F‐18 FDG PET‐CT for response evaluation in head and neck malignancy: Experience from a tertiary level hospital in south India

Abstract Background Head and neck squamous cell carcinoma (HNSCC) accounts for 90% of head and neck cancers. There has been no established qualitative system of interpretation for therapy response assessment using PET‐CT for HNSCC. Aim To assess response evaluation of nodal status in post‐treatment PET‐CT scans in HNSCC using a 5‐point Likert scale (Deauville score [DS]). Methods and Results Retro‐prospective analysis was performed of the nodal status of pre and post‐RT PET‐CT in patients diagnosed with HNSCC (n = 43) from May 2013 to March 2018. All eligible patients underwent a pre‐RT PET‐CT scan before the start of RT. Another post‐RT PET‐CT scan was performed 12 weeks after the completion of RT. The median time from completion of radiotherapy (RT) to post‐RT PET‐CT was 92 days; 80% of the patients had their post‐RT PET‐CT scan between 77 and 147 days after therapy. Of 43 patients (M/33, F/10, age range 18 to 80 years (median 54 years) selected for the study, good concordance was noted between DS and clinical response in these patients. The change in SUV from pre‐RT PET to post‐RT PET was analyzed using a paired t‐test. The P‐value was found to be statistically significant while comparing pre and post‐RT SUVmax levels showing that RT had significantly reduced the SUVmax levels of the nodes in DS 2‐3 groups whereas the number of patients was too small to allow a reliable calculation in DS 4‐5 groups. It was found that 36/39 patients with DS 1‐3 had no nodal recurrence showing a high NPV of 92.3%. Of the four patients with DS 4‐5, all had active disease showing PPV of 100%. Applying Fisher's exact test, the P‐value was found to be .004. Conclusion DS seems to satisfy the requirements for a simple qualitative method of interpreting PET scans and for identifying patients requiring neck dissection. Consensus regarding qualitative assessment would facilitate standardization of PET reporting in clinical practice and enable comparative multicentric studies


| INTRODUCTION
The annual incidence of head and neck squamous cell cancer (HNSCC) is about 680 000 new cases in the world, with a crude rate of 9.7 per 100 000 persons. 1 In the management of HNSCC patients, functional imaging performed with 18F-FDG PET-computed tomography (PET-CT) has several applications. 2 F-18 FDG PET-CT is endorsed by the National Comprehensive Cancer Network (NCCN) guidelines for the diagnosis of occult primary and staging. 3 PET-CT is very accurate in detecting metastases or second primary tumors elsewhere in the body. 2 Accurate delineation of target volumes is critical for intensity modulated radiation therapy (IMRT) treatments.
The role of imaging-based biomarkers has been explored, but none of them can be used routinely to improve the selection of responders before the start of or during treatment. [4][5][6][7][8] It has been well-known that PET-CT plays a significant role in the assessment of the response after chemoradiation (CRT) or radiation therapy (RT) alone. PET-CT has shown a high negative predictive value (NPV) if performed at least 8 to 16 weeks after completion of treatment. 9,10 Early identification of poor responders or nonresponders may allow modification of the treatment plan (volume and doses) and/or implementation of alternative therapeutic strategies to intensify treatment. Few data are available on at least two PET-CT scans over the whole RT course to evaluate changes in FDG uptake in the primary tumor as well as lymph node metastases. 11,12 The aim of this intensive monitoring during the treatment would also be to adjust the treatment plan according to the change in tumor volume in response to RT (adaptive RT). 13

| Aim
To assess response evaluation of nodal status in post treatment 18F-  Patients provided consent for the scans (but was under a waiver of informed consent approved for those in the retrospective series), and the study was approved by the Institutional Review Board.

| Inclusion criteria
Patients with node positive (on pre-RT PET scan) SCC of the larynx, hypopharynx and oropharynx, planned for organ preservation therapy with curative intent, and with no prior neck surgery, were included in the study. Patients were only eligible if the neck nodes demonstrated hypermetabolism on the pre-RT PET scan.

| Methods
All 43 eligible patients (33 male, 10 female; mean age ± SD, 53 ± 13 years) underwent a pre-RT PET-CT scan before the start of RT. Another post-RT PET-CT scan was performed 12 weeks after completion of RT. Patients without a pre-RT PET-CT study, without primary HNSCC, and with node negative scans were excluded. PET imaging was carried out in accordance with our standard clinical PET protocol, the patients were injected intravenously with FDG 3.7 MBq/kg body weight to a maximum dose of 370 MBq after a 4 to 6 hour fasting period. All patients were imaged with an integrated PET-CT system (Siemens Biograph True Point 6). After a 45 minutes-1-hour uptake period at rest, images were acquired for 2 minutes per bed position. At baseline and for follow-up studies, the CT scan was acquired together with the PET scan. CT scans helped in attenuation correction and anatomical localization.
All PET scans were visually evaluated by Nuclear Medicine Physicians regarding metabolic response. 14 In this study two experienced readers, without prior knowledge of the clinical outcome, re-evaluated all patients regarding metabolic neck node response. Images were assessed and SUVmax levels obtained using Multimodality workplace (Siemens Syngo 2009B, VE36 A SL10P25 sMMWP SPO4). Metabolic responses were scored according to the Deauville score. 15 Overall assessment is denoted by the overall score, which is the highest score among the scores for all the neck nodes. The Deauville scores are given in Table 1 together with the categories used in the present study.
Examples of corresponding PET images are shown in the following figures ( Figure 1A-E). If FDG uptake was seen in the neck nodes, the highest uptake was scored.

| Definition of response assessment
A complete response to RT in the neck and regional control (RC) was

| Statistical analysis
Data were summarized using the mean (SD)/Median for continuous variables based on the normality. The categorical data were expressed as number and frequency. The change in SUV from pre-RT PET to post-RT PET was analysed using paired t test. The association between the categorical data were analysed using Fisher's exact test. The log-rank test was used to compare the categorical predictors over the recurrence. A P value of <.05 was considered statistically significant. All the analysis were performed using STATA I/c 15 software.

| Follow-up
The median follow-up time from the date of completion of RT was 12 months (range 4-53 months) and two patients died within the period of the study, one of them was due to recurrent cholecystitis and the other due to disease progression. Of the 43 patients, seven were found to have disease progression during the follow-up period from the date of the scan to the last patient encounter at our institution. Of these, progression was confirmed in 5 (71.4%) patients by tissue diagnosis and 2 (38.6%) patients by imaging and clinical follow-up.
There was no disease progression in DS 1-2 groups.  Treatment response is an important factor for planning management and determining prognosis in HNSCC. It has been established that PET-CT has great potential to predict treatment response and helps in the early detection of residual or recurrent disease, which allows salvage therapy to be implemented and helps in predicting complete response, avoiding the need for unnecessary intervention. 22,23 Known limitations also include low PPVs, ascribed to inflammation and post-treatment effects, such as edema, fibrosis, asymmetry, and anatomic distortion. The high NPVs observed in these studies indicate that a negative post-treatment scan is suggestive of absence of active disease, thereby influencing treatment planning. 24 There is so far a need for consensus on qualitative assessment and reporting of PET scan results. There has been no established interpretation on focal uptake was assessed in relation to uptake in adjacent tissue and the liver. 29 There were three different categories: "positive" (for residual tumor), "negative" and "equivocal." NPV was found to be as high as 97.1% in the long-term follow-up even though all recurrences, irrespective of when they occurred, were included in the "false-negative" group. 12 As mentioned above, the NPV of DS used in this study was 92.3%. This may be due to the fact that the studies were scheduled 12 weeks after RT. Higher accuracy of PET scans has been noted in recent studies and meta-analyses, where it was scheduled later than 7 weeks after treatment. 30 In this study, we chose to focus on the neck nodes with the highest FDG uptake in relation to treatment response. We did not evaluate the primary site response but it would be of interest to investigate whether using DS could minimize the number of equivocal scans here as well. 34 The study results need to be interpreted within the context of this study. HPV status was not available for all the patients in the study, especially earlier in the study period.

| CONCLUSION
Equivocal PET scan in HNSCC poses clinical dilemma. DS based on Likert scale for assessment of FDG metabolism in neck nodes following organ preservation therapy in HNSCC is a promising tool to overcome this problem. All patients with DS 4 or 5 on post-treatment PET scan can be considered as non-responders and should be routinely scheduled for neck dissection.
Deauville score seems to satisfy the requirements for a simple qualitative method of interpreting PET scans and for identifying patients requiring neck dissection. Consensus regarding qualitative assessment would facilitate standardization of PET reporting in clinical practice and enable comparative multicentric studies.

CONFLICT OF INTEREST
The authors declare there is no conflict of interest.

ETHICAL STATEMENT
Patients provided consent for the scans (but was under a waiver of informed consent approved for those in the retrospective series), and the study was approved by the Institutional Review Board.