Receiving five or more cycles of neoadjuvant chemotherapy was associated with worse progression-free survival (PFS) and overall survival (OS) compared to receiving three or four cycles — despite maximal cytoreduction — according to a retrospective analysis of patients with newly-diagnosed ovarian cancer treated at Memorial Sloan Kettering Cancer Center (MSK).
Published in the International Journal of Gynecological Cancer, our study is one of the first to assess the potential interaction of neoadjuvant chemotherapy cycles and the degree of cytoreduction on survival outcomes. We found no significant differences in PFS or OS when comparing three versus four neoadjuvant cycles. However, receiving five cycles versus four was associated with worse PFS, even after adjusting for BRCA mutation status and complete gross resection rates (hazard ratio (HR) 2.20, 95% CI: 145–3.33, p < 0.001), and worse OS, even after adjusting for histology, response on imaging, and complete gross resection rates (HR 2.78, 95% CI: 1.37–5.63, p = 0.016). (1)
The decision to proceed with more than four neoadjuvant cycles and interval debulking surgery in select patients is complex, requiring careful consideration of clinical variables, imaging results, and the likelihood of disease recurrence on an individual patient basis. It is essential to provide careful counseling for all patients and integrate palliative care early for those with a poorer prognosis.
Neoadjuvant Chemotherapy for Ovarian Cancer
The use of neoadjuvant chemotherapy before interval debulking surgery for the treatment of ovarian cancer has increased since 2010, (2), (3) based on the hypothesis that chemotherapy may shrink cancer and render initially inoperable disease operable. Much research has focused on the optimal number of preoperative cycles. (4) Four large randomized studies comparing neoadjuvant chemotherapy followed by interval debulking surgery with primary debulking surgery examined the use of three to four cycles. (5), (6), (7), (8) However, in real-world practice, centers often treat patients with four cycles or more.
The decision to proceed with interval debulking surgery requires considering many factors, including the patient’s response to neoadjuvant chemotherapy, which is typically assessed via interval computed tomography (CT) imaging after two to three cycles, the ability to achieve complete cytoreduction, patient factors such as age and comorbidities, (9) and the individual surgeon’s philosophy.
Despite multiple retrospective studies suggesting that more cycles are associated with worse outcomes, (10), (11), (12), (13) many of these studies did not adjust for the degree of cytoreduction or other clinical variables. Other studies have emphasized the importance of optimal and complete cytoreduction on survival, (14), (15) and the degree of surgery may influence the effects of neoadjuvant chemotherapy.
We examined the prospectively maintained Ovarian Database at MSK to evaluate whether increasing the number of preoperative chemotherapy cycles influenced survival outcomes after adjusting for clinical variables and the degree of cytoreduction.
We identified 199 women who presented at MSK for newly diagnosed, pathologically verified ovarian, fallopian tube, or primary peritoneal epithelial cancer between July 2015 and December 2018. All patients received neoadjuvant chemotherapy and underwent interval debulking surgery.
Our research team extracted histology data from pathological records and categorized ovarian cancers as high-grade serous carcinoma or other. We defined stage at diagnosis according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. (16) We abstracted BRCA testing status and results from the medical record and used conditions present at diagnosis to calculate a Charlson comorbidity score, which measures 12 areas predictive of mortality. (17), (18)
We reviewed surgical and medical oncology notes to determine the indication for neoadjuvant chemotherapy and categorized them according to: (1) patient factors (Aletti Score (19) comorbidity, venous thromboembolism, clinical trial, or other; or (2) disease factors (stage IV unresectable, the extent of disease on imaging, on laparoscopy, or requiring thoracic surgery).
Chemotherapy regimens were categorized as follows: (1) weekly intravenous paclitaxel with carboplatin every three weeks; or (2) other, including intravenous paclitaxel and carboplatin every three weeks, intraperitoneal chemotherapy, and clinical trials. We noted the number of preoperative and postoperative chemotherapy cycles and reviewed charts in detail for patients receiving five or more neoadjuvant cycles. The reasons for receiving more cycles were classified as: (1) surgical reasons (disease too extensive for debulking); (2) medical reasons (functional status or delayed chemotherapy recovery); (3) venous thromboembolism; (4) patient preferences; or (5) logistics.
Finally, we reviewed radiologic reports from interval imaging obtained after two to three preoperative cycles and categorized them as: (1) response, defined as any amount of disease shrinkage on imaging; or (2) no response or disease progression, defined as no change, or growth on imaging.
Optimal debulking was defined as less than one cm of residual disease. Complete gross resection was defined as no visible residual disease at the completion of surgery.
For the total study population of 199 patients who received neoadjuvant chemotherapy and underwent interval debulking surgery, the median age was 66.5 years, with a range of 43 to 88 years. A large majority of patients (92 percent) had high-grade serous carcinoma. Most patients (67 percent) had stage IV disease at diagnosis, and 15 percent had a BRCA 1/2 mutation, but 15 percent of patients had not yet undergone genetic testing. The median Charlson comorbidity score was 8, with a range of 6 to 12, representing an intermediate perioperative risk. (20), (1)
A majority of patients, 72 percent, received weekly intravenous paclitaxel with carboplatin every three weeks. Twenty-eight percent of patients received other regimens, including intravenous paclitaxel and carboplatin every three weeks (n = 34), combination intravenous-intraperitoneal chemotherapy (n = 7), intravenous pegylated liposomal doxorubicin and carboplatin (n = 1), and weekly intravenous paclitaxel and carboplatin with nivolumab every three weeks on a clinical trial (n = 11). (1)
Most patients (70 percent) received neoadjuvant chemotherapy due to disease factors, and 91 percent had some response after two to three cycles. Patients who did not respond after two to three cycles received further imaging, and those with a response insufficient for proceeding with debulking surgery were not included in our study. (1)
Neoadjuvant Chemotherapy Cycles, Optimal Debulking, and Complete Gross Resection
The median number of neoadjuvant chemotherapy cycles was four, with a range of three to eight. Seventy-three patients (37 percent) received three cycles, 70 patients (35 percent) received four, and 56 patients (28 percent) received five or more. (1)
Overall, the median number of postoperative chemotherapy cycles was three, with a range of zero to six. Fifteen patients received no postoperative chemotherapy. As expected, the number of neoadjuvant and postoperative chemotherapy cycles were significantly and negatively correlated. The median number of postoperative cycles for patients who received three or four neoadjuvant cycles was three (range of two to six) and three (range of one to four), respectively. Patients who received five or more neoadjuvant cycles received fewer or no postoperative cycles but had no differences in other clinical factors, including age, stage, comorbidity score, neoadjuvant indication, chemotherapy regimen, and response on imaging after two or three preoperative cycles (p < 0.05). (1)
The rate of optimal debulking was 91 percent, and the rate of complete gross resection was 70 percent.
Complete gross resection rates were similar among patients receiving three, four, or five or more neoadjuvant cycles (68.5, 70.0, and 71.4 percent, respectively, p = 0.96). (1)
At a median follow-up of 15.7 months for progression-free survivors, there were 142 recurrences (71 percent) and two deaths without recurrence (1 percent). Median PFS was 12 months (95% CI: 10.1–13.9) overall, and 12.5 months (95% CI: 10.6–17.2), 14.6 months (95% CI: 11.2–18.3), and 8.2 months (95% CI: 6.9–11.3) for patients who received three, four, or five or more neoadjuvant chemotherapy cycles, respectively. (1)
Univariate PFS analysis revealed that receiving five or more neoadjuvant chemotherapy cycles was associated with significantly worse PFS compared to receiving three (HR 1.97, 95% CI: 1.32–2.96, p < 0.001) or four cycles (HR 2.04, 95% CI, 1.36–3.08, p < 0.001). There was no significant difference in PFS between patients receiving three versus four cycles. (1) The presence of BRCA 1/2 mutations, achieving optimal debulking or complete gross resection, and receiving postoperative chemotherapy were associated with improved PFS (p < 0.05).
Using a smoothed survival function (21) to assess the association between PFS and the number of neoadjuvant cycles as a continuous variable, we found a cut-off point at four cycles, suggesting that receiving five or more cycles was associated with worse PFS (p = 0.017). Therefore, we used four cycles as the comparator in multivariate models. We again found no significant differences in PFS between three and four cycles. Receiving five or more cycles was associated with worse PFS, even after adjusting for BRCA mutation status and complete gross resection (HR 2.2, 95% CI: 1.45–3.33, p < 0.001). (1)
For OS, 55 deaths were observed at a median follow-up of 21.2 months (range 1.6–45.4 months). Median OS was not reached overall and was 33.3 months (95% CI: 27 to not reached), not reached, and 28.9 months (95% CI: 19.7 to not reached) in patients who received three, four, or five or more cycles of neoadjuvant chemotherapy, respectively. (1)
Univariate analysis showed no significant differences in OS for patients receiving three or four neoadjuvant cycles. Receiving five or more cycles was significantly associated with worse OS compared to three cycles (HR 1.64, 95% CI: 0.89–3.0, p = 0.008) and four cycles (HR 2.88, 95% CI: 1.43–5.77, p = 0.008). Variables that were significantly associated with improved OS were the presence of high-grade serous carcinoma, presence of BRCA mutations, and achieving complete gross resection. No response on imaging after two or three cycles was significantly associated with worse OS (p < 0.05). (1)
Multivariate analysis revealed that receiving five or more cycles compared to four was significantly associated with worse OS, even after adjusting for high-grade serous carcinoma, response on imaging after two or three cycles, and achieving complete gross resection (HR 2.78, 95% CI: 1.37–5.63, p = 0.016). Notably, after adjusting for these factors, response on imaging after two or three cycles was no longer independently associated with OS. (1)
Rationale for Receiving Five or More Neoadjuvant Cycles
The most commonly cited reason for five or more neoadjuvant cycles was surgical (62 percent) due to disease that was too extensive for interval debulking surgery after two to three cycles, as evaluated by imaging, clinical evaluation, or both. Medical reasons (14 percent) for deferring surgery included patient performance status and delayed recovery from chemotherapy. Newly diagnosed venous thromboembolism resulted in surgical delay for 13 percent of patients. Patient preferences and initial refusal of surgery and scheduling logistics were cited in seven and four percent of delayed cases, respectively. (1)
In 35 patients who received five or more neoadjuvant cycles for surgical reasons, median PFS was 8.7 months (95% CI: 6.7–12.0), and OS was 33.0 months (95% CI: 19.7 to not estimable). For those who received five or more cycles for reasons other than surgical, median PFS was 7.8 months (95% CI: 4.4–12.3), and OS was 20.9 months (95% CI: 10.4 to not estimable). (1)
Improving Outcomes for Patients with Ovarian Cancer
Our findings on the optimal number of neoadjuvant chemotherapy cycles before interval debulking surgery deserve further exploration in more extensive studies investigating the association of specific stage and outcomes with imaging data since prognosis varies within different subtypes of stage III and IV disease.
At MSK, we are dedicated to helping our patients achieve their best potential outcomes. Our multidisciplinary team of medical oncologists and surgical oncologists collaborate to develop individualized treatment plans for each patient.
Our ovarian cancer surgery team is proficient in radical and interval debulking surgery. It is also the only team in the United States dedicated to removing metastatic ovarian cancer that has spread beyond the pelvis. More than 200 new ovarian cancer patients present for consultation at MSK annually. Studies have repeatedly found that patient survival is highest at institutions where surgeons perform a high number of operations.
Our surgical team uses minimally invasive surgical techniques, when appropriate, so that women may benefit from a faster recovery. We also perform fertility-sparing surgical procedures whenever possible for those who want to have children. MSK’s Cancer and Fertility Program addresses the growing need for comprehensive patient education about the impact of cancer diagnosis and treatments on fertility and family planning.
We do many ovarian cancer procedures at the Josie Robertson Surgery Center, our state-of-the-art facility in Manhattan for short-stay cancer treatment. Patients return home to complete their recovery either the same day or the next day. Specialists and treatments are also available in our regional outpatient locations.
We are currently conducting 24 clinical trials for patients with ovarian cancer, testing investigational drugs, immunotherapies, and combination approaches in various study phases.
The study was funded in part through the NIH/NCI Support Grant P30 CA008748. All study authors declare no competing interests.