PET/CT Follow up for Head and Neck Squamous Cell Carcinoma

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.