Clinical trial NCT06476639: Australian National Vulvar Cancer Trial
Official title: A Phase II Randomised Clinical Trial of Ultrasound Groin Monitoring Versus Groin Lymph Node Dissection to De-Escalate the Extent of Surgery in Vulvar Cancer
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Vulvar Cancer Stage I
Vulvar Cancer Stage II
Lymph Node Metastasis
Groin Node
Ultrasound Therapy; Complications
Keywords: Vulvar Cancer
Ultrasound Therapy
Lead sponsor: Queensland Centre for Gynaecological Cancer
Sponsor class: OTHER_GOV
Collaborators: name: Royal Brisbane and Women's Hospital
First posted: 2024-06-26
Enrollment: 240
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A phase II, open label, multicentre, three-group, randomised clinical trial.

240 eligible females aged 18 or older with clinically stage 1b or 2 vulvar cancer will receive a bilateral groin node ultrasound up to 30 days prior to planned surgery:

Participants with normal/negative baseline groin ultrasounds will be randomly assigned to two groups (2:1 randomisation). The Intervention group will receive bilateral groin node ultrasound every 2 months and clinical examinations every 3 months (groin lymph nodes are not removed). The Standard Group will undergo upfront full groin LND or sentinel node biopsy (SNB) based on clinician choice (according to local clinical practice management guidelines).

Participants with suspicious/indeterminate baseline groin ultrasound (third group) will receive an upfront full groin LND or SNB, consistent with the current standard treatment, according to local clinical practice management guidelines.
Primary purpose: OTHER

Brief summary: This study is a phase II, open label, multicentre, three-group, randomised clinical trial. The primary aim of this study is to determine whether intensive groin ultrasound monitoring (1) is effective and safe to replace invasive groin lymph node dissection (LND) to manage vulvar cancer, (2) decreases the morbidity associated with vulvar cancer surgery, and (3) is cost effective.

Detailed description: Treatment of vulvar cancer causes significant morbidity. Despite being a rare cancer, at least 2500 survivors of vulvar cancer live in Australia. Most survivors live with the detrimental, life-long impacts resulting from their cancer treatment because there are currently no alternatives to mitigate these impacts. The personal and societal burden this entails is significant. To control such cancer-associated burden is a national priority.

Clinical palpation of the groin region and computed tomography (CT) scans do not reliably detect groin node involvement. Hence, current clinical guidelines recommend all women diagnosed at apparent Stage I or II have a surgical groin LND. This can be performed as a full IFL (full LND) to remove all groin nodes, or as a sentinel node biopsy (SNB) to remove selected (one or two) nodes. SNB is less invasive, however, is appropriate only for vulvar cancers \<4cm in diameter and unifocal tumours (\~50% of all Stage I and II vulvar cancers). SNB is also associated with a false negative rate (10%) that increases the risk of undetected nodes.

In 25% of cases (\~80 Australian women per year), groin LND will reveal positive nodes (i.e., metastases), which triggers a referral for radiation treatment. If positive groin nodes are missed, and over time become enlarged, clinically palpable and attached to the overlying skin, \>90% of women will die within 12 months, despite subsequent treatment. Conversely, if groin node involvement is detected early (e.g., by ultrasound) while still small, survival outcomes are excellent. Ultrasound technology is potentially as accurate as LND due to recent advances in resolution and technologies such as 2D/3D volumetric assessments and tissue flow. Furthermore, ultrasound is superior to medical resonance imaging (MRI), and to standard CT and positron emission tomography (PET) scans in capturing groin node involvement because it has a higher resolution, avoids harmful radiation and the technology is readily accessible outside of high-volume metropolitan areas.

The investigators propose to reduce surgical morbidity by replacing upfront groin LND for vulvar cancer patients with serial high-resolution ultrasound to detect groin metastases. Groin LND will only be necessary for the few women with ultrasound-detected metastases when they are still small. The ANVU trial will determine the value of serial groin ultrasound examinations in stage 1 and 2 vulvar cancer patients and whether it is feasible and safe to de-escalate the extent of vulvar cancer surgery to achieve improved outcomes for affected patients.

Australian women with this rare cancer bear an unacceptably high (and potentially avoidable) treatment-related burden. This clinical trial is the first step to address this problem in a novel yet pragmatic way. The overall outcome of ANVU is a novel, less invasive alternative to vulvar cancer LND associated with significantly less morbidity, without compromising survival.

Eligibility criteria: Inclusion Criteria:

* Females, over 18 years, with histologically confirmed SCC, adenocarcinoma, or melanoma of the vulvar
* Clinically stage 1 or 2 on medical imaging (CT or MRI scan of pelvis, abdomen, and chest), without evidence of regional or distant metastatic disease
* Undergo IFL/SNB according to local clinical practice management guidelines
* Willing and able to comply with all study requirements, timing and/or nature of required assessments.
* Signed written informed consent
* Negative (serum or urine) pregnancy (BHCG) test ≤ 30 days of surgery ONLY in pre-menopausal women and women \< 2 years after the onset of menopause.

Exclusion Criteria:

* Women with non-invasive vulvar conditions (e.g. non-invasive non-mammary Paget's disease)
* SCC of the vulvar with depth of invasion ≤1 mm
* Clinical or medical imaging evidence of regional and/or distant metastatic disease
* Serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
* Other prior malignancies \<5 years before inclusion, except for successfully treated keratinocyte skin cancers, or ductal carcinoma in situ
* Estimated life expectancy of ≤6 months

Primary outcomes:
measure: Incidence of enlarged clinically palpable groin nodes (groin metastases) in women with vulvar cancer randomised to serial high-resolution groin ultrasound monitoring compared to standard upfront surgical groin LND.
timeFrame: 12 months after surgery
Secondary outcomes:
measure: Patient Reported Outcomes (PROMs)
timeFrame: 12 months after surgery
measure: Health Related Quality of Life (HRQL)
timeFrame: 12 months after surgery
measure: Pain
timeFrame: 12 months after surgery
measure: Adverse events
timeFrame: 12 months after surgery
measure: Lower limb lymphoedema
timeFrame: 12 months after surgery
measure: Cost-effectiveness
timeFrame: 12 months after surgery
measure: Disease-free survival
timeFrame: 12 months after surgery
measure: Overall survival
timeFrame: 12 months after surgery
measure: Clinical accuracy of high-resolution serial ultrasound to predict groin lymph node involvement
timeFrame: 12 months after surgery
measure: Utility of circulating tumour DNA to reliably reflect the presence or absence of positive groin lymph nodes
timeFrame: Study duration of up to 15 years
measure: Utility of plasma to reliably reflect the presence or absence of positive groin lymph nodes
timeFrame: Study duration of up to 15 years
measure: Utility of serum to reliably reflect the presence or absence of positive groin lymph nodes
timeFrame: Study duration of up to 15 years
measure: Utility of tumour mutations to reliably reflect the presence or absence of positive groin lymph nodes
timeFrame: Study duration of up to 15 years
Other outcomes:
Locations:
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Sydney
country: Australia
facility: The Royal North Shore Hospital
state: New South Wales
city: Darwin
country: Australia
facility: The Royal Darwin Hospital
state: Northern Territory
city: Auchenflower
country: Australia
facility: The Wesley Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Mater Hospital
state: Queensland
city: Brisbane
country: Australia
facility: St Andrew's War Memorial Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Buderim
country: Australia
facility: Buderim Private Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Heidelberg
country: Australia
facility: Mercy Hospital for Women
state: Victoria
city: Parkville
country: Australia
facility: Royal Women's Hospital
state: Victoria
city: Subiaco
country: Australia
facility: St John of God Hospital
state: Western Australia
Study officials:
affiliation: Director, Queensland Centre for Gynaecological Cancer Research
name: Andreas Obermair, MD
role: STUDY_CHAIR
References: