TWO STUDIES recently reported in The New England Journal of Medicine indicate that minimally invasive radical hysterectomy is associated with poorer survival outcomes than open abdominal radical hysterectomy in women with early-stage cervical cancer. As reported by Pedro T. Ramirez, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, open surgery was associated with superior disease-free and overall survival in the phase III LACC trial.¹ In a cohort study, reported by Alexander Melamed, MD, MPH, of Massachusetts General Hospital and Harvard Medical School, open surgery was associated with superior overall survival.²

Pedro T. Ramirez, MD

Alexander Melamed, MD, MPH

Phase III LACC Trial

Study Details: In the phase III trial,1 631 women with stage IA1 (lymphovascular invasion), IA2, or IB1 cervical cancer and histologic subtypes of squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma from 33 centers worldwide were randomly assigned between June 2008 and June 2017 to undergo minimally invasive surgery (n = 319) or open surgery (n = 312). Among patients in the minimally invasive surgery group, 84.4% underwent laparoscopy and 15.6% underwent robot-assisted surgery. The median age of patients was 46.0 years, 91.9% had stage IB1 disease, and both groups were similar at baseline for histologic subtypes, rate of lymphovascular invasion, rate of parametrial and lymph node involvement, tumor size, tumor grade, and use of adjuvant therapy. The primary outcome measure was the rate of disease-free survival at 4.5 years; noninferiority was to be claimed if the lower boundary of the two-sided 95% confidence interval (CI) of the between-group difference (minimally invasive surgery minus open surgery) was greater than 7.2 percentage points.

Disease-Free and Overall Survival: At the time of analysis, 59.7% of patients had reached the 4.5-year time point (median follow-up = 2.5 years). The trial did not reach its final intended enrollment, due to a safety alert from the data and safety monitoring committee based on observation of higher rates of recurrence and death in the minimally invasive surgery group.

The rate of disease-free survival at 4.5 years was 86.0% with minimally invasive surgery vs 96.5% with open surgery, a difference of −10.6 percentage points (95% CI = −16.4 to −4.7); since the lower boundary of the confidence interval included the noninferiority margin of −7.2 percentage points, noninferiority was not declared (P = .87 for noninferiority). Overall, disease recurrence or death from cervical cancer occurred in 27 of 319 patients in the minimally invasive surgery group and 7 of 312 patients in the open surgery group.

On proportional hazards models testing for superiority, minimally invasive surgery was associated with significantly poorer disease-free survival vs open surgery on an unadjusted analysis (3-year rate = 91.2% vs 97.1%, hazard ratio [HR] = 3.74, P = .002). In an analysis adjusting for age, body mass index, disease stage, lymphovascular invasion, lymph node involvement, and Eastern Cooperative Oncology Group performance status, the hazard ratio was 4.39 (P < .001). Minimally invasive surgery was also associated with a lower rate of overall survival (3-year rate = 93.8% vs 99.0%, HR = 6.00, 95% CI = 1.77–20.30), an increased risk of death from cervical cancer (3-year rate = 4.4% vs 0.6%, HR = 6.56, 95% CI = 1.48–29.00), and an increased risk of locoregional recurrence (3-year rate of locoregional recurrence–free survival = 94.3% vs 98.3%, HR = 4.26, 95% CI = 1.44–12.60).

The investigators concluded: “In this trial, minimally invasive radical hysterectomy was associated with lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy among women with early-stage cervical cancer.”

Cohort Study Findings

Study Details: The cohort study involved National Cancer Database data on 2,461 women who underwent radical hysterectomy for stage IA2 or IB1 cervical cancer from 2010 to 2013 at Commission on Cancer–accredited U.S. hospitals.2 Of them, 1,225 (49.8%) underwent minimally invasive surgery. Those undergoing minimally invasive surgery were more likely to be white; privately insured; from ZIP codes with a higher socioeconomic status; to have smaller, lower-grade tumors; and to have received a diagnosis later in the study period than women undergoing open surgery.

Of the women undergoing minimally invasive surgery, 978 (79.8%) underwent robot-assisted laparoscopy. Conversion from minimally invasive surgery to open surgery occurred in 2.9% of cases, with these cases counted in the minimally invasive surgery group.

Overall Survival: The median follow-up was 45 months. In a propensity score–weighted analysis, risk of death within 4 years after diagnosis was 9.1% among women who underwent minimally invasive surgery and 5.3% among those who underwent open surgery (HR = 1.65, P = .002). A subgroup analysis showed hazard ratios indicating poorer overall survival with minimally invasive surgery for women undergoing laparoscopic surgery (HR = 1.50, 95% CI = 0.97–2.31) or robot-assisted surgery (HR = 1.61, 95% CI = 1.18–2.21), squamous cell (HR = 1.65, 95% CI = 1.17–2.33) or adenocarcinoma histology (HR = 2.22, 95% CI = 1.08–4.55), and tumor size < 2 cm (HR = 1.46, 95% CI = 0.70–3.02) or ≥ 2 cm (HR = 1.66, 95% CI = 1.19–2.30).

A separate survival analysis included all women in the Surveillance, Epidemiology, and End Results 18 registry who had locoregionally confined cervical carcinoma and had undergone radical hysterectomy and lymphadenectomy from 2000 to 2010. In the period from 2000 to 2006, prior to the adoption of minimally invasive radical hysterectomy, there was a nonsignificant trend toward an increase in 4-year overall survival rate, consisting of an annual percentage increase of 0.3% (95% CI = −0.1 to 0.6). The increasing use of minimally invasive surgery between 2006 and 2010 was associated with an annual decrease in 4-year survival rate of 0.8% (95% CI = 0.3–1.4) during this period, reflecting a significant change in survival trend (P = .01).

The investigators concluded: “In an epidemiologic study, minimally invasive radical hysterectomy was associated with shorter overall survival than open surgery among women with stage IA2 or IB1 cervical carcinoma.” ■

DISCLOSURE: The study reported by Dr. Ramirez and colleagues was funded by The University of Texas MD Anderson Cancer Center and Medtronic. The study reported by Dr. Melamed and colleagues was funded by the National Cancer Institute, National Institute of Child Health and Human Development, American Association of Obstetricians and Gynecologists Foundation, Foundation for Women’s Cancer, Jean Donovan Estate, and Phebe Novakovic Fund. For full disclosures of the authors for both studies, visit www.nejm.org.

REFERENCES

1. Ramirez PT, Frumovitz M, Pareja R, et al: Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med 379:1895-1904, 2018.

2. Melamed A, Margul DJ, Chen L, et al: Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med 379:1905-1914, 2018.