Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05707078 |
| Other study ID # |
H-22067459 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 7, 2023 |
| Est. completion date |
December 30, 2030 |
Study information
| Verified date |
November 2023 |
| Source |
Rigshospitalet, Denmark |
| Contact |
Jacob H Rasmussen, MD; PhD |
| Phone |
+4535453251 |
| Email |
jacob.hoeygaard.rasmussen.01[@]regionh.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
PET/CT follow up for Head and Neck Squamous Cell Carcinoma The following is a presentation of
a prospective protocol, named PET/CT follow up for Head and Neck Squamous Cell Carcinoma (PET
Follow), including patients who have completed radiotherapy treatment for squamous cell
carcinoma of the head and neck (HNSCC).
The purpose of this study is to investigate the diagnostic performance of
18F-fluorodeoxy-D-glucose (FDG) Positron Emission Tomography/ Computed Tomography (PET/CT) in
patients with HNSCC after curative intended treatment.
Description:
PET/CT follow up for Head and Neck Squamous Cell Carcinoma The following is a presentation of
a prospective protocol, named PET/CT follow up for Head and Neck Squamous Cell Carcinoma (PET
Follow), including patients who have completed radiotherapy treatment for squamous cell
carcinoma of the head and neck (HNSCC).
Purpose The purpose of this study is to investigate the diagnostic performance of
18F-fluorodeoxy-D-glucose (FDG) Positron Emission Tomography/ Computed Tomography (PET/CT) in
patients with HNSCC after curative intended treatment.
Background Head and neck cancer HNSCC is the most frequent malignancy in the head and neck
area and arises from the mucosal lining in the oral cavity, naso-, oro-, hypo-pharynx and
larynx. HNSCC is a heterogeneous disease in regard to involved anatomical subsite and
prognosis. Patients with human papilloma virus (HPV) related tumors in oropharynx have a good
prognosis, whereas patients with tobacco and alcohol related tumors have a relatively poor
prognosis. Treatment involves surgery and or radiotherapy (RT) with or without concomitant
chemotherapy depending on disease stage and anatomical sublocation. Even with optimal
treatment approximately 40-50% of the patients experience recurrence after treatment and the
majority of recurrences occurs within 2 years after treatment. Early detection of possible
recurrence is important to enable possible salvage treatment early. In Denmark patients are
followed up, according to DAHANCA guidelines (www.dahanca.dk), with clinical examination 2,
6, 12, 18, 24 months after ended treatment and then yearly until five years after end of
treatment. Although clinical examination of HNSCC patients can be difficult, routine follow
up with imaging is not recommended in Denmark but may be used on clinical suspicion of
relapse. Especially the neck is difficult to assess clinically, and some centers have
implemented routine imaging 2-3 months after ended treatment. However, there are no consensus
guidelines regarding imaging modality, timing nor how to interpretate the results. This lack
of consensus challenges the management of the patients following imaging procedures with
uncertain and varying specificity and sensitivity. Figure 1 below depicts the current follow
up management in Denmark.
Imaging Both surgical and radiotherapeutic treatment alter the anatomy in HNSCC patients
which challenge both clinical examination and conventional anatomical imaging with CT and
Magnetic Resonance Imaging (MRI). Imaging with FDG-PET is based on assessment of cellular
metabolism and thus less influenced by changes in anatomical structures and could be of value
to distinguish between treatment related changes and recurrence. On the other hand, increased
FDG can be seen in residual/recurrent tumour as well as in inflammation caused by
radiotherapy or recent surgery. Previously, planned neck dissection after RT has been routine
in some countries. But in a recent clinical randomized trial (PET-NECK), surveillance with
PET/CT proved non-inferior compared to routine planned neck dissection after RT treatment. In
the PET-NECK study patients were classified in three categories based on the PET/CT
assessment as follows: 1) incomplete response (ICR); 2.) equivocal response (EQR) and 3.)
complete response (CR). Both patients with ICR and EQR underwent neck dissection and only
patients with CR continued with conventional follow up in the PET-NECK study. Based on the
PET-NECK study, several institutions have changed the management of patients from planned
neck dissection to surveillance with PET/CT and preserved neck dissection only for patients
with ICR or EQR. However, the follow up management has in some institutes changed beyond the
PET-NECK study using further surveillance for patients with ICR or EQR, despite lack of
direct evidence to validate the safety of this approach. These institutes have gradually
adopted a more conservative, watch and wait, approach using PET/CT surveillance for patients
with EQR and in some cases patients with ICR on the evaluation PET/CT after treatment. These
patients have a repeated PET/CT scan 1-6 months later instead of immediate neck dissection.
This change in day to day practice is based on institutional experience and a few
retrospective studies reporting, that some patients may be spared from unnecessary neck
dissection. The watch and wait approach are driven mainly by two reasons. 1) The high
negative predictive value of the evaluation PET/CT scan can identify patients who can be
spared of neck dissection; And 2) The lower positive predictive value reported in
meta-analyses raise a concern of unnecessary neck dissection in patients whom on the repeated
PET/CT are converted from EQR or ICR to CR. Especially in patients with HPV related disease
who have a fairly good prognosis and tumors that seems to take longer to respond to RT.
Planned neck dissection after RT has never been the standard of care in Denmark and post
treatment evaluation with imaging has been preserved for patients with clinical suspicion of
recurrence. As such, the PET-NECK study has in principal not changed the routine follow up
guidelines for HNSCC patients in Denmark. However, also in Denmark a growing concern for
overtreating patients has led to a more conservative approach using PET/CT scans for
surveillance and gradually adopting a watch and wait approach without clear consensus
recommendations nor evidence supporting this approach.
There are two main concerns with the watch and wait strategy both with several potential
issues and pitfalls. The first concern relates to the lack of clinical guidelines on whom,
how and when to scan. There is no agreement nor consensus on the timing of the subsequently
PET/CT scans, and no well-established standardization on how to interpretate the PET/CT
scans. And there is no direct evidence recommending a watch and wait approach, which has led
to some ambiguity in different recommendations for follow up management for HNSCC patients.
The second concern relates to the uncertainties in the diagnostic performance in PET/CT.
There is a high physiological FDG uptake in head and neck area challenging the
interpretation, especially after surgery or radiotherapy, and the potential correlation
between FDG uptake and vital tumor cells is low and not well understood.
In this study both concerns will be addressed by investigating the diagnostic performance of
PET/CT scans in the follow up management of patients treated for HNSCC.
Aim
To achieve the purpose of the study the following specific aim (SA) will be addressed:
-SA1: Investigate the diagnostic performance of PET/CT scan in a post treatment setting and
calculate positive and negative predictive values.
Methods This is a prospective two stage single arm study where patients undergoing
surveillance after treatment for HNSCC will be offered inclusion in the study to quantify the
sensitivity, specificity, positive and negative predictive values of PET/CT 3 months after
radiotherapy treatment. Patients who have completed curative intended radiotherapy for HNSCC
in the oral cavity, pharynx or larynx and meet the inclusion criteria will be asked to
participate in the study.
Study plan Approximately 600 hundred patients were treated for HNSCC in eastern Denmark in
2020 (DAHANCA annual report; available in danish only www.DAHANCA.dk). We therefore expect
300-400 patients would be relevant candidates for this study and 200-300 to be accrued yearly
after initiation of the protocol. The enrollment in the study will not delay any treatment in
case of recurrence. Figure 1 depicts the current conventional follow up and figure 2
illustrates the follow up for the patients included in the study. Changes from conventional
follow up are marked in red.
All included patients will have a PET/CT performed three months after ended treatment.
Patients with EQR or ICR will undergo neck dissection.
PET/CT The PET/CT scans will be performed in accordance with EANM guidelines. The
interpretation of the PET/CT scans regarding N-site will be performed according to the
Deauville scoring system. Deauville relies on visual inspection of the relative difference in
tumor metabolism compared to surrounding normal tissue and/or background uptake in the
mediastinal blood pool and liver. The Deauville criteria use 5-point scales, where scores 1
and 2 effectively represent a complete metabolic response. The Deauville scoring system is
already known and used in lymphoma patients and proved to minimize indeterminate scan results
in the study by Zhong et al.
A central review board will be established between the three participating departments of
Clinical Physiology and Nuclear Medicine at Rigshospitalet, Herlev and Køge. The PET/CT scans
will be assessed by consultants at two of the involved departments and in case of lack of
consensus, the third department will be involved to ensure consensus by at least two
departments. Beside above the PET/CT scans will be assessed and described as done in clinical
routine.
Surgery The neck dissection will be performed according to institutional guideline and the
preoperative workup is done as in normal routine as are the postoperative follow up.
Suspicious lymph nodes will be marked separately according to anatomical orientation
per-operatively. The remaining specimen will be assessed and marked according to specified
involved neck levels.
Pathology During the histologic processing all identified lymph nodes will be removed and
examined with HE-staining, complemented if needed with other immunohistochemical stains as
done in routine diagnostic setting. The per-operatively marked lymph nodes will be sectioned
continuously and all slices embedded in paraffin. A pathological positive lymph node is
defined by presence of vital tumor cells.
Statistical considerations In the PET NECK study 47 of the 270 (17%) patients in the
surveillance group had CR at primary site but ICR or EQR at N-site, and 19 patients (7%) had
ICR in both T and N site. In the retrospective studies in literature the numbers of patients
with EQR or ICR are higher and reported from 37-40% in patients with HPV related HNSCC to 55%
in patients with HPV unrelated HNSCC and 51% in a cohort including patients with both HPV
related and unrelated HNSCC. In other words, the numbers of patients with CR, EQR and ICR
varies considerably between the different studies.
Stage one Based on the ambiguous results presented above, the first step in this two-stage
study is 1) to investigate how many patients will achieve CR, EQR and ICR on PET/CT performed
three months after treatment and 2) to identify a group of EQR patients on imaging with low
risk of pathologically viable tumor (<5%).
In terms of statistical power assessment, a sample size of 160 achieves 80% power to detect a
difference (P1-P0) of 0.0550 using a one-sided exact test with a target significance level of
< 0.0500 (The actual significance level achieved by this test is 0.0305). These results
assume that the population proportion under the null hypothesis (P0) is 0.0500.
In other words, a sample of 160 patients is required to determine that the patients in that
group has less than 10.5% risk of viable tumor cells assuming the underlying true risk is 5%.
Assuming 20% attrition or dropout, we should design for 200 patients undergoing NECK
dissection. With 200-300 patients included yearly and 20-50% with EQR or ICR based on the
literature, we expect 40-100 patients will have a NECK dissection performed yearly. Based on
this assumption we expect to complete the first stage within two to three years.
This is a realistic level for training a risk model in the first stage of the study. However,
given that the model will be data generated in this first stage, there is a need for a
confirmatory stage where the treatment is unchanged, but the risk model is fixed for
validation.
The included variables will include patient information such as smoking history and age and
clinical examination including ultrasound and clinical assessment of remission at T- and N-
site (complete remission or incomplete remission), p16 status, UICC stage, subsite and PET
results (CR, EQR and IR). Please see below subheading "Respect for the subjects' physical and
mental integrity and privacy".
Annual interim analyses During both stage one and stage two an annual interim analysis will
be conducted and presented for the steering committee.
Stage two In the confirmatory stage we will proceed with a corresponding sample and sample
size as in stage one for model building and validate the model for predicting a low risk
(<5%) of pathological viable tumor cells of stage one. The combined dataset of stage one and
stage two will be used to determine the diagnostic properties of imaging (positive predictive
value and negative predictive value) using best expert judgement.
Further stages Further stages will be considered adapted to the findings from stage one and
two and the most important clinical questions remaining and will be conducted as shared
decision making with the patients based on the predictive values established from stage one
and two. The future stages will aid in avoiding unnecessary operations in patients with low
risk and avoid delaying salvage treatment with extra control scans in patients with high
risk. Separate protocols for further stages will be sent to the scientific ethics committee
for approval and will not be initiated before approval.
Steering committee A steering committee will be established to assess the annual interim
analyses. Beside the already involved investigators, we propose one person from each of the
participating institutions and departments.
Inclusion criteria for the project patients
- Informed consent
- Age above 18
- Completed curative treatment for HNSCC of the oral cavity, nasopharynx, oropharynx,
hypopharynx or larynx Exclusion criteria
- Patient refusal
- Patients with clinical N0 neck
- Patients who had neck dissections prior to radiotherapy
- Patients who are clinical inoperable for any reason
Investigators Capitol Region Department of Otorhinolaryngology, Head & Neck Surgery and
Audiology, Rigshospitalet Signe B Gram, Jacob H Rasmussen, Irene Wessel and Christian von
Buchwald. Department of Oncology, Section of Radiotherapy, Rigshospitalet Ivan R Vogelius and
Jeppe Friborg Department of Oncology, Herlev Hospital Elo Verner Andersen Department of
Clinical Physiology and Nuclear Medicine, Rigshospitalet Barbara M Fischer and Danijela
Dejanovic Department of Clinical Physiology and Nuclear Medicine, Herlev Charlotte Birk
Christensen Department of Pathology, Rigshospitalet Giedrius Lelkaitis Region Zealand
Department of Otorhinolaryngology, Head & Neck Surgery, Køge Hospital Gitte Hvilsom
Department of Oncology, Næstved Hospital Mohammad Farhadi Department of Clinical Physiology
and Nuclear Medicine, Køge Hospital Oriol Puig Calvo Dissemination of results The results
whether positive, negative or inconclusive will be published in international peer-reviewed
journals and submitted to national and international conferences.
