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based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.
The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.
The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).
At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).
The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.
Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.
Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.
The treatment groups were balanced with respect to baseline characteristics, they noted.
The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.
“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.
Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.
Even though the trial was initially powered on the assumption that there would be a 4.5 year follow-up for all patients, only 59.7% reached that length of follow-up. However, the trial still reached 84% power to detect noninferiority of the primary outcome (disease-free survival) with minimally invasive surgery, which was not found, they noted.
Similarly, in the population-based cohort study of 2,461 women who underwent radical hysterectomy for stage IA2 of IB1 cervical cancer between 2010 and 2013, 4-year mortality was 9.1% among 1,225 patients who underwent minimally invasive surgery vs. 5.3% among the 1,236 patients who underwent open surgery (HR, 1.65), Alexander Melamed, MD, of Harvard Medical School, Boston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1804923).
Of note, the 4-year relative survival rate following radical hysterectomy for cervical cancer remained stable prior to the widespread adoption of minimally invasive approaches; an interrupted time-series analysis involving women who underwent surgery during 2000-2010, which was also conducted as part of the study, showed a decline in 4-year survival of 0.8% per year after 2006, coinciding with increased use of minimally invasive surgery, the investigators said.
For the main patient-level analysis, the researchers used the National Cancer Database, and for the time-series analysis they used information from the Surveillance, Epidemiology, and End Results program database.
“Our findings suggest that minimally invasive surgery was associated with a higher risk of death than open surgery among women who underwent radical hysterectomy for early-stage cervical cancer. This association was apparent regardless of laparoscopic approach, tumor size, or histologic type,” they concluded.
The findings are unexpected, eye-opening, and should inform practice, according to Ritu Salani, MD, of the Ohio State University, Columbus.
“This is something we have to discuss with patients,” she said in an interview, noting that while these aren’t perfect studies, they “are the best information we have.
Data reported in September at a meeting of the International Gynecologic Cancer Society show that surgical complications and quality of life outcomes are similar with minimally invasive and open surgery, therefore the findings from these two new studies suggest a need to shift back toward open surgery for patients with cervical cancer, she said.
One “catch” is that survival in the open surgery group in the LACC trial was unusually high and recurrence rates unusually low, compared with what might be expected, and the explanation for this observation is unclear.
“There may be some missing pieces that they haven’t been able to explain, but it’s not clear that they would change the outcome,” she said.
Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients.
“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*
Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.*
SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.
*This article was updated 11/9/2018.
The findings by Ramirez et al. and Melamed et al. are striking in part because previous studies focused more on surgical than clinical outcomes.
They are powerful, but scientific scrutiny demands consideration of potential study-design or study-conduct issues. For example, all cancer recurrences in the LACC trial were clustered at 14 of 33 participating centers, raising questions about factors that contributed to recurrence at those centers .
Still, the findings are alarming and deal a blow to the use of minimally invasive surgical approaches in cervical cancer patients. They don’t necessarily “signal the death knell” of such approaches.
Select patients may still benefit from a less invasive approach; none of the patients with stage lA2 disease, and only one with stage lB1, grade 1 disease had a recurrence in the LACC trial.
Further, patients with tumors smaller than 2 cm also did not have worse outcomes with minimally invasive surgery in either study. However, until further details are known, surgeons should proceed cautiously and counsel patients regarding these study results.
Amanda N. Fader, MD , made her comments in an accompanying editorial (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395 ). Dr. Fader is with the Johns Hopkins University, Baltimore. She reported having no relevant disclosures.
The findings by Ramirez et al. and Melamed et al. are striking in part because previous studies focused more on surgical than clinical outcomes.
They are powerful, but scientific scrutiny demands consideration of potential study-design or study-conduct issues. For example, all cancer recurrences in the LACC trial were clustered at 14 of 33 participating centers, raising questions about factors that contributed to recurrence at those centers .
Still, the findings are alarming and deal a blow to the use of minimally invasive surgical approaches in cervical cancer patients. They don’t necessarily “signal the death knell” of such approaches.
Select patients may still benefit from a less invasive approach; none of the patients with stage lA2 disease, and only one with stage lB1, grade 1 disease had a recurrence in the LACC trial.
Further, patients with tumors smaller than 2 cm also did not have worse outcomes with minimally invasive surgery in either study. However, until further details are known, surgeons should proceed cautiously and counsel patients regarding these study results.
Amanda N. Fader, MD , made her comments in an accompanying editorial (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395 ). Dr. Fader is with the Johns Hopkins University, Baltimore. She reported having no relevant disclosures.
The findings by Ramirez et al. and Melamed et al. are striking in part because previous studies focused more on surgical than clinical outcomes.
They are powerful, but scientific scrutiny demands consideration of potential study-design or study-conduct issues. For example, all cancer recurrences in the LACC trial were clustered at 14 of 33 participating centers, raising questions about factors that contributed to recurrence at those centers .
Still, the findings are alarming and deal a blow to the use of minimally invasive surgical approaches in cervical cancer patients. They don’t necessarily “signal the death knell” of such approaches.
Select patients may still benefit from a less invasive approach; none of the patients with stage lA2 disease, and only one with stage lB1, grade 1 disease had a recurrence in the LACC trial.
Further, patients with tumors smaller than 2 cm also did not have worse outcomes with minimally invasive surgery in either study. However, until further details are known, surgeons should proceed cautiously and counsel patients regarding these study results.
Amanda N. Fader, MD , made her comments in an accompanying editorial (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395 ). Dr. Fader is with the Johns Hopkins University, Baltimore. She reported having no relevant disclosures.
based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.
The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.
The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).
At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).
The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.
Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.
Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.
The treatment groups were balanced with respect to baseline characteristics, they noted.
The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.
“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.
Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.
Even though the trial was initially powered on the assumption that there would be a 4.5 year follow-up for all patients, only 59.7% reached that length of follow-up. However, the trial still reached 84% power to detect noninferiority of the primary outcome (disease-free survival) with minimally invasive surgery, which was not found, they noted.
Similarly, in the population-based cohort study of 2,461 women who underwent radical hysterectomy for stage IA2 of IB1 cervical cancer between 2010 and 2013, 4-year mortality was 9.1% among 1,225 patients who underwent minimally invasive surgery vs. 5.3% among the 1,236 patients who underwent open surgery (HR, 1.65), Alexander Melamed, MD, of Harvard Medical School, Boston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1804923).
Of note, the 4-year relative survival rate following radical hysterectomy for cervical cancer remained stable prior to the widespread adoption of minimally invasive approaches; an interrupted time-series analysis involving women who underwent surgery during 2000-2010, which was also conducted as part of the study, showed a decline in 4-year survival of 0.8% per year after 2006, coinciding with increased use of minimally invasive surgery, the investigators said.
For the main patient-level analysis, the researchers used the National Cancer Database, and for the time-series analysis they used information from the Surveillance, Epidemiology, and End Results program database.
“Our findings suggest that minimally invasive surgery was associated with a higher risk of death than open surgery among women who underwent radical hysterectomy for early-stage cervical cancer. This association was apparent regardless of laparoscopic approach, tumor size, or histologic type,” they concluded.
The findings are unexpected, eye-opening, and should inform practice, according to Ritu Salani, MD, of the Ohio State University, Columbus.
“This is something we have to discuss with patients,” she said in an interview, noting that while these aren’t perfect studies, they “are the best information we have.
Data reported in September at a meeting of the International Gynecologic Cancer Society show that surgical complications and quality of life outcomes are similar with minimally invasive and open surgery, therefore the findings from these two new studies suggest a need to shift back toward open surgery for patients with cervical cancer, she said.
One “catch” is that survival in the open surgery group in the LACC trial was unusually high and recurrence rates unusually low, compared with what might be expected, and the explanation for this observation is unclear.
“There may be some missing pieces that they haven’t been able to explain, but it’s not clear that they would change the outcome,” she said.
Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients.
“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*
Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.*
SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.
*This article was updated 11/9/2018.
based on findings from the randomized, controlled phase 3 Laparoscopic Approach to Cervical Cancer (LACC) trial of more than 600 women.
The alarming findings, which led to early study termination, also were supported by results from a second population-based study. Both studies were published concurrently in the Oct. 31 issue of the New England Journal of Medicine.
The disease-free survival at 4.5 years among 319 patients who underwent minimally invasive surgery in the LACC trial was 86.0% vs. 96.5% in 312 patients who underwent open surgery, Pedro T. Ramirez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395).
At 3 years, the disease-free survival rates were 91.2% in the minimally invasive surgery group and 97.1% in open surgery group (hazard ratio for disease recurrence or death from cervical cancer, 3.74).
The differences between the groups persisted after adjustment for age, body mass index, disease stage, lymphovascular invasion, and lymph-node involvement. In the minimally invasive surgery group, the findings were comparable for those who underwent laparoscopic vs. robot-assisted surgery, the investigators found.
Further, at 3 years, overall survival was 93.8% vs. 99.0% (HR for death from any cause, 6.00), death from cervical cancer was 4.4% vs. 0.6% (HR, 6.56), and the rate of locoregional recurrence-free survival was 94.3 vs. 98.3 (HR, 4.26) in the minimally invasive and open surgery groups, respectively.
Study participants were women with a mean age of 46 years with stage IA1, IA2, or IB1 cervical cancer, with most (91.9%) having IB1 disease, and either squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. They were recruited from 33 centers worldwide between June 2008 and June 2017. Most of those assigned to minimally invasive surgery underwent laparoscopic surgery (84.4%), and the remaining patients underwent robot-assisted surgery.
The treatment groups were balanced with respect to baseline characteristics, they noted.
The minimally invasive approach is widely used given that guidelines from the National Comprehensive Cancer Network and European Society of Gynecological Oncology consider both surgical approaches acceptable, and since retrospective studies suggest laparoscopic radical hysterectomy is associated with lower complication rates and comparable outcomes. However, there are limited prospective data regarding survival outcomes in early stage disease with the two approaches, the researchers said.
“Our results call into question the findings in the literature suggesting that minimally invasive radical hysterectomy is associated with no difference in oncologic outcomes as compared with the open approach,” they wrote, noting that a number of factors may explain the differences, such as concurrent vs. sequential analyses in the current studies vs. prior studies (in sequential analyses, earlier procedures may have been performed under broader indications and less clearly defined radiotherapy guidelines), and the possibility that “routine use of a uterine manipulator might increase the propensity for tumor spillage” in minimally invasive surgery.
Strengths of the study include its prospective, randomized, international multicenter design and inclusion of a per-protocol analysis that was consistent with the intention-to-treat analysis, and limitations include the fact that intended enrollment wasn’t reached because of the “safety alert raised by the data and safety monitoring committee on the basis of the higher recurrence and death in the minimally invasive surgery groups,” as well as the inability to generalize the results to patients with low-risk disease as there was lack of power to evaluate outcomes in that context.
Even though the trial was initially powered on the assumption that there would be a 4.5 year follow-up for all patients, only 59.7% reached that length of follow-up. However, the trial still reached 84% power to detect noninferiority of the primary outcome (disease-free survival) with minimally invasive surgery, which was not found, they noted.
Similarly, in the population-based cohort study of 2,461 women who underwent radical hysterectomy for stage IA2 of IB1 cervical cancer between 2010 and 2013, 4-year mortality was 9.1% among 1,225 patients who underwent minimally invasive surgery vs. 5.3% among the 1,236 patients who underwent open surgery (HR, 1.65), Alexander Melamed, MD, of Harvard Medical School, Boston, and his colleagues reported (N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1804923).
Of note, the 4-year relative survival rate following radical hysterectomy for cervical cancer remained stable prior to the widespread adoption of minimally invasive approaches; an interrupted time-series analysis involving women who underwent surgery during 2000-2010, which was also conducted as part of the study, showed a decline in 4-year survival of 0.8% per year after 2006, coinciding with increased use of minimally invasive surgery, the investigators said.
For the main patient-level analysis, the researchers used the National Cancer Database, and for the time-series analysis they used information from the Surveillance, Epidemiology, and End Results program database.
“Our findings suggest that minimally invasive surgery was associated with a higher risk of death than open surgery among women who underwent radical hysterectomy for early-stage cervical cancer. This association was apparent regardless of laparoscopic approach, tumor size, or histologic type,” they concluded.
The findings are unexpected, eye-opening, and should inform practice, according to Ritu Salani, MD, of the Ohio State University, Columbus.
“This is something we have to discuss with patients,” she said in an interview, noting that while these aren’t perfect studies, they “are the best information we have.
Data reported in September at a meeting of the International Gynecologic Cancer Society show that surgical complications and quality of life outcomes are similar with minimally invasive and open surgery, therefore the findings from these two new studies suggest a need to shift back toward open surgery for patients with cervical cancer, she said.
One “catch” is that survival in the open surgery group in the LACC trial was unusually high and recurrence rates unusually low, compared with what might be expected, and the explanation for this observation is unclear.
“There may be some missing pieces that they haven’t been able to explain, but it’s not clear that they would change the outcome,” she said.
Justin Chura, MD, director of gynecologic oncology and robotic surgery at Cancer Treatment Center of America’s Eastern Regional Medical Center in Philadelphia, said in an interview, “The results of the study by Ramirez et al. are certainly disappointing for those among us who are advocates of minimally invasive surgery (MIS). In my own practice, I transitioned to minimally invasive radical hysterectomy approximately 10 years ago. Now that approach has to be reconsidered. While there are likely subsets of patients who will still benefit from a MIS approach without worsening oncologic outcomes, we do not have robust data to reliably identify those patients.
“One factor that warrants further investigation is the use of a uterine manipulator. While I do not use a manipulator out of personal preference (one less step in the operating room), the idea of placing a device through the tumor or adjacent to it, has biologic plausibility in terms of displacing tumor cells into lymphatic channels,” he said. “Until we have more data, an open approach appears to be preferred.”*
Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani and Dr. Chura are members of the Ob.Gyn. News editorial board, but reported having no other relevant disclosures.*
SOURCE: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.
*This article was updated 11/9/2018.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Cervical cancer recurrence and survival rates were worse with minimally invasive vs. open surgery in a prospective study.
Major finding: Disease-free survival at 4.5 years was 86% with minimally invasive vs. 96.5% with open surgery.
Study details: The phase 3 LACC trial of more than 600 women with cervical cancer, and a population based study of nearly 2,500 women with cervical cancer.
Disclosures: Dr. Ramirez and Dr. Melamed each reported having no relevant disclosures. Dr. Salani is a member of the OB.GYN. News editorial board, but reported having no other relevant disclosures.
Source: Ramirez P. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1806395.