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Primary chemotherapy noninferior to surgery in advanced ovarian cancer
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Primary chemotherapy demonstrated non-inferior survival outcomes compared with primary surgery in patients with advanced ovarian cancer, according to the results of a randomized phase 3 trial.
Further, the receipt of chemotherapy prior to surgery resulted in fewer adverse events and improved quality of life, results showed.
Surgery followed by platinum chemotherapy is the current international standard of care for women with stage III or IV ovarian cancer, according to study background. However, previous observational studies demonstrated a link between extended survival rates and a lower postoperative tumor residuum, and, thus, researchers sought to evaluate the effects of primary chemotherapy prior to surgery.
Sean Kehoe, MD, Lawson Tait professor of gynecological cancer at the University of Birmingham, and colleagues of the CHORUS trial evaluated data from 550 women with suspected stage III or IV ovarian cancer. Treatment occurred at 87 hospitals in the U.K. and New Zealand.
Researchers randomly assigned patients to undergo primary surgery followed by six cycles of chemotherapy (n = 276) or three cycles of primary chemotherapy followed by surgery and three additional cycles of completion chemotherapy (n = 274). Chemotherapy cycles consisted of carboplatin area under the curve (AUC) 5 or AUC 6 plus 175 mg/m2 paclitaxel, an alternative carboplatin combination or carboplatin monotherapy.
Researchers stratified patients by randomization center, radiological tumor size, clinical stage and chemotherapy regimen.
OS served as the primary endpoint. PFS and quality of life served as secondary endpoints.
Researchers observed 231 deaths in the primary surgery cohort and 220 deaths in the primary chemotherapy cohort at data cutoff. Eighty-eight percent of patients (n = 399) died due to ovarian cancer, 1% (n = 4) died due to treatment and 11% (n = 48) died due to other causes.
Patients in the primary surgery cohort and primary chemotherapy cohort demonstrated similar median OS (22.6 months vs. 24.1 months) and a similar 3-year survival rate (32% vs. 34%).
The HR for death was 0.87 favoring primary chemotherapy (upper bound of the one-sided 90% CI 0.98 [95% CI, 0.72-1.05]).
Patients in the primary chemotherapy cohort demonstrated a median PFS of 12 months, whereas the primary surgery cohort demonstrated a median PFS of 10.7 months (HR = 0.91; 95% CI, 0.76-1.09).
In the per-protocol analysis — which included 251 women from the primary surgery cohort and 253 women from the primary chemotherapy cohort — 209 deaths occurred in the primary surgery cohort and 203 deaths occurred in the primary chemotherapy cohort. Women in the primary chemotherapy cohort demonstrated a median OS of 25.8 months, whereas women in the primary surgery cohort demonstrated a median OS of 23.7 months (HR = 0.89 favoring chemotherapy; 95% CI, 0.73-1.08).
Analysis of global quality-of-life scores adjusted for baseline scores indicated the primary chemotherapy group demonstrated a trend toward higher mean scores at 6 months (mean difference, –7.6 months; 95% CI, –13.3 to –1.9) and 12 months (mean difference, –5.7; 95% CI, –13.6 to 2.3).
More women in the primary surgery group experienced grade 3 or grade 4 adverse events (24% vs. 14%, P = .0007) and death within 28 days of surgery (6% vs. < 1%; P = .001) than women in the primary chemotherapy cohort. Hemorrhage was the most commonly reported adverse event in both groups (primary surgery, 3% vs. primary chemotherapy, 6%).
Forty-nine percent of the primary surgery cohort and 40% of the primary chemotherapy cohort experienced a chemotherapy-related toxic event, the most common of which was uncomplicated neutropenia (20% vs. 16%). One death from neutropenic sepsis occurred in the primary chemotherapy group.
“The trial showed that shrinking the tumor before surgery reduced side effects and hospital stay — meaning improved quality of life, without compromising survival, which is better for patients,” Kehoe said in a press release. “We are so thankful to the women who took part in the trial and their families … Because of their generosity we can improve the lives of others.”
Limitations of the CHORUS trial should be considered before the international standard of care is changed, Sokbom Kang, MD, PhD, of the National Cancer Center in Goyang, South Korea, wrote in an accompanying editorial.
“Unfortunately, the CHORUS trial has a similar weakness to the EORTC-NCIC trial [Vergote I, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa0908806.] — the low quality of surgical care,” Kang wrote. “For example, in the primary surgery group in CHORUS, 27% of patients did not receive bilateral oophorectomy and 24% of patients did not receive a hysterectomy. Additionally, more than 80% of patients did not receive upper abdominal surgeries. As a result, the median time for surgery was only 120 minutes and optimum cytoreduction was achieved only in 41% of the primary surgery group.”
However, further research related to the efficacy of primary surgery remains necessary, Kang concluded.
“Future research by advocates of radical surgery should focus on proving that primary surgery is more effective than primary chemotherapy with high quality delayed surgery,” Kang wrote. “Hasty conclusions should not be made before we have enough evidence.” – by Cameron Kelsall
Disclosure: Kehoe reports no relevant financial disclosures. Other researchers report employment roles with the Medical Research Council. Kang reports no relevant financial disclosures.
Perspective
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Joshua P. Kesterson, MD
Neoadjuvant chemotherapy is equal to primary surgery for the treatment of advanced stage ovarian cancer. Or is it? Kehoe and colleagues — in their paper detailing the CHORUS trial, an open label, randomized phase 3 trial comparing primary chemotherapy vs. primary surgery for advanced stage ovarian cancer — determined that primary chemotherapy is not inferior to primary surgery. PFS and OS were similar between the two groups. These results are the product of a prospective, randomized controlled trial, the gold standard in clinical research. The authors conclude that, “In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer.” Based on the design of this study, it possesses internal validity. However, one needs to look closer at this study population to determine if the study has external validity, whereby results can be and should be applied to all women with advanced ovarian cancer. The study population consists of 550 women, a majority with stage III epithelial ovarian cancer, randomized to either primary surgery or primary chemotherapy. Those in the primary surgery group were left with greater than 1 cm residual disease 59% of the time after primary surgery. During primary surgery, a bilateral salpingo-oophorectomy was not performed 24% of the time. An omentectomy was not performed in 14% of cases and only an omental biopsy was performed in 12% of cases. So if one were to restate the conclusions by defining the study population, it might read: In a population of women with advanced ovarian cancer, a majority of whom were suboptimally debulked and a significant proportion of whom did not receive complete surgical staging, survival with primary chemotherapy is not inferior to primary surgery. Do the conclusions sound as definitive? Worthy of justifying an alteration in the current standard of care for women with ovarian cancer? I would argue not. Further confounding the conclusions is the favorable survival benefit conferred by optimal cytoreduction (in the supplementary appendix). This study, secondary to its limitations, does not establish chemotherapy as the equal of quality, aggressive primary debulking surgery for advanced epithelial ovarian cancer.
At the heart of the matter is the combination of, and sequencing of, surgery and chemotherapy in the treatment of ovarian cancer, and the ability of each individually and synergistically to impact ovarian cancer’s inherent biologic aggressiveness. Horowitz and colleagues in their post hoc analysis of GOG 182, a study of patients with advanced stage epithelial ovarian cancer who underwent primary cytoreduction before randomization to platinum-based chemotherapy, evaluated the contribution of disease burden, complexity of surgery and residual disease on outcomes (Horowitz NS, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.56.3106.). Interestingly, initial disease burden remained a significant prognostic indicator despite optimal cytoreduction. Future research regarding the optimal sequencing of aggressive cytoreductive surgery and chemotherapy in a prospective study is warranted, as well as non-invasive or minimally-invasive means to predict which patients are likely to undergo and benefit from a complete tumor resection.
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