CARACO: Study Shows Safety of Leaving Uninvolved Lymph Nodes in Ovarian Cancer

Routine removal of healthy lymph nodes should not be a part of ovarian cancer treatment, according to results of the CARACO trial.

Retroperitoneal pelvic and para-aortic lymphadenectomy (RPPL) in patients undergoing either primary or interval surgery during ovarian cancer treatment for advanced epithelial ovarian cancer (AEOC) resulted in no benefit and significant harm, the new study found.

“[RPPL] brings only toxicity and it does not increase survival ... because we have a lot of improvement with other treatments than surgery,” lead author Jean-Marc Classe, MD, PhD, said during a press conference at the annual meeting of the American Society of Clinical Oncology. “It’s a surgical de-escalation, because it is not useful.”

Enrollment for the multicenter, phase III CARACO trial stagnated after the LION trial (N Engl J Med . 2019 Feb 28;380[9]:822-832) showed no benefit to doing RPPL in patients undergoing primary surgery for AEOC. Ultimately, the CARACO trial did not enroll the prespecified sample size needed in order for the researchers to show that not doing RPPL was superior. 

Dr. Classe, a surgical oncologist at Nantes Université, in Nantes, France, explained that primary surgery is currently much less common than interval surgery for AEOC , thus it was important to design the CARACO trial to explore the risks and benefits of RPPL in a patient population that included more interval surgery.

CARACO enrolled 379 patients, with median age 64-65 years, and was closed prematurely due to stagnation of enrollment. Patients were randomized to no-RPPL (n = 193) or RPPL (n = 186), with about 75% in each arm receiving interval surgery (neoadjuvant chemotherapy, followed by cytoreductive surgery and adjuvant chemotherapy), and about 25% receiving primary surgery (initial cytoreductive surgery followed by adjuvant chemotherapy). There was a similar postsurgical rate of no residual disease (85.6% and 88.3% in the no-RPPL and RPPL groups, respectively), and lymph node metastases were diagnosed in 43% of the patients in the RPPL arm, with a median of 3 involved lymph nodes.

After a median follow-up of 9 years both the primary endpoint of progression-free survival (PFS), and secondary endpoint of overall survival (OS) showed no advantage to RPPL, with a median PFS of 14.8 months in the no-RPPL arm and 18.5 months in the RPPL arm (HR 0.96), and a median OS of 48.9 months and 58.0 months respectively (HR 0.92).

Surgery in the lymphadenectomy arm was 300 minutes versus 240 minutes.

“We observed statistically significant more morbidity in the lymphadenectomy arm with more transfusion (72 vs 57 patients), more re-intervention (15 vs 6 patients), more urinary injury (7 vs zero patients),” said Dr. Classe. Mortality was the same in both arms.

There were 314 events observed in the trial, which was 22 events fewer than the required sample size to show superiority. However, Dr. Classe said, a “worst-case scenario” calculation, assuming that all events would have favored lymphadenectomy, did not change the overall result.

The discussant for the trial, Shitanshu Uppal, MD, assistant professor in the division of gynecologic oncology at the University of Michigan in Ann Arbor, agreed that the study investigators adequately addressed this concern with the “counterfactual scenario.” He added that “as utilization of neoadjuvant chemotherapy goes up these results are really helpful in consolidating the results of the prior LION study, that lymph node dissection has no role in interval debulking surgery as well.”

Commenting on the study during the press conference, Michael Lowe, MD, associate professor in the division of surgical oncology at Emory University School of Medicine in Atlanta, said the CARACO study investigators’ efforts “underscore the difficulty of designing and accruing surgical clinical trials, especially clinical trials in which patients are offered less surgery.” He said the trial’s findings are consistent with other clinical trials in breast cancer and melanoma “that likewise showed similar outcomes for patients that did not undergo removal of clinically normal appearing lymph nodes.”

He pointed out that all of these studies highlight that the focus should turn to improving medical therapies.

Echoing this sentiment, Julie Gralow, MD, ASCO chief medical officer and executive vice-president, said, “it is very clear that lymph node dissection has significant morbidity ... and it’s very clear that we should not be doing more surgery than is needed ... In advanced ovarian cancer where the majority already have distant disease [focusing] on systemic therapy is probably what will have the most impact.”

Christina Annunziata, MD, PhD, senior vice president, Extramural Discovery Science, at the American Cancer Society, and an expert in ovarian cancer, said the analysis “leaves little doubt that there would be a statistically significant difference between the two arms. The numbers are small, but since this study results were consistent with the similar LION trial, I think that this study will tip the balance further towards omitting the lymphadenectomy in both primary and interval surgeries,” she said in an interview.

Dr. Annunziata added that surgeons are already omitting the dissection based on the LION study.

The study was funded by the French National Institute of Cancer. Dr. Classe disclosed consulting or advisory roles for GlaxoSmithKline, Myriad Genetics, and Roche.

None of the other experts interviewed for this piece declared having any relevant disclosures.

Routine removal of healthy lymph nodes should not be a part of ovarian cancer treatment, according to results of the CARACO trial.

Retroperitoneal pelvic and para-aortic lymphadenectomy (RPPL) in patients undergoing either primary or interval surgery during ovarian cancer treatment for advanced epithelial ovarian cancer (AEOC) resulted in no benefit and significant harm, the new study found.

“[RPPL] brings only toxicity and it does not increase survival ... because we have a lot of improvement with other treatments than surgery,” lead author Jean-Marc Classe, MD, PhD, said during a press conference at the annual meeting of the American Society of Clinical Oncology. “It’s a surgical de-escalation, because it is not useful.”

Enrollment for the multicenter, phase III CARACO trial stagnated after the LION trial (N Engl J Med . 2019 Feb 28;380[9]:822-832) showed no benefit to doing RPPL in patients undergoing primary surgery for AEOC. Ultimately, the CARACO trial did not enroll the prespecified sample size needed in order for the researchers to show that not doing RPPL was superior. 

Dr. Classe, a surgical oncologist at Nantes Université, in Nantes, France, explained that primary surgery is currently much less common than interval surgery for AEOC , thus it was important to design the CARACO trial to explore the risks and benefits of RPPL in a patient population that included more interval surgery.

CARACO enrolled 379 patients, with median age 64-65 years, and was closed prematurely due to stagnation of enrollment. Patients were randomized to no-RPPL (n = 193) or RPPL (n = 186), with about 75% in each arm receiving interval surgery (neoadjuvant chemotherapy, followed by cytoreductive surgery and adjuvant chemotherapy), and about 25% receiving primary surgery (initial cytoreductive surgery followed by adjuvant chemotherapy). There was a similar postsurgical rate of no residual disease (85.6% and 88.3% in the no-RPPL and RPPL groups, respectively), and lymph node metastases were diagnosed in 43% of the patients in the RPPL arm, with a median of 3 involved lymph nodes.

After a median follow-up of 9 years both the primary endpoint of progression-free survival (PFS), and secondary endpoint of overall survival (OS) showed no advantage to RPPL, with a median PFS of 14.8 months in the no-RPPL arm and 18.5 months in the RPPL arm (HR 0.96), and a median OS of 48.9 months and 58.0 months respectively (HR 0.92).

Surgery in the lymphadenectomy arm was 300 minutes versus 240 minutes.

“We observed statistically significant more morbidity in the lymphadenectomy arm with more transfusion (72 vs 57 patients), more re-intervention (15 vs 6 patients), more urinary injury (7 vs zero patients),” said Dr. Classe. Mortality was the same in both arms.

There were 314 events observed in the trial, which was 22 events fewer than the required sample size to show superiority. However, Dr. Classe said, a “worst-case scenario” calculation, assuming that all events would have favored lymphadenectomy, did not change the overall result.

The discussant for the trial, Shitanshu Uppal, MD, assistant professor in the division of gynecologic oncology at the University of Michigan in Ann Arbor, agreed that the study investigators adequately addressed this concern with the “counterfactual scenario.” He added that “as utilization of neoadjuvant chemotherapy goes up these results are really helpful in consolidating the results of the prior LION study, that lymph node dissection has no role in interval debulking surgery as well.”

Commenting on the study during the press conference, Michael Lowe, MD, associate professor in the division of surgical oncology at Emory University School of Medicine in Atlanta, said the CARACO study investigators’ efforts “underscore the difficulty of designing and accruing surgical clinical trials, especially clinical trials in which patients are offered less surgery.” He said the trial’s findings are consistent with other clinical trials in breast cancer and melanoma “that likewise showed similar outcomes for patients that did not undergo removal of clinically normal appearing lymph nodes.”

He pointed out that all of these studies highlight that the focus should turn to improving medical therapies.

Echoing this sentiment, Julie Gralow, MD, ASCO chief medical officer and executive vice-president, said, “it is very clear that lymph node dissection has significant morbidity ... and it’s very clear that we should not be doing more surgery than is needed ... In advanced ovarian cancer where the majority already have distant disease [focusing] on systemic therapy is probably what will have the most impact.”

Christina Annunziata, MD, PhD, senior vice president, Extramural Discovery Science, at the American Cancer Society, and an expert in ovarian cancer, said the analysis “leaves little doubt that there would be a statistically significant difference between the two arms. The numbers are small, but since this study results were consistent with the similar LION trial, I think that this study will tip the balance further towards omitting the lymphadenectomy in both primary and interval surgeries,” she said in an interview.

Dr. Annunziata added that surgeons are already omitting the dissection based on the LION study.

The study was funded by the French National Institute of Cancer. Dr. Classe disclosed consulting or advisory roles for GlaxoSmithKline, Myriad Genetics, and Roche.

None of the other experts interviewed for this piece declared having any relevant disclosures.

Routine removal of healthy lymph nodes should not be a part of ovarian cancer treatment, according to results of the CARACO trial.

Retroperitoneal pelvic and para-aortic lymphadenectomy (RPPL) in patients undergoing either primary or interval surgery during ovarian cancer treatment for advanced epithelial ovarian cancer (AEOC) resulted in no benefit and significant harm, the new study found.

“[RPPL] brings only toxicity and it does not increase survival ... because we have a lot of improvement with other treatments than surgery,” lead author Jean-Marc Classe, MD, PhD, said during a press conference at the annual meeting of the American Society of Clinical Oncology. “It’s a surgical de-escalation, because it is not useful.”

Enrollment for the multicenter, phase III CARACO trial stagnated after the LION trial (N Engl J Med . 2019 Feb 28;380[9]:822-832) showed no benefit to doing RPPL in patients undergoing primary surgery for AEOC. Ultimately, the CARACO trial did not enroll the prespecified sample size needed in order for the researchers to show that not doing RPPL was superior. 

Dr. Classe, a surgical oncologist at Nantes Université, in Nantes, France, explained that primary surgery is currently much less common than interval surgery for AEOC , thus it was important to design the CARACO trial to explore the risks and benefits of RPPL in a patient population that included more interval surgery.

CARACO enrolled 379 patients, with median age 64-65 years, and was closed prematurely due to stagnation of enrollment. Patients were randomized to no-RPPL (n = 193) or RPPL (n = 186), with about 75% in each arm receiving interval surgery (neoadjuvant chemotherapy, followed by cytoreductive surgery and adjuvant chemotherapy), and about 25% receiving primary surgery (initial cytoreductive surgery followed by adjuvant chemotherapy). There was a similar postsurgical rate of no residual disease (85.6% and 88.3% in the no-RPPL and RPPL groups, respectively), and lymph node metastases were diagnosed in 43% of the patients in the RPPL arm, with a median of 3 involved lymph nodes.

After a median follow-up of 9 years both the primary endpoint of progression-free survival (PFS), and secondary endpoint of overall survival (OS) showed no advantage to RPPL, with a median PFS of 14.8 months in the no-RPPL arm and 18.5 months in the RPPL arm (HR 0.96), and a median OS of 48.9 months and 58.0 months respectively (HR 0.92).

Surgery in the lymphadenectomy arm was 300 minutes versus 240 minutes.

“We observed statistically significant more morbidity in the lymphadenectomy arm with more transfusion (72 vs 57 patients), more re-intervention (15 vs 6 patients), more urinary injury (7 vs zero patients),” said Dr. Classe. Mortality was the same in both arms.

There were 314 events observed in the trial, which was 22 events fewer than the required sample size to show superiority. However, Dr. Classe said, a “worst-case scenario” calculation, assuming that all events would have favored lymphadenectomy, did not change the overall result.

The discussant for the trial, Shitanshu Uppal, MD, assistant professor in the division of gynecologic oncology at the University of Michigan in Ann Arbor, agreed that the study investigators adequately addressed this concern with the “counterfactual scenario.” He added that “as utilization of neoadjuvant chemotherapy goes up these results are really helpful in consolidating the results of the prior LION study, that lymph node dissection has no role in interval debulking surgery as well.”

Commenting on the study during the press conference, Michael Lowe, MD, associate professor in the division of surgical oncology at Emory University School of Medicine in Atlanta, said the CARACO study investigators’ efforts “underscore the difficulty of designing and accruing surgical clinical trials, especially clinical trials in which patients are offered less surgery.” He said the trial’s findings are consistent with other clinical trials in breast cancer and melanoma “that likewise showed similar outcomes for patients that did not undergo removal of clinically normal appearing lymph nodes.”

He pointed out that all of these studies highlight that the focus should turn to improving medical therapies.

Echoing this sentiment, Julie Gralow, MD, ASCO chief medical officer and executive vice-president, said, “it is very clear that lymph node dissection has significant morbidity ... and it’s very clear that we should not be doing more surgery than is needed ... In advanced ovarian cancer where the majority already have distant disease [focusing] on systemic therapy is probably what will have the most impact.”

Christina Annunziata, MD, PhD, senior vice president, Extramural Discovery Science, at the American Cancer Society, and an expert in ovarian cancer, said the analysis “leaves little doubt that there would be a statistically significant difference between the two arms. The numbers are small, but since this study results were consistent with the similar LION trial, I think that this study will tip the balance further towards omitting the lymphadenectomy in both primary and interval surgeries,” she said in an interview.

Dr. Annunziata added that surgeons are already omitting the dissection based on the LION study.

The study was funded by the French National Institute of Cancer. Dr. Classe disclosed consulting or advisory roles for GlaxoSmithKline, Myriad Genetics, and Roche.

None of the other experts interviewed for this piece declared having any relevant disclosures.