FDG-PET/CT to reduce the need for sentinel lymph node biopsy in early-stage oral cancer.

In the Netherlands 3017 patients were diagnosed with head and neck squamous
cell carcinoma (HNSCC) in 2020, of whom 920 had oral squamous cell carcinoma
(OSCC). In HNSCC the detection of lymph node metastases (LNM) is highly
important because adequate treatment of the neck, i.e. neck dissection and/or
radiotherapy is available. Sentinel lymph node biopsy (SLNB) can reliably
detect occult LNM in early-stage (cT1-2N0) OSCC and is now incorporated in many
national guidelines. Management of the neck based on SLNB has some limitations.
SLNB remains an invasive surgical procedure with associated morbidity. An
eventual subsequent completed neck dissection (CND) is a second stage procedure
in 30% of patients and should proceed in a timely fashion, which may be a
logistic problem. Moreover, subsequent CND is more challenging than elective
neck dissection (END) and harbours a higher risk of complications.

Although promising results have been reported, the role of FDG-PET/CT to detect
occult LNM in HNSCC patients is unclear. Studies are difficult to compare:
different scan protocols, definitions of the N0 neck, criteria for PET
positivity, ways of reading scans, and reference standards have been used.
Routine histopathological examination of neck dissection specimens can miss
micrometastases, whereas step serial sectioning and immunohistochemistry (as
performed in SLNB) can increase the yield by as much as 15.2%. Therefore, the
most reliable reference standard, which has not been used in PET/CT studies
before, is SLNB and follow-up without treatment of the neck in case of negative
SLNB. Since PET imaging has improved considerably due to technical advances
enabling integration of PET and CT devices, improvements in detector
capabilities yielding higher image resolution, and optimization of head and
neck acquisition parameters, prospective studies are needed.

The number of SLNB procedures and second stage CND can be reduced by performing
direct neck dissection without SLNB procedures in patients in whom occult LNM
can be predicted with very high positive predictive value (PPV) by FDG-PET/CT.
By varying cut-off levels scoring criteria can be developed and optimized to
predict the presence of lymph node metastases with high PPV instead of high
sensitivity, which is usually done. When focused on high PPV the sensitivity
will probably be lower, but missed LNM will then be detected by SLNB when
performed after negative FDG-PET/CT.

In this study, we aim to investigate the possibility of FDG-PET/CT to reduce
the number of (positive) SLNB procedures in patients with early stage oral
squamous cell carcinoma and a clinically negative neck.

This study is designed as a prospective Dutch multicenter cohort study. A total
of 159 patients with early-stage OSCC (cT1-3, cN0, M0), scheduled for transoral
tumor resection and SLNB, will be included in a multicenter study to evaluate
the potential reduction of SLNB procedures using newly developed FDG-PET/CT
scoring criteria and assess the diagnostic accuracy of FDG-PET/CT for the
detection of cervical lymph node metastasis in cN0 OSCC patients with and
without use of these scoring criteria.

Patients with early-stage oral cavity carcinoma (cT1-3, cN0, M0; tumor location
will be limited to the intraoral areas of mucosal lip, buccal mucosa, lower
alveolar ridge, upper alveolar ridge, retromolar gingiva, retromolar trigone,
floor-of-the-mouth, hard palate, and the mobile portion of the oral tongue)
scheduled for transoral tumor resection with SLNB will be asked to participate
in the study.

After informed consent is obtained each included patient will undergo
FDG-PET/CT and SLNB within a maximum of 3 weeks. It is likely that the majority
of the cases, the SLNB and FDG-PET/CT can be performed within a one-week
timeframe. Efforts will be made to achieve this timeframe.

The PET/CT will be acquired using dedicated EANM Research Ltd. (EARL2)
accredited PET/CT systems. Patient preparation, scanner calibration, image
acquisition, and reconstruction will be performed according to EANM standards.
After a fasting period of at least 6 hours, patients receive an intravenous
injection of FDG. Approximately 60 min after the administration of the tracer a
PET-low dose CT of the head and neck and chest (arms down) are acquired. After
the PET-low dose CT a contrast-enhanced CT of the head and neck will be
performed. When the patient has had a previous allergic reaction after
administration of contrast fluid, only a PET-low dose CT of the head and neck
and chest is sufficient for participating in this study and a contrast-enhanced
CT will not be performed. To avoid false-positive results by cytological
puncture, PET/CT has to be performed before ultrasound-guided fine needle
aspiration cytology (USgFNAC). Patients with positive USgFNAC will be excluded
for further analysis since the neck is not clinically negative. With a
prevalence of 27% and a sensitivity of 15.4%, it is expected that 4.2% of
patients will have to be excluded for this reason.

The results of the PET/CT scan will not be used to alter surgical planning.
Institutional nuclear physicians will score the PET/CT scan on potential other
tumor sites in the thorax and upper abdomen. Relevant findings will be reported
to the referring physician (e.g. infection or secondary malignancy in the
lungs). After the SLNB each PET/CT scan will be individually scored by a panel
of 5 experienced nuclear physicians without specific guidelines. The SLNB will
be blinded for the PET/CT scan. All nodes with increased FDG uptake are scored
as definitely positive, probably positive, equivocal, or probably negative. If
a discrepancy occurs, adjudication will be conducted by a third nuclear
physician. These results will be compared with the SLNB results and follow-up
as the reference standard.

On histopathological examination of the neck dissection specimen efforts should
be made to identify FDG-positive nodes and examine these similar to sentinel
nodes. If no neck dissection is performed, the neck will be observed to see of
eventually missed metastases become clinically manifest.

The SLNB procedure will be performed according to the practical and consensus
guidelines. Patients will undergo lymphoscintigraphy (including SPECT-CT) after
peritumoral injection of [99mTc]Tc-nanocolloid(-ICG), the day before surgery or
the day of surgery. Patients with a positive SLNB will undergo a neck
dissection. In case of a negative SLNB patients are observed during follow-up
according to the national guidelines.

Follow-up will be at least 12 months after SLNB to allow missed occult lymph
node metastases to become clinically detectable. It is expected that 80% of the
missed lymph node metastases (false negative) will become manifest in the first
12 months. Although not included in this research project (because of time
limitations), included patients will be asked for participation in a long-term
follow-up study, with at least two years follow-up, to assess late regional
recurrences and improve the reference standard even further.

In addition, to gain insight into the patients* preferences and experience with
diagnostic modalities, semi-structured interviews will be conducted with
patients at the University Medical Center Utrecht and until data saturation has
been reached..

Patients will undergo additional FDG-PET/CT before treatment. The SNLB
procedure is standard care for these patients in the participating centers.
Early-stage OSCC patients usually do not undergo FDG-PET/CT. FDG-PET/CT may
detect other tumor sites. Patients may benefit from this, but false-positive
findings may give a burden to the patients. This may include other additional
examinations to confirm PET/CT findings. FDG-PET/CT is considered a safe
procedure, with limited radiation exposure. Therefore, we conclude the risk is
negligible for this study according to the NFU guidelines.