Explore and assess the utility of the routine 2-year post-treatment FDG PET/CT scan on head and neck squamous cell carcinoma patients

Introduction

Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive malignancies, arising from the mucosal epithelium in the upper aerodigestive tract (1). HNSCCs have been traditionally associated with exposure to tobacco and excessive alcohol consumption (2,3). Recent studies have shown that HNSCCs that arise in the oropharynx are linked to prior infection with oncogenic strains of human papillomavirus (HPV), particularly HPV-16 and HPV-18 (3,4). In fact, there is a growing proportion of HNSCC driven by HPV, estimated to contribute to 70% of oropharyngeal cancers, most prevalent in younger (50–69 years old) age cohort (5,6). In 2018, HNSCC was the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths; the incidence of HNSCC is anticipated to rise 30% by 2030 (7). The current preventative strategies of HNSCCs involve primary prevention of reducing tobacco, alcohol, and areca nut usage, as well as prophylactic HPV vaccination. However, oncogenic strains of HPV have high prevalence (approximately 4% in the US) across adult age groups, peaking in 50–60 age group, which is also the age group for the most diagnosis of HPV+ HNSCC (5,6). It may take decades for HPV vaccination to have an effect in reducing HNSCC occurrence on a population level, as of now, we must focus on effective secondary prevention strategies to reduce disease burden of HNSCC. Currently, effective clinical screening had proven to be difficult, with up to 40% of patients having regional nodal involvement and disease classified as stage IVA or B at initial presentation (8,9). Even after curative treatments, the locoregional recurrence rate for HPV+ HNSCC and HPV− HNSCC still remains high at 9% and 26% respectively (10). Cancer recurrence typically occurs within the first three years post-treatment, with most patients unaware of the relapse due to the lack of new symptoms (11,12). The consensus among different guidelines recommends post-therapeutic surveillance for HNSCC patients for up to 5 years (11). Nonetheless, patients with recurrent HNSCC generally have a poor prognosis, with median overall survival under 12 months (13). In recent years, novel targeted therapies, such as nivolumab have shown effectiveness at improving prognosis in recurrent/platinum-refractory HNSCCs. HPV+ HNSCCs also have a wide variety of target regimens without surgery, and numerous clinical trials are under evaluation (8,14-18). These therapies could potentially change management planning and improve prognosis of recurrent HNSCCs, especially HPV+ HNSCCs.

The use of [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the diagnosis/treatment of HNSCC is invaluable; it is the mainstay investigation for staging HNSCC and emerging surveillance tool for residual and recurrent disease (19). FDG PET/CT has improved the post-treatment detection of residual or recurrent disease. FDG PET/CT can detect post-treatment tissue changes from recurrences that are undetectable from physician examinations, or conventional imaging such as CT or magnetic resonance imaging (MRI) (20,21). In asymptomatic patients with HNSCC, post-treatment FDG PET/CT have higher sensitivity and specificity than CT and MRI, which are often inconclusive in differentiating tumor recurrences due to post-chemoradiotherapy inflammation and fibrosis (22).

In a meta-analysis of diagnostic accuracy of follow-up FDG PET/CT in patients with head and neck cancer, 23 studies constituting a total of 2,247 FDG PET/CT studies at least four months after treatment had a pooled sensitivity and specificity of 0.92 [95% confidence interval (CI): 0.90–0.94], and 0.87 (95% CI: 0.82–0.91), respectively (23). Another meta-analysis shows FDG PET/CT have superior specificity in comparison to FDG PET alone, with further improvement in specificity if the scan is taken after 12 weeks posttreatment (24). The PETNECK study published in 2016 provided strong evidence for routine usage of FDG PET/CT as surveillance for early recurrences or incomplete chemoradiotherapy response, sparing patients from the adverse effects and cost of unnecessary neck dissections (25,26). A study consisting of 388 HNSCC patients shows that 95% of disease recurrence occurred within the first 24 months, and 100% within the first 48 months (27), suggesting post-treatment follow up should be continued for the first 4 years. A study on using PET for surveillance of asymptomatic recurrence of cervical cancer, another HPV-related oncology concluded that earlier recurrence detection can potentially enable more salvage therapy, and warrants the continuation of such surveillance (28).

Several cost-effective analyses have indicated that PET/CT guided management for HNSCC is cost-effective in the long-term (29,30). A recent study also indicated that a routine 6-month post treatment surveillance PET/CT for HPV+ HNSCC is cost-effective, despite the lower recurrence rate of HPV+ HNSCC and a slightly reduce sensitivity and specificity in comparison to HPV− HNSCC (30,31). There is currently no study on the cost-effectiveness of long-term PET/CT surveillance for HNSCC, but some studies have shown FDG PET/CT conducted at 3-, 12-, and 24-month post-treatment periods have increasing detection accuracy and fewer equivocal scans (21,24).

FDG PET/CT’s utility goes beyond an investigative tool for local recurrences. In a study with 293 head and neck cancer patients, 103 patients had at least one finding unrelated to their cancer, approximately 35% of incidental findings were concerning for malignancy, with 25.5% of these concerning cases being confirmed malignancies (32). Despite the additional cost and emotional stress, the consensus is that the incidental findings of FDG PET/CT should be properly investigated and treated (33).

There is numerous well-established evidence of FDG PET/CT being an accurate surveillance tool for HNSCC recurrence, yet there have been no conclusive results suggesting FDG PET/CT surveillance improves the prognosis of HNSCC patients. This may be due to a lack of prospective studies with a large HNSCC population. However, it is safe to assume with the advent of new therapies for relapsed HNSCC, especially HPV+ HNSCC, including immunotherapy, molecular targeted agents, and improved surgical/radiotherapy techniques for isolated recurrences, early detections with effective secondary prevention strategies in asymptomatic recurrences would undoubtedly offer patients more treatment benefits and potentially better survival outcomes (15,16).

This study therefore aimed to assess the utility of the routine 2-year post-treatment FDG PET/CT scan on the detection of recurrences and incidental findings for HNSCC patients. We present this article in accordance with the STROBE reporting checklist (available at https://www.theajo.com/article/view/10.21037/ajo-23-11/rc).

Methods

HNSCC patients who underwent treatment with curative intent and had FDG PET/CT imaging between October 2010 to December 2021 at Royal North Shore Hospital (RNSH) or North Shore Private Hospital were reviewed retrospectively for study eligibility. Inclusion criteria were previously untreated HNSCC, 3-month and 2-year post-treatment FDG PET/CT imaging, and scheduled consultation and physical examination reports from the RNSH Head and Neck Cancer clinic. Patients without confirmed HNSCC recurrence, no physical or radiological suspicion of recurrence/new malignancy during routine clinic follow ups prior to 2-year surveillance FDG PET/CT, and patients with only retrospective recall of symptoms post 2-year PET/CT, without prior expression of concerns at routine follow up clinics. Patients with initial distant metastasis or who received palliative treatment as therapy were excluded from the study. A total of 154 consecutive patients were included in the final analyses. Patients were characterized based on demographics including age, sex, primary tumour site, HPV status for the oropharyngeal squamous cell carcinoma (SCC) subgroup, and tumour tumor, node, metastasis (TNM) staging based on the American Joint Committee on Cancer (AJCC) staging manual 8^th edition (34). All 2-year FDG PET/CT interpretations were categorized into positive, negative, or equivocal. A positive result was determined when high malignancy suspicion was recorded; an equivocal result was determined when further investigation needs to be done to rule out malignancy; a negative result was determined when no evidence of local, regional, or distant metastasis was found. Two-year FDG PET/CT interpretations were confirmed against histopathologic verification or subsequent imaging. In patients with negative FDG PET/CT findings, routine or follow-up investigations of up to 5 years were documented for any post-2-year FDG PET/CT recurrence.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by North Sydney Local Health district Human Research Ethics Committee and determined to meet the requirements of the National Statement on Ethical Conduct in Human Research [2007] (project number: 2021/ETH11301). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Statistical analysis

Each FDG PET/CT scan was identified as a true positive, true negative, false positive, or false negative. Combining data from all FDG PET/CT was used to calculate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. A 95% CI for sensitivity, specificity, and accuracy was calculated using the Clopper-Pearson exact method, 95% CI for PPV and NPV was calculated by the Transformed logit method. The median time elapsed for all 2-year FDG PET/CT scans after treatment was calculated. For patients with recurrence post-2-year PET/CT, the median time of recurrence detection post 2-year FDG PET/CT was calculated.

Results

Demographic data

The final analysis included 154 patients, with a male-to-female ratio of over 4:1 (126:28), and a median age of 60 years. The demographic data is outlined in Table 1. The oropharynx was the most common primary site of SCC (53%), with 61 out of 82 patients having P16 result positive tumours (74%). Subsequent primary sites in order of commonality are lips/oral cavity (18%), unknown (8%), nasopharynx (7%), larynx (6%), salivary glands (4%), nasal cavity/paranasal sinuses (3%) and hypopharynx (1%). TNM staging showed that 36% of the patients had advanced-stage disease at the onset of diagnosis (stage III =18%, stage IVa/b =18%).

Two-year post-treatment surveillance PET/CT characteristics

The median time for the 2-year FDG PET/CT performed was at 24-month post-treatment, with the earliest at 20 months, and the latest at 45 months. Results are outlined in Table 2. Among the 154 2-year FDG PET/CT, 129 (84%) have been reported as negative, 7 (5%) reported as positive, and 18 (12%) as equivocal readings. All seven positive PET/CT have been confirmed by gold-standard histopathology or imaging investigations as true positives. There was no negative PET/CT that have been overturned as false negatives. Three (17%) of the 18 equivocal PET/CT have been confirmed positive by further investigations. In total, 10 (6%) out of 154 PET/CT have confirmed recurrences or new primary malignancy, the most common type is distant metastasis (n=6), followed by regional recurrence (n=2), local recurrence (n=1) and new primary (n=1). Five out of 6 (83%) distant metastases are in the lung, and 1 (17%) in the bone.

Years 2–5 follow up results

Further analysis of the negative 2-year PET/CT determined 92 out of 129 patients have completed the 5-year post-treatment follow-up period. Among these 92 patients, four (4%) have developed recurrence post-2-year PET/CT. The median time for the recurrence is 21 months post 2-year PET/CT, with the earliest recurrence at 13-month post-2-year PET/CT, and the latest 48-month post-2-year PET/CT. The types of recurrences detected were regional (n=2), local (n=1), and unknown (n=1) recurrence that could be a new primary or distant metastasis of previously treated HNSCC. Details are presented in Table 3.

PET/CT diagnostic performance

In this study, the 2-year FDG PET/CT have a sensitivity, specificity, PPV, NPV, and accuracy all at 100% (95% CI: 59.04–100%, 97.18–100%, 97.32–100% for sensitivity, specificity, and accuracy, respectively). The 95% CI could not be calculated for PPV and NPV due to the logit transformation method requiring none 0 or 1 PPV and NPV. Details are presented in Table 4.

Discussion

The usage of FDG PET/CT in assessing treatment response and detecting early recurrence of HNSCC is highly effective (23,24), and the 3-month post-treatment FDG PET/CT scan is now a standard protocol in many institutions (11). However, there remains uncertainty about the utility of long-term FDG PET/CT surveillance in HNSCC patients.

This study is the largest study to date that examines the utility of a routine surveillance FDG PET/CT at the 2-year post-treatment timeframe for asymptomatic HNSCC patients. We have put a heavy emphasis on the asymptomatic aspect in our study cohort selection to mimic the real-world effect of a surveillance test. Overall, our study cohort characteristics in terms of sex, age, and primary tumour site are highly congruent with the general epidemiology characteristics of HNSCC worldwide (1,9). In our study cohort, 61 patients had HPV-positive oropharyngeal cancer, which represented 74% of total oropharyngeal cancer (n=82), or 40% of all HNSCC. The high occurrence of HPV in oropharyngeal cancer is consistent with previous (3,6).

We have used the AJCC 8^th edition for TNM staging of HNSCC patients (34), the main difference from the previous edition is the overall downgrade in clinical staging of HPV-positive oropharyngeal cancers. As a result, our cohort had a significantly smaller number of advanced onset HNSCC at 36% (stage III =18%, stage IVa/b =18%), in comparison to many previous studies using the AJCC 7^th edition TNM staging guide, quoting up to 40% of HNSCC having stage IVa/b at onset, and up to 75% advanced stage HNSCC at the onset (9,21). Some studies have suggested an increased rate of recurrence for advanced-stage HNSCC, especially the oral cavity subsite, and a decreased recurrence rate for HPV+ oropharyngeal SCC, but this is likely limited to the first-year post-treatment (10,35,36). Our study did not find any significant association between primary disease site, initial stage, or HPV status in relation to recurrence rate.

The 2-year FDG PET/CT detected a total of ten positive recurrences or new malignancies in a cohort of 154 patients. The 6% recurrence rate is similar to a previous study which had 4% (3 of 77) recurrence at 24 months in the clinically occult patient (21). Among the 10 positive recurrences, seven had FDG PET/CT readings as positive, while the remaining three positive recurrences were part of the 18 equivocal readings that underwent further investigations. All 129 (84%) negative readings were true negatives.

The diagnostic performance of the 2-year FDG PET/CT has achieved 100% in sensitivity, specificity, PPV, NPV, and accuracy. This overwhelming diagnostic accuracy came with no surprise to us, as many previous studies have achieved similar statistics, and concluded the increase in diagnostic accuracy of FDG PET/CT in HNSCC as post-treatment time progresses (21,24,37). The 2-year FDG PET/CT has relatively low equivocal readings at 12% (18/154) compared to 3- or 6-month post-treatment PET/CT (24).

Most of the recurrences detected at the 2-year FDG PET/CT are distant metastasis (N=6), with five metastases to the lung, and one to the bone. This pattern of recurrences and metastasis have also been documented in previous studies (21,38,39). One study suggested that HPV+ HNSCC have increased chance of lung metastasis in comparison to HPV− HNSCC (40), however, in our study, we did not find such pattern. Only three (2%) locoregional recurrences were detected by 2-year PET/CT, which highlight the effectiveness of the 3- and 6-month post-treatment PET/CT monitoring regime (41,42).

To assess the recurrence rate at the 2–5-year period post-treatment, four patients (4%) had asymptomatic recurrence with a median time of 21 months (range, 13 to 48 months) after the 2-year FDG PET/CT. Three of the four detected recurrences are locoregional. The rate of recurrence post 24-month is lower (4%) in comparison to the recurrence rate at the 24-month period (6%).

Patients with early detection of asymptomatic locoregional recurrences can be offered salvage treatment with curative intent, potentially improving survival outcomes in these patients. The ten patients with confirmed recurrence or new malignancy by the 2-year FDG PET/CT underwent various treatments. Previous studies have suggested beneficial survival outcomes for locoregional recurrences that are salvaged early (43,44), and a late lapse (>10 months) of recurrence was associated with better survival than an early lapse of recurrence (45). Contradicting evidence has also been documented. In a study by Ho et al. in 2013, there were no survival benefits of PET/CT detected locoregional recurrences or distant metastasis in comparison to clinically detected recurrences (21). We believe that the lack of difference in survival benefits could be explained by: a short time lag between asymptomatic patients detected by PET/CT before showing symptoms, such that the short time frame difference between the asymptomatic and control group cannot result in changes in disease progression or treatment efficacy; and/or lack of highly effective treatment options that are sensitive to disease progression at the time of study published. Nonetheless, it is optimistic that emerging treatment options would be effective enough to utilize the small timeframe gained by asymptomatic recurrence detection and improve patient survival outcomes (14,16).

Earlier detection of metastatic disease has the potential to offer patients advantage in treatment options. Among the six distant metastases detect by the surveillance PET/CT, one lung metastasis patient was enrolled in Checkmate 651 clinical trial targeting metastasized HNSCC. Although the clinical trial concluded with not meeting the overall survival target, it does show that nivolumab and ipilimumab treatment offers better safety profile for patients (46). This patient is now clinically stable, with almost 5 years off treatment. Another patient had lung and bone metastasis detected during the routine surveillance PET/CT and had two doses of nivolumab immunotherapy in 2019 and 2023. He is currently stable without disease progression. We believe that early asymptomatic detection had potentially offered these patients the opportunity for treatment, and improvement in the quality of their lives.

The limitations of this study include its retrospective design and a lack of salvage outcome analysis for recurrences. The focus of our study is the utility of the 2-year post-treatment FDG PET/CT in detecting asymptomatic recurrence, thus, we have limited our cohort to only patients with no prior recurrences or suspicion of recurrences. Under such conditions, we could not find a sufficient sample size to create a control group (patients with clinically detected recurrence at 2-year post-treatment, previously asymptomatic) for an analysis with sufficient power. Also, a large portion of our cohort was recently investigated, and we believe that insufficient time has elapsed for a Kaplan-Meier estimate. Therefore, it is difficult to evaluate the true benefits of 2-year post-treatment FDG PET/CT as a routine surveillance tool in terms of overall patient survival.

The cost effectiveness of this routine surveillance is also an important question to address. A study in the US has concluded that 6 monthly surveillance PET/CT for HPV+ HNSCC is cost-effective, as long as PET/CT cost remains lower than $1,678 USD. At 24-month post-treatment, the recurrent rate is lower than at 6-month post-treatment, but the diagnostic accuracy significantly increases, resulting in less invasive procedures for equivocal scans (21,24,30). Moreover, PET/CT is becoming more accessible with Medicare cost of $953 AUD as of 2023. With increasing prevalence in the younger population, early detection and treatment will confer a large increase in disability-adjusted life year (DALY). PET/CT offers a decent dose of radiation that may introduce morbidity due to premature cancer. Study have shown that ¹⁸FDG PET/CT induced morbidity cancer risk for a male at 50 years [0.0008 (or 1/1,280)] and 75 years [0.0003 (or 1/2,900)], respectively (47). We believe that a 6% recurrence detection rate is significant enough to justify the continuation of PET/CT as a surveillance tool at 2-year post-treatment for HNSCC patients, to allow salvage curative or palliative treatment options to be considered and offered.

Conclusions

Routine surveillance using PET/CT at 2-year post-treatment for asymptomatic HNSCC patients is an invaluable tool. It can detect a significant number of clinically occult recurrences with excellent diagnostic accuracy, and the potential to improve survival outcomes, offer early treatment options, and decrease morbidity and mortality for patients. Larger controlled studies with cost-effective analysis are warranted to further investigate the benefits of 2-year post-treatment FDG PET/CT for asymptomatic HNSCC patients.

Acknowledgments

The authors would like to acknowledge the staff at the Head and Neck Cancer Clinic at Royal North Shore hospital for their support.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://www.theajo.com/article/view/10.21037/10.21037/ajo-23-11/rc

Data Sharing Statement: Available at https://www.theajo.com/article/view/10.21037/ajo-23-11/dss

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-23-11/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-23-11/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by North Sydney Local Health district Human Research Ethics Committee and determined to meet the requirements of the National Statement on Ethical Conduct in Human Research [2007] (project number: 2021/ETH11301). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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