Val Gebski

Toward Incorporating Health-Related Quality of Life as Coprimary End Points in Clinical Trials: Time to Achieve Clinical Important Differences and QoL Profiles

PURPOSE Besides morbidity and mortality, quality of life (QoL) is a key outcome of cancer treatments. Trials on the basis of clinical outcomes have expectations that QoL outcomes can be either tolerated or improved. Simultaneously considering QoL and clinical outcomes is challenging with lack of suitable metrics allowing incorporation of QoL as coprimary end points in clinical trial design and utilization of hierarchical hypothesis testing. METHOD We propose combining time to achieving a minimal clinically important difference (MCID) and probabilities of a MCID occurring in each QoL domain to provide QoL metrics analogous to those used for clinical end points. For QoL domains of interest, these yield QoL profiles, time to MCID, and number needed to treat. Incorporation of QoL as coprimary end points in clinical trial designs through hierarchical hypothesis testing can easily be achieved. The noninferiority designed Laparoscopic Approach to Carcinoma of the Endometrium trial, evaluating laparoscopic versus open abdominal surgery for endometrial cancer with Functional Assessment of Cancer Therapy–General QoL domains, is used to illustrate the usefulness of these metrics. RESULTS This analysis revealed that laparoscopic surgery had a significant shorter time to MCID for physical and functional well-being QoL domains (physical mean: 1.5 months, 95% CI, 0.5 to 2.6; P = .002; and functional mean: 1.4 months; 95% CI, 0.4 to 2.4; P = .003) than abdominal surgery, but little difference between the two approaches for psychologic social and emotion well-being. Probability profile plots show a consistent > 2-fold higher chance of attaining a MCID for physical and functional well-being over time for laparoscopic compared with abdominal surgery. CONCLUSION This analysis reinforces the potential value of novel MCID metrics and their usefulness in raising the profile of QoL outcomes to complement clinical end points. The methods will allow health professionals to counsel patients about QoL outcomes and clinical outcomes simultaneously.

A phase III randomized clinical trial comparing sentinel node biopsy with no retroperitoneal node dissection in apparent early-stage endometrial cancer – ENDO-3: ANZGOG trial 1911/2020

Sentinel node biopsy is a surgical technique to explore lymph nodes for surgical staging of endometrial cancer, which has replaced full retroperitoneal lymph node dissection. However, the effectiveness of sentinel node biopsy, its value to patients, and potential harms compared with no-node dissection have never been shown in a randomized trial. Stage 1 will test recovery from surgery. Stage 2 will compare disease-free survival at 4.5 years between patients randomized to sentinel node biopsy versus no retroperitoneal node dissection. The primary hypothesis for stage 1 is that treatment with sentinel node biopsy will not cause detriment to patient outcomes (lymphedema, morbidity, loss of quality of life) and will not increase treatment-related morbidity or health services costs compared with patients treated without a retroperitoneal node dissection at 12 months after surgery. The primary hypothesis for stage 2 is that disease-free survival at 4.5 years after surgery in patients without retroperitoneal node dissection is not inferior to those receiving sentinel node biopsy. This phase III, open-label, two-arm, multistage, randomized non-inferiority trial (ENDO-3) will determine the value of sentinel node biopsy for surgical management of endometrial cancer. Patients with endometrial cancer are randomized to receive: (1) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy with sentinel node biopsy or (2) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection. In stage 1, 444 patients will be enrolled to demonstrate feasibility and quality of life. If this is demonstrated, we will enroll another 316 patients in stage 2. Inclusion criteria include women aged 18 years or older with histologically confirmed endometrial cancer; clinical stage 1, who meet the criteria for laparoscopic or robotic total hysterectomy and bilateral salpingo-oophorectomy. Patients with uterine mesenchymal tumors are excluded. The endpoint for stage 1 is surgical recovery, with the proportion of patients returning to usual daily activities at 3 months post-surgery as measured with the EQ-5D. Stage 2 is disease-free survival at 4.5 years. 760 participants (both stages). Stage 1 commenced in January 2021 and is planned to be completed in December 2024 when 444 participants have completed 12 months' follow-up. Stage 2 will enroll a further 316 participants for a total of 760 patients. NCT04073706.

LACC Trial: Final Analysis on Overall Survival Comparing Open Versus Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The aim of this study was to compare overall survival between open and minimally invasive radical hysterectomy with participants followed for 4.5 years. The primary objective was to evaluate whether minimally invasive surgery was noninferior in disease-free survival (DFS) to abdominal radical hysterectomy. Secondary outcomes included overall survival. Sample size was based on DFS of 90% at 4.5 years and 7.2% noninferiority margin for minimally invasive surgery. A total of 631 patients were enrolled: 319 assigned to minimally invasive and 312 to open surgery. Of these, 289 (90.6%) patients underwent minimally invasive surgery and 274 (87.8%) patients open surgery. At 4.5 years, DFS was 85.0% in the minimally invasive group and 96% in the open group (difference of –11.1; 95% CI, –15.8 to –6.3; P = .95 for noninferiority). Minimally invasive surgery was associated with lower rate of DFS compared with open surgery (hazard ratio [HR], 3.91 [95% CI, 2.02 to 7.58]; P < .001). Rate of overall survival at 4.5 years was 90.6% versus 96.2% for the minimally invasive and open surgery groups, respectively (HR for death of any cause = 2.71 [95% CI, 1.32 to 5.59]; P = .007). Given higher recurrence rate and worse overall survival with minimally invasive surgery, an open approach should be standard of care.

Sentinel Node Biopsy in Endometrial Cancer

Endometrial cancer (EC) is the most common gynaecological cancer. Current treatment of EC typically includes removal of the uterus and to determine the extent of the disease (removal of fallopian tubes, ovaries \& if required a lymph node dissection (surgical staging)). While lymph node dissection may be valuable to guide the need for adjuvant treatment (chemo or radiotherapy) after surgery, it has been a topic of controversy for the last 30 years. In some patients it causes morbidity, specifically lymphoedema. This recently has been replaced with sentinel node biopsy (SNB). It requires an injection of a dye into the cervix with specific equipment \& surgical dissection of the lymph node in which the dye first becomes visible. Despite this promising proposition \& similar to a lymph node dissection, the value to patients, cost effectiveness \& potential harms (e.g. lymphedema) of SNB compared to no-node dissection in EC has never been established. Aim: determine the value of SNB for patients, the healthcare system and exclude detriment to patients using a randomised approach 1:1. Stage 1 - 444 patients. Stage 2 additional 316 patients. Primary Outcome Stage 1: Proportion of participants returning to usual daily activities at 12 months from surgery using the EQ-5D which will determine when women in both groups can return to their usual activities. Primary Outcome Stage 2: Treatment non-inferiority as evaluated by disease-free survival status at 4.5 years post-surgery, as measured by the time interval between the date of randomisation and date of first recurrence. Confirmation of recurrent disease will be ascertained through clinical assessment, radiological work-up and/or histological results.

Laparoscopic Approach to Cervical Cancer

The goal of this clinical research study is to compare the long-term outcomes of different surgical methods for the treatment of cervical cancer. The long-term outcome of a total abdominal radical hysterectomy (TARH) will be compared against laparoscopy. In this study, the laparoscopy will be done with or without robotic technology.

Laparoscopic Approach to Cancer of the Endometrium

The primary objective of this study is to assess disease-free survival at 4.5 years postoperatively for women with apparent Stage 1 endometrial cancer, comparing patients who are randomised to receive Total Laparoscopic Hysterectomy (TLH) and patients who are randomised to receive Total Abdominal Hysterectomy (TAH).