Neoadjuvant chemotherapy may be optimal first-line treatment in advanced ovarian cancer
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Increased use of neoadjuvant chemotherapy appeared associated with improvements in short-term mortality without sacrificing long-term survival in ovarian cancer, according to a comparative effectiveness research study in JAMA Oncology.
The difference-in-differences analysis compared cancer programs with high use vs. low use of neoadjuvant chemotherapy (NACT), as researchers understood the “tremendous treatment selection bias in traditional analysis” of patients who receive this treatment vs. those who undergo upfront surgery.
“Gynecologic oncologists have traditionally believed in the superiority of primary surgery but have also known that this is a more morbid procedure,” Alexander Melamed, MD, MPH, assistant professor in the division of gynecologic oncology in the department of obstetrics and gynecology at New York-Presbyterian/Columbia University Medical Center, told Healio.
“For these reasons, they have selectively administered NACT to patients who are sicker and older and those with the highest burden of disease,” he continued. “Given that disease burden and health status are difficult to measure, patient-level comparisons between those patients selected to receive NACT or those selected to undergo primary surgery will always make primary surgery appear more advantageous than it really is. Unfortunately, the literature is full of studies that make this error.”
Following the publication in 2010 of the first randomized clinical trial that demonstrated the noninferiority of NACT vs. primary debulking surgery, Melamed and colleagues sought to determine whether the differential adoption of NACT by U.S. cancer centers for advanced-stage epithelial ovarian cancer was associated with differences in OS.
The analysis included 39,299 women diagnosed with stage IIIC and IV epithelial ovarian cancer between January 2004 and December 2015 who were followed through the end of 2018, with data analyzed between September 2020 and January 2021.
Of them, 19,562 women (mean age, 63.9 years; standard deviation, 12.6; 82.5% white) were treated in 332 cancer programs that increased use of NACT and 19,737 patients (mean age, 63.5 years; standard deviation, 12.6; 81.8% white) were treated at 332 programs that marginally increased the use of NACT during the time period.
Results showed, when compared with cancer programs with low use of NACT, programs with high use had similar median OS and larger declines in short-term mortality.
In the cohorts treated at facilities with increased use of NACT (from 21.7% between 2004 and 2009 to 42.2% between 2010 and 2015) vs. those that maintained lower NACT use (20.1% to 22.5%) after 2010, standardized median OS improved by similar magnitudes — from 31.6 months (interquartile range [IQR], 12.3-70.1) to 37.9 months (IQR, 17-84.9) with high use (6.3-month difference; 95% CI, 4.2-8.3) and from 31.4 months (IQR, 12.1-67.2) to 36.8 months (IQR, 15-80.3) with low use (5.4-month difference; 95% CI, 3.5-7.3). This equated to a difference-in-differences of 0.9 months (95% CI, 1.9 to 3.7).
Additionally, 1-year mortality declined more in programs with high (from 25.6% to 19.3%; risk difference, 5.2%; 95% CI, 6.4 to 4.1) vs. low (from 24.9% to 21.8%; risk difference, 3.2%, 95%CI, 4.3 to 2) use of NACT. This equated to a difference-in-differences of 2.1% (95% CI, 3.7 to 0.5).
The findings suggest NACT may be an appropriate first-line treatment strategy for many patients with advanced-stage ovarian cancer, Melamed and colleagues concluded. The results could also help narrow the divergence in practice and help clear some of what the researchers referred to as “considerable controversy” regarding the appropriate use of NACT.
“There is a long-standing dogma — still commonly believed — that removing as much cancer as possible before chemotherapy should improve survival in patients with ovarian cancer. The origins of this dogma reach back 50 years and are based on theory, mathematical modeling and a particular interpretation of the classic observation that patients who have little or no disease after upfront cytoreductive surgery live longer than those with more residual tumor,” Melamed told Healio.
According to the dogma, removal of bulky disease increases the effectiveness of chemotherapy by removing resistant clones and leaving behind better-profused tumor cells that would be more sensitive to systemic chemotherapy, Melamed said.
“The dogma predicts that NACT should be an inferior approach,” he continued. “This was so widely believed that when the first randomized controlled trial comparing the treatments showed that NACT was noninferior to primary surgery, a large portion of the U.S. gynecologic oncology community concluded that there was something wrong with the trial.
“On the other hand, there were those who looked at the data and said, ‘Well if I can give a less morbid treatment with similar long-term results, that’s something I should be doing more often,’” Melamed added. “As more randomized data have been reported, I think more and more folks are realizing that maybe the trials are not [wrong], maybe the dogma is.”
Melamed said another, still-unreported randomized trial comparing NACT to primary surgery is ongoing, but because it is taking place at highly specialized centers in the U.S. and Europe, he is skeptical of the findings, as they may not be applicable to the centers where most women in the U.S. receive their care.
“For example, the harms of upfront surgery can probably be mitigated at such centers due to exceptional surgical experience, postoperative care and expertise in managing complications,” he said. “Unfortunately, the reality is that most women in this country lack access to these kinds of centers and receive care in smaller community cancer programs that treat a modest number of cases of ovarian cancer.”
For more information:
Alexander Melamed, MDMPH, can be reached at Department of Obstetrics and Gynecology, Columbia University Vagelos College of Physicians and Surgeons, 161 Fort Washington Ave., Room 456, New York, NY 10032; email: am5195@cumc.columbia.edu.
Perspective
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Stephen C. Rubin, MD
For many years, standard management of advanced epithelial ovarian cancer has utilized a multimodal approach of primary surgical cytoreduction followed by combination chemotherapy. In the last decade, this approach has been challenged by the publication of four randomized trials evaluating the use of several cycles of NACT by surgical debulking and additional chemotherapy. For the most part, these trials have shown the neoadjuvant approach provides equivalent oncologic outcome and improved short-term morbidity and mortality compared with primary cytoreductive surgery.
In the current study, the authors have taken a big-data approach to evaluating this issue. Using the National Cancer Database, they evaluated about 39,000 women with advanced epithelial ovarian cancer treated in 664 different cancer programs, assessing outcome measures in programs with low use of NACT compared with those with high use. Both categories of programs showed a similar steady increase in median OS of women diagnosed during the years of the study, from 2004 to 2015. However, those programs with high uptake of NACT showed greater improvements in short-term mortality.
This large database study, taken together with the randomized trial data, provides reassurance that the NACT approach is appropriate for many women with advanced epithelial ovarian cancer.
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