Two studies in JAMA suggest open surgery may be safer

Minimally invasive surgery for gynecologic cancer has been embraced over the past two decades and touted for its efficacy, fewer complications, and reduced recovery time; however, two studies in JAMA Oncology suggest that careful patient selection and surgical skill need to be taken into account when deciding to use this approach.

In a systematic review and meta-analysis of observational studies, Roni Nitecki, MD, from the Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, and colleagues found that patients undergoing MIS for early-stage cervical cancer had a 56% higher hazard of death over open surgery (HR, 1.56; 95% CI, 1.16-2.11; P = .004).

Koji Matsuo, MD, PhD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, and colleagues reported their observational study of women with early-stage ovarian cancer undergoing MIS and found an increased risk of capsule rupture, which was associated with increased mortality. They noted that guidelines from the National Comprehensive Cancer Network (NCCN) suggest that MIS should be limited to “select patients and experienced surgeons.”

These two studies, Amer Karam, MD, and Oliver Dorigo, MD, PhD, both from the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University, California, noted in an accompanying editorial, underscore the results of a recent randomized controlled study that raised concerns about MIS in gynecologic cancers.

“The Laparoscopic Approach to Cervical Cancer (LACC) trial, which compared minimally invasive versus open radical hysterectomy in early-stage cervical cancer, reported an almost 4-fold increased recurrence risk and a 6.6-times higher likelihood of death associated with MIS,” Karam and Dorigo wrote. “The results of the LACC trial remain controversial but were followed by a global decrease in the use of MIS for treatment of early-stage cervical cancer.

The editorialists noted that the studies from Matsuo, et al, and Nitecki, et al, are important additions “to the growing body of literature that suggest a worse outcome for patients with gynecologic cancers who are treated with MIS.”

Nitecki and colleagues set out to assess the risk of cancer recurrence and all-cause mortality associated with MIS (laparoscopic/robot assisted) compared with open radical hysterectomy in early stage cervical cancer (International Federation of Gynecology and Obstetrics 2009 stage IA1-IIA). They culled data from observational studies performed in an academic setting that were optimized to control for confounding. Their data sources included Ovid MEDLINE, Ovid Embase, PubMed, Scopus, and Web of Science.

Of 49 studies, they included 15 in their meta-analysis. There were 9,499 women who underwent radical hysterectomy with 4,684 (49%) receiving MIS. Just over half (2,675) of those in the MIS group underwent robot-assisted laparoscopy. In total, there were 530 cancer recurrences and 451 deaths.

“The pooled hazard of recurrence or death was 71% higher among patients who underwent minimally invasive radical hysterectomy compared with those who underwent open surgery (hazard ratio [HR], 1.71; 95%CI, 1.36-2.15; P < .001), and the hazard of death was 56%higher (HR, 1.56; 95%CI, 1.16-2.11; P = .004),” Nitecki and colleagues reported.

In drilling down to see if there was a difference between MIS with robot assist, they found there was no significant difference in the risk of recurrence or death, “(2.0% increase in the HR for each 10-percentage point increase in prevalence of robot assisted surgery [95% CI,−3.4% to 7.7%]) or risk of all-cause mortality (3.7% increase in the HR for each 10-percentage point increase in prevalence of robot assisted surgery [95% CI,−4.5% to 12.6%]).”

While the study authors noted that these results are consistent with the LACC trial, “the magnitude of associations estimated in the present study is considerably smaller than the effects reported by the LACC trial.” This, they noted, is likely because of the “likelihood of residual confounding in observational studies leading to an underestimation of the risk of recurrence and death in minimally invasive surgery, as well as bias in the LACC trial findings as a result of early stoppage leading to an over-estimation of these harms.”

Nonetheless, Karam and Dorigo noted that the results of Nitecki et al’s review are likely more on par with real-world outcomes. Still, the editorialists wrote that it is difficult to pinpoint why there are differences in outcome between MIS and radical hysterectomy for cervical cancer.

“Standard pathological characteristics and surgical aspects specific to MIS, including carbon dioxide insufflation or manipulation of the cervix during the procedure, have not been verified as risk factors for poorer outcomes,” the editorialists wrote. “The particular expertise of the surgeon has been theorized as a risk factor for poor outcomes given that minimally invasive radical hysterectomies are especially technically challenging procedures that require appropriate training and experience.”

The latter observation again underscores the NCCN guidelines, which Matsuo and colleagues cited in their study of women with stage 1 epithelial ovarian cancer. Their data were culled from the National Cancer Database from 2010 to 2015.

“Among 8,850 women (mean [SD] age, 55.6 [13.7] years) with stage I ovarian cancer, 2,600 women (29.4%) underwent MIS,” the study authors wrote. “Use of MIS increased from 19.8% (263 of 1,330) in 2010 to 34.9% (554 of 1589) in 2015 (1.8-fold increase; P < .001).”

Of these, capsule rupture was seen in 22.5% (1,994 women). They noted that there was an increase in occurrence over time, from 20.2% (269 of 1,330) in 2010 to 23.9% (379 of 1,589) in 2015 (18.3% relative increase; Cochran-Armitage trend test P = .02).

Moreover, they found that there was an independent association between MIS and capsule rupture (adjusted relative risk, 1.17; 95% CI, 1.06- 1.29). This was also seen with larger tumor size.

“Women with ruptured tumors were more likely than women with nonruptured tumors to receive chemotherapy(unilateral tumors: 1,252 of 1,869[67.0%] versus 2,500 of 6,484 [38.6%]; and bilateral tumors: 100 of 125 [80.0%] versus 219 of 372 [58.9%]; P < .001),” they wrote.

They noted that the median follow-up was 39.4 months with a 4-year overall survival rate decreasing by 5.0% from 2010 (91.0%) to 2015 (86.0%).

“Women with ruptured tumors had lower overall survival compared with those with nonruptured tumors in univariable analysis: 4-year rates, 86.8% for open surgery and ruptured tumors, 88.9% for MIS and ruptured tumors,90.5%for open surgery and nonruptured tumors, and 91.5% for MIS and nonruptured tumors(log-rank test, P = .001),” Matsuo and colleagues wrote.

MIS with capsule rupture was independently associated with all-cause mortality.

Capsule rupture is associated with decreased overall survival in ovarian cancer, the editorialists pointed out, and noted that the reasons for the increase in rupture reported by Matsuo and colleagues is not clear and should be subject to further investigation.

Karam and Dorigo noted that, in their study, Matsuo and colleagues found that “a concerning high percentage of patients (23.3%) did not undergo a lymphadenectomy as a surrogate indicator for staging; hence, they were not treated according to the standard of care for ovarian cancer.” However, that lack of staging, the editorialists pointed out, is not clear.

Despite the many benefits of MIS in gynecologic cancers, the editorialists noted that the “short-term advantages of MIS for gynecologic cancers should be weighed against the risks of potentially worse long-term outcomes.”

  1. Two studies reported in JAMA Oncology suggest that women undergoing MIS for early-stage cervical cancer had a 56% higher hazard of death over open surgery, and women with early-stage ovarian cancer undergoing MIS had an increased risk of capsule rupture, which was associated with increased mortality.

  2. Be aware that both studies are meta-analyses of observational studies but do underscore the results of the randomized Laparoscopic Approach to Cervical Cancer (LACC) trial that reported an almost 4-fold increased recurrence risk and a 6.6-times higher likelihood of death associated with MIS.

Candace Hoffmann, Managing Editor, BreakingMED

Nitecki et al’s study was supported by a National Cancer Institute Cancer Center Support Grant and a National Institutes of Health K grant.

Nitecki disclosed no other relevant relationships.

Matsuo reported receiving an honorarium from Chugai, textbook editorial expense from Springer, and investigator meeting attendance expense from VBL Therapeutics outside the submitted work.

Karam reported receiving personal fees from Clovis Oncology, AstraZeneca, GSK, and UpToDate outside the submitted work.

Dorigo reported receiving personal fees for advisory boards from Nektar, GSK/Tesaro, Myriad, Merck, Clovis, Personalized Adoptive Cell Therapy (PACT) Pharma, Geneos and Genentech; receiving support for lectures from GSK/Tesaro and AstraZeneca; salary support for clinical trial activities from Genentech, AbbVie, Clovis, IMV, Millennium and Pharmamar; travel support from IMV outside the submitted work; and salary for medical legal expert witness testimony.

Cat ID: 120

Topic ID: 78,120,730,120,692,191,693,192