Laparoscopic cytoreduction After Neoadjuvant ChEmotherapy (LANCE)

Abstract

Background:

Observational studies have supported the practice of offering minimally invasive interval debulking surgery after neoadjuvant chemotherapy for well selected patients with advanced epithelial ovarian cancer. However, there are no prospective randomized data comparing the oncologic efficacy of minimally invasive and open interval debulking surgery in epithelial ovarian cancer.

Primary Objective:

The primary objective of this study is to examine whether minimally invasive surgery is non-inferior to laparotomy in terms of oncologic outcome in women with advanced stage epithelial ovarian cancer that responded to 3 or 4 cycles of neoadjuvant chemotherapy.

Study Hypothesis:

We hypothesize that in patients who had a complete or partial response to neoadjuvant chemotherapy, minimally invasive interval debulking surgery is not inferior to laparotomy

Trial Design:

The Laparoscopic cytoreduction After Neoadjuvant ChEmotherapy (LANCE) trial is an international, prospective, randomized, multicenter, non-inferiority phase III trial to compare minimally invasive surgery versus laparotomy in women with advanced stage high-grade epithelial ovarian cancer that had a complete or partial response to 3 or 4 cycles of neoadjuvant chemotherapy and normalization of CA-125. The first 100 subjects will be enrolled into a pilot lead-in to determine feasibility. The study will be considered feasible and will continue to Phase III under the following conditions: 1) the accrual rate reaches at least 80% of the target rate after all pilot sites are open, 2) the crossover rate in the minimally invasive group is less than 25%, and 3) the difference of complete gross resection between the minimally invasive and open group is less than 20%. If the study is determined to be feasible, all remaining subjects will be enrolled into the Phase III portion.

Major Inclusion/Exclusion Criteria:

Patients with stage IIIC or IV high-grade epithelial ovarian, primary peritoneal or fallopian tube carcinoma who had a complete or partial response to 3 or 4 cycles of NACT based on imaging and normalization of CA-125 will be enrolled. Patients with evidence of tumor not amenable to minimally invasive resection on pre-operative imaging will be excluded.

Primary Endpoint:

The primary endpoint is non-inferiority of disease-free survival in minimally invasive versus laparotomic interval debulking surgery.

Sample Size:

To demonstrate non-inferiority with a margin of 33% in the Hazard Ratio (HR = 1.33), 580 patients will be randomized.

Introduction

Epithelial ovarian cancer is the eighth most common cancer among women, however, it is the fifth leading cause of death. [1] According to global estimates, 225,000 new cases are detected each year, and 140,000 women annually die from the disease. Three phase III trials and a recent meta-analysis have found that women with advanced ovarian cancer who were randomized to neoadjuvant chemotherapy followed by interval debulking surgery have equivalent survival to those randomly assigned to primary cytoreductive surgery and adjuvant chemotherapy. [2-5] While primary cytoreductive surgery was the traditional treatment for advanced ovarian cancer, utilization of neoadjuvant chemotherapy has increased substantially in the United States. [6] By 2016, 1 in 3 patients with stage IIIC or IV ovarian cancer received chemotherapy prior to surgery. Recent guidelines from the American Society of Clinical Oncology and the Society of Gynecologic Oncology recommend neoadjuvant chemotherapy and interval surgery for women with high perioperative risk, or low likelihood of achieving optimal cytoreduction at primary surgery. [7]

In women who have a response to neoadjuvant chemotherapy, it has been proposed that interval cytoreduction can be achieved using minimally invasive surgery. [8-11] While the minimally invasive approach has become common in gynecologic practice, [12, 13, 15] studies that have investigated it in other anatomic sites have yielded contradictory results. Among women with early stage endometrial cancer, minimally invasive surgery improves perioperative outcomes without impairing survival, [12, 13] whereas in early-stage cervical cancer minimally invasive radical hysterectomy, until recently the standard approach, is inferior to open radical hysterectomy. [14] In ovarian cancer, small uncontrolled observational studies [8-11] and an analysis of the National Cancer Database [11] have demonstrated a high rate of complete cytoreduction, good perioperative outcomes, and excellent progression-free survival among women who underwent minimally invasive interval cytoreduction. While these studies suggest that this approach may be reasonable and effective in well-selected patients, there is no randomized evidence to support this approach. Importantly, despite the absence of high-quality evidence, the use of minimally invasive interval cytoreductive surgeries is on the rise reaching 21% in 2016. [15]

At this time, available evidence suggests equipoise between minimally invasive and open interval cytoreductive surgery for women with advanced ovarian cancer who have had a complete, or near complete, response to neoadjuvant chemotherapy. A randomized trial comparing these approaches is warranted. We propose an international validation study of interval minimally invasive cytoreductive surgery.

Methods

Trial Design

The Laparoscopic cytoreduction After Neoadjuvant ChEmotherapy (LANCE) trial is an international, prospective, randomized, multicenter, non-inferiority phase III trial to compare MIS to laparotomy in terms of disease-free survival in women with advanced stage high-grade epithelial ovarian cancer that had a complete or partial response to 3 or 4 cycles of neoadjuvant chemotherapy. The intended chemotherapy regimen will be established on an individual basis, will depend on patient’s fitness, choice, and usual local practice, and will be pre-specified before random assignment. The recommended regimen will be paclitaxel (175 mg/m² of body surface) administered as a 3-hour infusion immediately followed by an intravenous infusion of carboplatin (area under the curve of 6) over 1 hour. However, other regimens and combinations will be allowed, including first-line therapeutic clinical trials (e.g. immunotherapy, (Poly-(ADP)-ribose inhibitors, combination treatments, etc.) are allowed if pre-specified before random assignment. Up to 580 patients will be randomized prospectively prior to surgery (by minimization) in a 1:1 ratio to one of the 2 study arms: Arm A (experimental arm): patients will have minimally invasive surgery; or Arm B (reference arm): patients will have a laparotomy. The first 100 subjects will be enrolled into a pilot lead-in to determine feasibility. The study will be considered feasible and will continue to Phase III under the following conditions: 1) the accrual rate reaches at least 80% of the target rate after all pilot sites are open, 2) the crossover rate in the minimally invasive group is less than 25%, and 3) the difference of complete gross resection between the groups is less than 20%. If the feasibility endpoints are not reached, accrual will be suspended, and a detailed evaluation will take place by the trial steering committee. Mitigation strategies will be reviewed and, if possible, consideration of an amendment or a recommendation of trial termination will made.

If the study is determined to be feasible, all remaining subjects will be enrolled into the Phase III portion. Patients will be followed for a maximum of 2 years after the final patient is enrolled or once the patient’s 5-year follow-up phase is complete, whichever occurs first. The study schema is described in Figure 1.

Figure 1. Study Schema.

*Chemotherapy regimen & enrollment on other first-line therapeutic clinical trials will be allowed but will be pre-specified before random assignment.

NACT: Neoadjuvant chemotherapy; MIS: Minimally invasive surgery

The LANCE trial is a non-commercial trial that does not receive any support from the industry. Participating institutions will not receive any financial compensation for inclusion in the study. All trial related expenses (regulatory services, statistics, electronic database, and data quality monitoring) are covered by research grants.

Participants

Participants are eligible for the study if the following inclusion criteria are met: (1) adult women over age 18 with stage IIIC or IV, high-grade serous, endometrioid, clear-cell, transitional, invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian-tube carcinoma; (2) complete or partial response to 3 or 4 cycles of neoadjuvant chemotherapy; (3) normalization of CA-125 according to participating centers’ reference ranges; (4) timeframe of less than 6 weeks from the last cycle of chemotherapy to interval debulking surgery; (5) patients that received only 3 cycles of chemotherapy, must have completed their regimen within 9 weeks, patients that received 4 cycles of chemotherapy, must have completed their regimen within 12 weeks; (6) Eastern Cooperative Oncology Group performance status 0-2.

Patients with evidence of disease that is not amenable to minimally invasive resection on pre-operative imaging (CT, PET-CT, or MRI) including but not limited to: failure of improvement of ascites during neoadjuvant chemotherapy (trace ascites is allowed), small bowel or gastric tumor involvement, colon or rectal tumor involvement, diaphragmatic tumor involvement, splenic or hepatic surface or parenchymal tumor involvement, mesenteric tumor involvement, or tumor infiltration of the lesser peritoneal sac, will be excluded from the study. Patients with mucinous histology will also be excluded. In addition, patients with a history of previous malignancies, and those unable to tolerate Trendelenburg or have any other contraindication to minimally invasive surgery will be excluded from the study.

Primary Endpoints

The primary objective of this study is disease-free survival (non-inferiority of minimally invasive surgery versus laparotomy) after 3 to 4 cycles of neoadjuvant. Disease-free survival is defined as the time interval between randomization and physical or radiographic evidence of recurrence (local/distant) or death (all causes), whichever occurs first. The onset of clinical progression is defined as either radiographic evidence of increasing disease as assessed by a clinical radiologist with (Response Evaluation Criteria in Solid Tumors criteria, version 1.1, as guidance), [16] an overall deterioration in health, or a rise in the CA-125 level as assessed by the Gynecologic Cancer Inter Group criteria. [17]

Important secondary objectives include health-related quality of life assessed with European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30), QLQ-OV28 (ovarian supplement) and Functional Assessment of Cancer Therapy-General short-form (FACT-G7), overall survival, surgical morbidity and mortality, intraoperative injuries, and rate of minimally invasive debulking converted to laparotomy.

Sample Size

We aim to demonstrate a non-inferiority of the minimally invasive approach with a non-inferiority margin of 33% in the Hazard Ratio (HR = 1.33). Under the assumptions of a median disease-free survival of 23 months in both arms, an accrual rate of 7 patients per month in the first 14 months after all pilot sites are open, and 20 patients per subsequent months after all sites open, 552 patients should be randomized in 31 months to observe the required 323 events, given a one-sided type I error rate of 5%, a power of 80%, and with 2 years of follow-up. Taking into account 5% lost to follow-up, a total of 580 patients will be enrolled.

If feasible, the study will continue to the phase III portion and consideration to stopping the study will be given if any of the following events occur: (1) annual patient accrual is less than 30 for all sites; (2) less than 75% of patients are available for follow-up; (3) there is an unacceptably high incidence of complications (>8%) in the minimally invasive group.

Randomization

After completion of pre-randomization assessments, patients who meet all eligibility requirements will be randomized 1:1 by minimization to the experimental arm (arm A, minimally invasive surgery) or the reference are (arm B, laparotomy). Randomization will be stratified by the following criteria: stage of the disease, BRCA status, receipt of maintenance treatment (Poly-(ADP)-ribose inhibitors and/or angiogenesis inhibitors), and enrollment in other experimental non-surgical clinical studies.

Statistical Methods

If the study proceeds to the phase III portion, the main survival analysis will be performed according the intention-to-treat principle. Kaplan Meier curves will be used to describe disease-free survival over time. The log-rank test will be used to compare survival between the control and experimental arms. The treatment effects will be summarized by means of a hazard ratio with its associated 95% confidence interval.

Continuous variables will be summarized using descriptive statistics, and two-sample t-tests will be used to compare experimental and control arms. Linear regression will be used to compare the two arms while adjusting for potential confounding factors. Qualitative variables will be summarized by means of counts and percentages. The chi-squared test will be used to compare experimental and control arms. Logistic regression will be used to compare two arms while adjusting for potential confounding factors.

Overall survival, defined as time interval between randomization and death (all causes) will be estimated using the Kaplan-Meier method, and will be described using the median with its 95% confidence interval. When appropriate, multivariate Cox analyses will be performed, in which a univariate selection procedure will serve to identify eligible explanatory variables with univariate Cox (using the Wald Test) p-value lower than 0.10 as potential prognostic value.

Safety data will be summarized using descriptive statistics, and adverse events and serious adverse events will be tabulated by type and severity. Fisher’s exact test or chi-squared tests will be used to compare the two arms. Quality of life scores between the two randomized arms will be evaluated at 1 and 3 months after surgery. A linear mixed model will be fitted for each quality of life scale score, adjusted for corresponding baseline assessment scores, time effect, patient’s age, weight (in kilograms) at study entry, and marital status. The interaction between treatment and time will be examined for the similarity of treatment effects at 1, and 3 months post-surgery, with the significance level for an interaction set at .05. If the interaction effect is significant, then treatment effects at each postsurgical assessment will be tested at a significance level of .025 by comparing least-square means between the two arms. Otherwise, the mixed model will be refitted without the interaction, and treatment effects will be tested as an overall effect over the postsurgical assessments.

All tests will be performed at a two-sided significance level of 5% (95% Confidence interval), with the exception of the tests for the primary endpoint of non-inferiority using one-sided test at a significance level of 5%.

Discussion

From the time Joseph V. Meigs, a gynecologic surgeon at Massachusetts General Hospital, described ovarian tumor debulking surgery in 1934,[18] until the beginning of this century, ovarian cancer surgery was strictly conducted via an exploratory laparotomy. As the minimally invasive approach gained acceptance in gynecology,[11,12] its utility expanded to ovarian cancer surgery as well. Initially this was limited to management of early-stage disease, and assessment of resectability in advanced disease, but now the National Cancer Network Guidelines endorse the minimally invasive technique as an approach for interval debulking surgery in “select patients”.[19] While there is no clear guidance defining the ideal candidate for minimally invasive interval debulking surgery, approximately 1 in 4 women will undergo this procedure after neoadjuvant chemotherapy.[14]

The adoption of minimally invasive interval debulking surgery is based on limited observational studies. Gueli Alletti et al. [9] performed this procedure in 30 women with clinical response to neoadjuvant chemotherapy and achieved resection of all visible disease in 29 women. All patients were alive with a median follow up of 10.5 months. Similarly, in a retrospective study, Corrado et al. [10] found that interval minimally invasive cytoreduction was associated with low rates of intra- and postoperative complications, and at a median follow-up of 15 months, 26 of 30 patients were alive without recurrence. Recently, the INTERNATIONAL MISSION trial, a multi-center retrospective study of 127 women who underwent minimally invasive surgery after neoadjuvant chemotherapy for ovarian cancer, demonstrated a median progression-free survival of 23 months and a 5-year overall survival rate of 52%. [20] Finally, Melamed et al. [11] utilized the National Cancer Database to compare 450 women who underwent Minimally invasive cytoreduction with 2,621 women who underwent laparotomy and found no difference in overall survival or surgical outcomes between these groups, even after adjusting for numerous potential confounders.

While these findings are promising, results demonstrating impaired survival in patients undergoing minimally invasive radical hysterectomy for cervical cancer [14] should caution against the acceptance of minimally invasive interval debulking surgery in the absence of prospective randomized data. The LANCE trial will provide an assessment of the oncologic efficacy of this approach. By controlling for known and unknown confounders via randomization, this trial will produce unbiased comparative estimates of disease-free survival, as well as overall survival, intra- and post-operative complication rates, and post-surgical quality of life associated with each surgical modality. The results of this trial may change the standard of care for well-selected patients undergoing interval debulking surgery after neoadjuvant if non-inferiority of minimally invasive surgery is demonstrated. However, these data may also demonstrate inferior oncologic outcomes associated with minimally invasive interval debulking surgery and may lead to cessation of this practice.