argued that upfront treatment with primary neoadjuvant chemotherapy could negatively impact survival.
“The long-standing dogma in the field is that aggressive debulking surgery that leaves behind no visible cancer makes adjuvant chemotherapy more effective,” said Dr. Melamed. “The idea of giving three cycles of chemotherapy prior to surgery and then doing three more cycles conflicted with this point of view.”
In 2010, a randomized trial from Vergote et al showed that neoadjuvant chemotherapy followed by interval debulking surgery was noninferior to primary debulking surgery followed by chemotherapy for patients with bulky stage IIIC or IV ovarian carcinoma,3 but this trial was “greeted with a lot of skepticism in the United States,” said Dr. Melamed. Although three subsequent randomized trials have produced similar results, there is still incredulity in the field, he added.
National Cancer Database Analysis
For this study, Dr. Melamed and colleagues used the National Cancer Database to identify women who received treatment (chemotherapy, surgery, or both) for stage IIIC or IV epithelial ovarian cancer between 2004 and 2016. The researchers calculated the proportion of women diagnosed in each year who were treated with primary neoadjuvant chemotherapy. For those with mature survival data, median survival rates were calculated using the Kaplan-Meier method.
Researchers included a total of 72,171 women who were treated for advanced ovarian cancer during the study period. Between 2004 and 2006, 17.6% of women received neoadjuvant chemotherapy followed by interval debulking surgery, and there was no change in uptake during these years, said Dr. Melamed. Between 2006 and 2011, however, the frequency of neoadjuvant chemotherapy rose by 7.9% per year, and after 2011, uptake increased to 10.3% per year, Dr. Melamed reported. By 2016, nearly half of patients (45.1%) received primary neoadjuvant chemotherapy.
Despite the accelerated uptake of neoadjuvant chemotherapy, however, survival rates continued to rise, suggesting the noninferiority observed in the randomized trials is reflected in real-world data, said Dr. Melamed. During the same period, median survival improved steadily by 2.1% per year, increasing from 31.1 months in 2004 to 37.8 months in 2013.
Neoadjuvant Chemotherapy and Perioperative Mortality
To study the effects of neoadjuvant chemotherapy on short-term outcomes in advanced ovarian cancer, Dr. Melamed and colleagues used the National Cancer Database to analyze a separate cohort of patients who received upfront treatment for stage IIIC or IV epithelial ovarian cancer between 2004 and 2015. The researchers identified hospitals that increased use of neoadjuvant chemotherapy after the publication of Vergote et al3 and those who continued to use the approach restrictively. In “liberal use” hospitals the rate of neoadjuvant chemotherapy increased from 19.8% in the preadoption period (2004–2009) to 39.6% in the postadoption period (2010–2015), whereas in “restrictive use” hospitals the rate of neoadjuvant use remained unchanged (18.2% to 18.9%).
The researchers identified a total of 33,877 women treated in 492 hospitals. In the postadoption period, 48.9% of these women were treated in hospitals that used neoadjuvant chemotherapy liberally. Using this difference-in-differences design, they found that liberal use of neoadjuvant chemotherapy led to a larger decline in 90-day postoperative mortality between the pre- and postadoption periods vs restrictive use. In hospitals that used neoadjuvant chemotherapy liberally to treat advanced ovarian cancer, 90-day postoperative mortality fell from 7.1% to 3.9% in the postadoption period. In restrictive-use hospitals, on the other hand, 90-day postoperative death rates fell from 7.7% to 5.9% (P = .004).
“Although long-term survival improved equally in both groups, hospitals that adopted liberal use of neoadjuvant chemotherapy had significantly decreased rates of perioperative deaths compared with restrictive-use hospitals,” said Dr. Melamed. “These approaches may produce the same long-term outcomes, but the short-term outcomes with neoadjuvant chemotherapy look better based on this analysis.”
Despite these findings, Dr. Melamed acknowledged there may still be holdouts who continue to defend the traditional approach. Those who remain skeptical of neoadjuvant chemotherapy will have to wait for results from a fifth randomized trial4 to settle this debate once and for all, he said. Results of the TRUST trial are expected after 5 years of follow-up in 2024.
DISCLOSURE: Dr. Melamed reported no conflicts of interest.
1. Knisely AT, St. Clair CM, Hou JY, et al: Trends in median survival and upfront treatment among women with advanced ovarian cancer in the United States: 2004–2016. 2020 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Abstract 175. Presented March 29, 2020.
2. Melamed A, Rauh-Hain JA, Knisely AT, et al: The effect of liberal vs restrictive use of neoadjuvant chemotherapy for ovarian cancer on postoperative mortality and long-term survival: A quasi-experimental study. 2020 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Abstract 165. Presented March 30, 2020.
3. Vergote I, Tropé CG, Amant F, et al: Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363:943-953, 2010.
4. Reuss A, du Bois A, Harter P, et al: TRUST: Trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33/AGO-OVAR OP7). Int J Gynecol Cancer 29:1327-1331, 2019.
Alexandra Leary, MD, PhD
Alexandra Leary, MD, PhD, of the Gustave Roussy Institute of Oncology, Paris, underscored the controversy surrounding the use of neoadjuvant chemotherapy in advanced ovarian cancer, suggesting the discord may be “more cultural and emotional than scientific” to some...