It is well established that the best predictor of overall and progression-free survival in patients with advanced ovarian cancer is complete surgical resection of macroscopic disease. However, optimal primary debulking surgery (PDS) can be a daunting prospect, as many patients with advanced ovarian cancer have extensive disease in the upper abdomen. In recent years, some gynecologic oncologists have raised concerns about the morbidity associated with complicated abdominal surgery and have started moving toward neoadjuvant chemotherapy (NACT) with interval debulking surgery. During the Education Session “Neoadjuvant Chemotherapy: Location, Location, Location,” to be held June 6, experts will discuss the pros and cons of these two approaches to treating patients with advanced ovarian cancer.
“This debate has been going on for years, and we may never get a perfect answer,” said session Chair Alexandra Leary, MD, PhD, of Gustave Roussy Cancer Center, Paris. “Upfront complete surgery is the best treatment for advanced ovarian cancer, but in some cases it is not feasible or is associated with unacceptable morbidity.”
Dr. Alexandra Leary
Cancer centers are divided in which treatment approach they usually take. Whereas Dr. Leary’s center treats the majority of patients with NACT, she estimates that other centers choose PDS in 90% of cases.
The session will revisit the debate and address aspects of patient health and tumor biology that may help guide clinicians in deciding how to sequence surgery and chemotherapy, Dr. Leary said.
Although a number of retrospective studies have reported on outcomes with PDS and NACT, there are now two randomized clinical trials directly comparing the two options. The first trial was published in 2010 and enrolled 632 patients with stage IIIC or IV ovarian cancer from 59 institutions in Europe. In this trial, NACT and PDS were associated with similar rates of overall and progression-free survival.1
A second trial, published in 2015, had similar results. NACT was noninferior to PDS in terms of overall survival among 550 patients with stage III or IV ovarian cancer in the United Kingdom and New Zealand. The study also found significantly lower rates of serious postoperative adverse events, such as hemorrhage, in the NACT group and a trend toward higher quality of life in this group at 6 and 12 months after starting treatment.2
“This study supports NACT as a standard of treatment that can be offered to patients as an alternative to primary surgery,” said Sean Kehoe, MA (Ox), MD, DCH, FRCOG, of the University of Birmingham, United Kingdom, who led the 2015 study.
During the session, Prof. Kehoe will discuss what the research can tell oncologists about the patients for whom NACT and PDS are suitable. The patient groups in both trials were older, with a median age between 62 and 66 years, so results cannot be generalized to the entire population of patients with ovarian cancer. In addition, the patient groups in the trials may have had more advanced disease than the average patient with ovarian cancer as the median overall survival was lower than expected in both the PDS group and the NACT group (22.6 and 24.1 months, respectively).
“Maybe I would go with NACT in those patients who are sicker and elderly” because they are similar to the participants in the clinical trials, Prof. Kehoe said.
Primary Debulking Surgery
However, during his presentation, Dennis S. Chi, MD, FACOG, FACS, of Memorial Sloan Kettering Cancer Center, will argue that, although some centers predominantly use PDS, there are some doctors who are too quick to use NACT for all patients with advanced ovarian cancer. “NACT should not be the knee-jerk reaction based on these two trials,” Dr. Chi said.
Dr. Dennis S. Chi Photo courtesy of Juliana Thomas Photography
All patients should be evaluated as candidates for PDS, and then of those, “maybe anywhere from 20% to 30% would be best treated with NACT,” Dr. Chi said. He agrees with Prof. Kehoe that patients for whom NACT may be the best choice tend to be the oldest and sickest, who cannot tolerate extensive surgery. For these patients, the two trials at least support that NACT may be noninferior to PDS. But for patients who are more likely to tolerate surgery, “why should I use the results of these trials to treat the 45 year-old mother of three who has stage III disease when I can get all the disease out with PDS?” Dr. Chi asked.
In order to maximize the benefit of PDS, doctors must be proficient in operating on the upper abdomen or call colleagues for assistance if they are not. “If one sees disease on the diaphragm or cancer on liver, one should not use it as absolute criteria to not operate,” Dr. Chi said. “If you can’t take out the disease there, then call someone who can. It’s about doing whatever you have to do safely and having no visible cancer left at the end of the operation.”
Part of the reason for the poor survival outcomes in the two trials could be that a high percentage of the patients had disease that was suboptimally debulked, Dr. Chi said. It is important to conduct a randomized study comparing NACT with PDS performed at experienced surgical centers, and German researchers are about to begin one such trial called the International TRUST (Trial of Radical Upfront Surgical Therapy vs. NACT/IDS) study. Dr. Chi is trying to obtain funding to start a TRUST study in the United States, and many centers in the United States have agreed to participate because “people are so passionate about this question and what questions this kind of study will answer,” he said.
Translational Research Opportunities
One of the concerns about NACT, and a reason that more research is needed, is that performing chemotherapy on a bulky tumor before surgery could increase the risk of selecting resistant clones, Dr. Leary said. Her presentation will focus on aspects of tumor biology, such as whether the histology is indicative of chemosensitivity, which could be considered when deciding between NACT and PDS.
“If complete primary debulking surgery is not possible for tumor-related or patient-related reasons, then the use of NACT should be viewed as a research opportunity to study in vivo predictors of sensitivity and mechanisms of acquired resistance to chemotherapy,” Dr. Leary said.
NACT could make it possible to evaluate possible molecular predictors of chemo-responsiveness. Recent studies have suggested that BRCA1/2 mutations and CCNE1 amplifications could be associated with sensitivity and resistance to platinum chemotherapeutic agents, respectively. In the next couple of years, it may be possible to use genetic markers to inform treatment sequence, Dr. Leary said.