Simple Hysterectomy Deemed Noninferior to Radical Version in Low-Risk, Early-Stage Cervical Cancer

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Patients with low-risk, early-stage cervical cancer had non-inferior outcomes after simple hysterectomy compared with radical with low-risk, early-stage cervical cancer, according to findings the Canadian Cancer Trials Group CX.5/SHAPE trial (NCT01658930) presented ahead of the 2023 ASCO Annual Meeting.¹

At a median follow-up of 4.5 years, the 3-year pelvic recurrence rate in the intent-to-treat population, was 2.52% in patients who underwent a simple hysterectomy compared with 2.17% of patients who had a radical hysterectomy. This equates to a 0.35% difference with an upper 95% confidence limit of 2.32%, which was below the prespecified limit of 4%.

“Therefore, we can claim noninferiority of simple hysterectomy to radical hysterectomy,” lead study author Marie Plante, MD, professor in the Department of Obstetrics, Gynecology, and Reproduction at the Université Laval in Quebec City, Canada, said in a press briefing ahead of the conference. “Following adequate and rigorous preoperative investigation […] simple hysterectomy can now be considered the new standard of care for patients with low-risk, early-stage cervical cancer, leading to surgical de-escalation.”

The overall cervical cancer incidence has decreased over the past 20 years, Plante said, though there are a higher proportion of women who present with the disease at both a younger age and with low-risk, early-stage disease.

“Although radical surgery is highly effective for the treatment of that low-risk population, women are at risk of suffering ‘survivorship’ issues particularly in relation to long-term surgical side effects including compromised bladder, bowel, and sexual function,” Plante said, adding that the radical approach also includes removal of the parametrium and upper vagina. “So radical surgery requires more extensive surgical skills and training, and is associated with more surgical complications.”

Retrospective data have suggested that less radical surgery, which would be considered a surgical de-escalation approach, may not only be a safer option for patients, but would be associated with decreased morbidity.²

The SHAPE trial, which is a Gynecologic Cancer Intergroup study led by the Canadian Cancer Trials Group, was comprised of 700 patients with low-risk cervical cancer, which was defined by squamous cell, adenocarcinoma, or adenosquamous carcinoma; stage IA2 or IB1 disease; less than 10 mm stromal invasion on loop electrosurgical excision/cone; less than 50% stromal invasion on MRI; a maximum dimension of 20 mm; and disease that was either grade 1 to 3 or not assessable.

These patients were randomized 1:1 to undergo radical hysterectomy or simple hysterectomy. Regardless of which arm they were enrolled onto, surgery included pelvic lymph node dissection with an optional sentinel lymph node (SN) mapping. Should SN mapping be conducted, it is preferred to use the laparoscopic approach, though the mode is optional.

Patients were stratified by Cooperative Group, SN mapping (yes vs no), stage (IA2 vs IB1), histological type (squamous vs adenocarcinoma/adenosquamous), and grade (1-2 vs 3 vs not assessable).

The primary end point is 3-year pelvic recurrence rate.

Additional findings showed that simple hysterectomy was noninferior to radical hysterectomy across prespecified patient subgroups, including IB1 histologic stage (2.76% with simple hysterectomy vs 2.33% with radical hysterectomy; difference, 0.43; 90% CI, -1.71 to 2.57), squamous histology (2.05% vs 2.05%; difference, 0.00; 90% CI, -1.71 to 2.57), adenocarcinoma/adenosquamous histology (3.26% vs 2.35%; difference, 0.91; 90% CI, -2.52 to 4.34), tumor grade 1 to 2 (2.63% vs 1.05%; difference, 1.58; 90% -0.68 to 3.84), tumor grade not assessable (3.53% vs 5.79%; difference, -2.26; 90% CI, -7.54 to 3.02), predefined patients (2.76% vs 2.34%; difference, 0.42; 90% CI, -1.72 to 2.56), and per-protocol patients whose excluded eligibility was not met following surgery (2.89% vs 2.45%; difference, 0.44; 90% CI, -1.80 to 2.68).

Furthermore, data showed that pelvic recurrences were 3.1% in those who underwent a simple hysterectomy (n = 350) compared with 2.9% (n = 350) for patients who had a radical hysterectomy. Extra pelvic recurrences occurred in 2.0% and 0.6% of patients, respectively, and the pelvic and extra pelvic recurrence rate was 0.9% and 0.6%, respectively. Extra pelvic-only recurrence rates were 1.1% in the simple hysterectomy group and 0% in the radical approach group; pelvic or extra pelvic recurrence rates were 4.3% and 2.9%, respectively.

Seven deaths occurred in both arms (2.0% in each), and 4 deaths (1.1%) were due to cervical cancer with simple hysterectomy vs 1 (0.3%) with radical hysterectomy. Deaths from another primary malignancy and other medical conditions were 0.3% (n = 1) and 0.6% (n = 2), respectively, in the simple hysterectomy group and 0.9% (n = 3) and 0.9% (n = 3) in the radical hysterectomy group.

Regarding postsurgical complications, intraoperative injuries occurred in 7.1% (n = 24) of patients who underwent simple hysterectomy and in 6.4% (n = 22) of those who had radical hysterectomy (P = .77). These occurred in the bladder (n = 3 vs n = 5, respectively; P = .14), ureter (3 vs 5; P = .73), nerve (5 vs 2; P = .28), bowel (n = 2 each; P = 1.00), vein (4 vs 1; P = .21), and other (7 vs 3; P = .22).

Surgical-related adverse events (AEs) occurred within 4 weeks of surgery, known as acute AEs, in 42.6% of patients on the simple hysterectomy arm vs 50.6% of those on the radical hysterectomy arm (P = .04). Late AEs, which were 4 weeks after surgery, occurred in 53.6% and 60.5% of patients, respectively (P = .08).

There were fewer acute urinary incontinence AEs in the simple hysterectomy arm (2.4%) than in the radical hysterectomy arm (5.5%; P = .048); the rate of late urinary incontinence AEs were 4.7% and 11.0%, respectively (P = .003). Acute urinary retention AEs were seen in 0.6% and 11.0% of patients, respectively (P <.0001) and late ones were in 0.6% on the simple hysterectomy arm and in 9.9% of patients on the radical hysterectomy arm (P <.0001). These data were statistically significant, Plante noted.

Quality of life and sexual health were also assessed via sexual-vaginal functioning (EORTC QLQ-CX24) and sexual pain (FSFI Pain Scale). Sexual-vaginal functioning was improved with simple hysterectomy at 3, 6, and 12 months (all P <.0001). Findings were similar regarding sexual pain with simple hysterectomy at 3 months (P = .003), 6 months (P = .02), and 12 months (P = .002).

Plante added that both approaches were further assessed via sexual health scores and favored the simple hysterectomy group, including the EORTC QLQ-C30 pain scale (effect estimate, -4.53; P = .02), EORTC QLQ-CX4 symptom experiences (effect estimate, -2.12; P = .02), EORTC QLQ-CX4 body image (effect estimate, -5.22; P = .02), EORTC QLQ-CX4 sexual worry (effect estimate, -6.67; P = .04), EORTC QLQ-CX4 sexual activities (effect estimate -7.59; P = .003), EORTC QLQ-CX4 sexual enjoyment (effect estimate, -7.67; P = .049), FSFI Desire (effect estimate, 0.37; P = .002), FSFI Arousal (effect estimate 0.38; P = .003), FSFI Lubrication (effect estimate, 0.36; P = .008), FSFI Total Score (effect estimate 1.82; P = .006), and FSDS Total Score (effect estimate, -2.47; P = .02).

During the press briefing, Kathleen N. Moore, MD, MS, associate director of clinical research at Stephenson Cancer Center, director of the Oklahoma TSET Phase I Program, and professor in the Section of Gynecologic Oncology at the University of Oklahoma College of Medicine, commented on the global implications of the SHAPE findings following Plante’s presentation of data.

“The SHAPE trial shows that amongst those carefully selected tumors, radical hysterectomy can be converted to a simple hysterectomy, including minimally invasively. You still have to do nodes—that’s an important thing to remember,” Moore emphasized. “But you can do this without loss of oncologic control and importantly with reduction in surgical complications, postoperative morbidities—specifically, urologic morbidity. The moment this is presented, this will be the new standard of care. It represents a huge step forward in the care of women with early-stage cervical cancer. Honestly, the de-escalation may allow these women in low- and middle-income countries […] better access to curative surgical interventions.”

_REFERENCES:

_{1. Plante M, Kwon J, Ferguson S, et al. An international randomized phase III trial comparing radical hysterectomy and pelvic node dissection vs simple hysterectomy and pelvic node dissection in patients with low-risk early-stage cervical cancer. J Clin Oncol. 2023;41(suppl; abstr LBA5511).}

_{2. Schmeler K, Frumovitz M, Ramirez PT. Conservative management of early stage cervical cancer: is there a role for less radical surgery? Gynecol Oncol. 2011;120(3):321-325. doi: 10.1016/j.ygyno.2010.12.352}