18F FDG PET/CT and H ead a n d N e c k Ca n c e r Patient Management and Outcomes Sara Sheikhbahaei, MD, MPHa, Charles Marcus, MDa, Rathan M. Subramaniam, MD, PhD, MPHa,b,c,* KEYWORDS Head and neck squamous cell cancer Survival outcome Management change Prognosis Therapy response
KEY POINTS 18F-Fluoro-deoxyglucose (FDG)-PET/computed tomography (CT) is considered a cost-effective imaging for the diagnosis and staging of head and neck cancer (HNC) and provides more accurate staging compared with conventional work-up; accurate staging improves therapy selection. High negative predictive value (NPV) of FDG-PET/CT in therapy assessment and follow-up can be used to individualize follow-up regimens in patients who have been treated for HNC. Patients with negative post-therapy or follow-up FDG-PET/CT have significantly longer survival than those with a positive post-therapy or follow-up FDG-PET/CT. The optimal timing for performing the first follow-up FDG-PET/CT scan could be approximately 6 months post-treatment; subsequent follow-up FDG-PET/CT can be tailored based on the findings and clinical context. The use of FDG-PET/CT during follow-up adds value to clinical assessment, detects recurrence, could alter patient management for salvage or palliative treatment, and could predict survival.
HNC accounts for 650,000 cases annually worldwide.1 The incidence of HNC has remained relatively stable over the past decade, with a decrease in the average age at diagnosis mostly due to a rise in disease associated with human papillomavirus (HPV).2,3 In the United States, there is an estimate of 55,000 new HNC cases every year and approximately 12,000 deaths each year.2 Head and neck squamous cell carcinoma (HNSCC) accounts for 90% of HNCs and is known
to have high rates of recurrence.4 The 5-year locoregional and distant failure rates in patients treated with induction chemotherapy (ICT) and chemoradiotherapy (CRT) are found to be 31% and 13%, respectively.5 The overall 5-year survival rate for all stages is approximately 60%.6 The survival depends on several factors, the most important of which is disease staging.4,7,8 The 5-year survival varies widely from 91% in stage I to less than 4% in metastatic stage IV patients.8 Moreover, follow-up and surveillance of patients with treated HNSCC is especially important,
The authors have nothing to disclose. a Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, JHOC 3230, 601 North Caroline Street, Baltimore, MD 21287, USA; b Department of Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins School of Medicine, 601 North Caroline Street, Baltimore, MD, USA; c Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, 624 North Broadway, Baltimore, MD 21205, USA * Corresponding author. Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, 601 North Caroline Street/JHOC 3235, Baltimore, MD 21287. E-mail address: [email protected] PET Clin - (2015) -–http://dx.doi.org/10.1016/j.cpet.2014.12.001 1556-8598/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
pet.theclinics.com
INTRODUCTION
2
Sheikhbahaei et al because significant morbidity and mortality in these cases are associated with recurrent disease.9 This underscores the need for better imaging modalities for staging, therapy selection, assessing response, and predicting outcome. FDG-PET/CT is a valuable imaging test for management of many human solid tumors.10–14 There is a growing body of evidence that indicates FDG-PET/CT has a significant impact on HNC staging, on therapeutic assessment, and during surveillance.6,7,9,15–25 The objective of this article is to review the value of FDG-PET/CT for patient management and outcome.
VALUE OF FDG PET/CT – INITIAL TREATMENT STRATEGY Impact on Staging and Therapeutic Planning FDG-PET/CT has been rapidly adopted for diagnosis and staging purposes of HNC since 2001.7 In a cohort of 436 HNC patients from 4 integrated health systems, VanderWalde and colleagues26 report an increasing trend in performing pretreatment FDG-PET/CT scan, from 12.5% in 2005 to 34% in 2008. The use of FDG-PET/CT in detecting
occult primary tumors, tumor size and stage, locoregional nodal spread, and distant nodal/ organ metastases has been well established.7,17,27 National Comprehensive Center Network (NCCN) clinical practice guidelines in HNC (updated version 2013) recommend performing PET/ CT in initial staging of patients who seem to have stages III and IV disease of oral cavity, oropharynx, hypopharynx, and larynx.28 They also suggest using PET/CT in evaluation of distant metastasis in nasopharyngeal carcinoma and mucosal melanoma as well as evaluation of occult primary tumors, particularly in patients presenting with a neck mass (Fig. 1).28 Furthermore, treatment protocols for HNCs depend mainly on primary tumor location and staging.4,7,27 The goal of HNC therapy is either cure or palliation, depending on disease severity or progression. The mainstay of treatment has evolved gradually from surgery to radiation therapy (RT)/CRT. Recommended treatment in early or localized disease (stages I–II) of oral cavity, pharyngeal, and laryngeal cancer is surgical resection or definitive RT. Patients with locally advanced disease (stages III–IV) are typically
Fig. 1. Impact of FDG-PET/CT on staging: anterior maximum-intensity projection (MIP) (A), axial fused FDG-PET. CT (B–E) images of a 57-year-old man who underwent a staging FDG-PET/CT study for a T4N2aM1, HPV-positive, SCC of the right tongue base. The staging PET/CT study revealed metabolically active (SUVmax 17.3) right tongue base mass (red arrow, B) with additional metastatic lesions in the brain (red arrow, C) (SUVmax 10.4), lungs (SUVmax 11.2), and paraspinal soft tissue (red arrow, E) (SUVmax 9.2).
18F FDG PET/CT and Head and Neck Cancer: Patient Management and Outcomes treated with concurrent CRT. Some patients with stages III to IVB disease can be treated with ICT to shrink a primary tumor in preparation for future surgery or RT. Current standard of treatment of patients with metastasis or recurrent disease is single-agent or combination palliative chemotherapy.8,27–30 The cost of treatment constitutes a large percentage of the overall expenses of care in patients with HNC.3 Therefore, an accurate staging improves decision making and helps in avoiding unnecessary interventions.3,17,31 FDGPET/CT provides more accurate staging in HNCs compared with conventional work-up and may alter management (Fig. 2). Several studies have corroborated this functionality.7,32–36
Studies by Wang and colleagues32 and Deantonio and colleagues33 showed that FDG-PET/CT scan results in staging changes in 57% (16 of 28) and 22% (5 of 22) of patients, respectively, compared with neck CT. Similarly, Abramyuk and colleagues34 conducted a retrospective study on 102 untreated HNC patients to evaluate the effect of FDG-PET/CT on stage modification and patients’ management compared with conventional staging. Histopathology confirmation considered as reference standard. Implementation of FDGPET/CT led to a significant change in tumor (T), nodal (N), metastasis (M), and clinical staging. In T staging, inclusion of FDG-PET/CT resulted in downstaging of 36 patients and upstaging of 10
Fig. 2. Change in stage and impact on treatment planning: axial CT (A, C) and fused FDG-PET/CT (B, D) images of a 56-year-old man who was clinically diagnosed with a T1N0M0 left tonsillar SCC, who underwent a staging FDGPET/CT study. The study revealed an intensely FDG avid (SUVmax 11.3) mass in the left tonsillar fossa (red arrows, A, B) and a metabolically active (SUVmax 8.7), metastatic, left level 2 cervical lymph node (red arrows, C, D), thereby changing the stage to T1N2bM0 and changing the treatment plan from single modality therapy to combined chemoradiation.
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Sheikhbahaei et al patients compared with conventional imaging. In N staging, 27 patients were downstaged whereas 8 were upstaged. In M staging, FDG-PET/CT shifted 13 of 102 patients from M0 to M1. Overall, by using FDG-PET/CT, 9 patients were upstaged and 18 patients were downstaged. The implementation of FDG-PET/CT also resulted in treatment change—RT modification—in 14 patients. Furthermore, in a multicenter prospective study on 233 newly diagnosed HNSCC patients, Lonneux and colleagues35 showed that FDG-PET/CT scan altered the staging in 43% of patients, 30% of whom were classified to a more advanced stage and 13% were classified as having a less advanced stage. In addition, FDG-PET/CT imaging altered the therapeutic plan in 32 (13.7%) patients. In another study conducted by Ha and colleagues,36 among 36 untreated HNSCC patients, FDG-PET/CT changed the treatment plan in 11 (31%) of cases. A recent systematic review evaluates the cost and economic burden associated with HNSCC.3 Although using a combined hybrid PET/CT scan seems expensive as an initial screening test, Wissinger and colleagues3 have indicated that the resultant reduction of unnecessary additional procedures or treatments offset the cost of FDG-PET/ CT for the health service. Thus FDG-PET/CT is considered a cost-effective screening imaging for the diagnosis and staging of HNSCC. Also, a prospective cost minimization analysis study in Australia showed that assessing nodal response with incorporation of FDG-PET/CT helped avoid the need for many unnecessary neck dissections, resulting in a considerable cost reduction for health service.31 These results suggest that implementation of FDG-PET/CT before treatment allows optimization of therapeutic goals in further management. In a recent study, however, VanderWalde and colleagues26 described the stage migration phenomenon during the PET era. In this retrospective cohort, a total of 958 patients diagnosed with HNC, identified via tumor registries, were included. Patients were categorized into pre-PET era (2000–2004, n 5 522) and PET era (2005– 2008, n 5 436). Based on the results, within the PET era, FDG-PET/CT implementation was significantly associated with increased diagnosis of locally advanced disease (odds ratio [OR] 2.86). Although use of PET was significantly associated with stage-specific survival benefit in patients with locally advanced disease (2-year survival in PET vs no PET: 52.2% vs 32.1%), there was no difference in overall survival (OS) in all patients (2-year survival in PET vs no PET: 53.2% vs 55.5%). They suggest that the improved survival in patients with locally advanced disease could
be a reflection of a selection bias or stage migration. Although the retrospective nature of the study, unknown intention and timing of PET scan, and nonrepresentative study population could have confounded the results, further research needs to be performed to determine whether the use of PET scan improves the OS in all patients with HNC.
Impact on Detection of Unknown Primary Tumors Cancer of unknown primary (CUP) is defined as the presence of histologic proved metastatic disease, with no identified primary tumor at presentation after a thorough conventional workup.7,37 Several studies indicated the usefulness of FDG-PET/CT scan in detection of unknown primary tumors (Fig. 3).37–39 In a meta-analysis of 16 studies comprising a total of 302 patients, Rusthoven and colleagues37 reported an overall sensitivity of 88.3%, specificity of 74.9%, and accuracy of 78.8% for FDG-PET/CT in the detection of primary tumors in patients with cervical metastases. FDG-PET detected 24.5% of tumors that were not apparent after comprehensive diagnostic work-up. Kwee and Kwee39 in another metaanalysis estimated the tumor detection rate and pooled sensitivity and specificity of FDG-PET/CT as 34%, 84%, and 84%, respectively, considering patients with cervical and extracervical metastatic CUP. The heterogeneity in the extent of subsequent diagnostic work-up among the included studies might overestimate their result. The detection of primary tumors in patients with CUP could be a decisive criterion in further management of patients and leads to RT planning modification, target volume delineation, and reduction in treatment-associated morbidities.7 Patients with known primaries in the head and neck receive site-specific treatment, whereas patients with persistent unknown primaries are treated with panmucosal RT or empirical chemotherapy.38
Impact on Detection of Second Primary Tumors Patients with HNSCC often harbor synchronous multiple primary cancers due to smoking and drinking habits.7,40,41 The most frequent site of secondary tumors is aerodigestive tract and head and neck (Fig. 4). Distant metastasis and second primary tumors are among the leading cause of treatment failure and death in patients with HNSCC.17,41 FDG-PET/CT has been increasingly used for the detection of synchronous tumors and considered to have a good diagnostic performance. A review of 12 studies published between
18F FDG PET/CT and Head and Neck Cancer: Patient Management and Outcomes
Fig. 3. Localization of primary tumor: axial CT (A, C) and fused FDG-PET/CT (B, D) images of an 80-year-old man who presented with a neck mass. Clinical evaluation revealed asymmetric appearance of the right hemilarynx. He underwent an FDG-PET/CT study for further evaluation. The study revealed an intensely FDG avid (SUVmax 12.6) right supraglottic mass (red arrow, C, D) with metabolically active (SUVmax 11.5), metastatic cervical lymphadenopathy (red arrow, A, B).
2000 and 2011 evaluated the utility of FDG-PET/ CT in detecting distant metastasis/second primary tumors in patients with HNC at initial staging, reporting pooled sensitivity and specificity of 88% (83–93%) and 95% (94–96%) for FDG-PET/CT, respectively.40 The ability of detection of malignancies by FDGPET/CT depends on the site and type of malignancies.17 Himeno and colleagues42 discussed the limitation of FDG-PET/CT in detection of Tis and T1a esophageal cancers. Hanamoto and colleagues43 conducted a study on 347 untreated HNSCC patients to evaluate the utility of FDGPET/CT in detection of synchronous tumors at initial staging. The sensitivities of FDG-PET/CT for detection of synchronous esophageal cancers were 0% in T1a, 60% in T1b, 0% in T2, 100% in T3, and 100% in T4, respectively. Similar studies also indicated the lower diagnostic sensitivity of FDG-PET/CT in early detection of synchronus tumors of upper gatrointestinal tract, especially esophageal cancer in patients with HNSCC.42,44
Overall, FDG-PET/CT has a good sensitivity and specificity compared with MR imaging or CT alone in HNC imaging (Fig. 5).45 Studies comparing the utility of FDG-PET/CT versus other conventional anatomic imaging in the staging of HNC suggest that FDG-PET/CT is often superior in detecting small regional lymph node metastases (20 cm3), TLG (>70 g), and ring-shaped uptake pattern significantly predicted patient outcome in
terms of disease-specific survival (DSS) and DFS. Even after correction for the stage and definitive therapy, MTV and uptake pattern remained significantly associated with DSS. In a prospective study on 52 patients with HNC, Apostolova and colleagues54 revealed that pretherapeutic SUVmax, MTV, and TLG are significant predictors of disease progression and OS. They propose a novel FDG-PET/CT marker, asphericity—the spatial heterogeneity of FGD uptake, as an independent prognostic factor in HNC survival. The combination of high MTV and asphericity showed a high HR for progression-free survival (HR 22.7) and OS (HR 13.2). Furthermore, Abd El-Hafez and colleagues55 prospectively studied 126 patients with oral cavity SCC who underwent pretreatment FDG-PET/CT scan. Patients were followed-up at least 24 months after surgery. Results showed that tumor TLG and nodal SUVmax are independently associated with 2-year DSS. In addition, they proposed a 3-point prognostic scoring system based on presence of neck node, high tumor TLG, and high nodal SUVmax. Patients with score-3 showed a 32-fold increased risk of cancer death compared with those without risk factors (2-year DSS: 26% vs 97%). There is strong evidence for the potential function of pretreatment FDG-PET/CT quantitative parameters in predicting survival and prognosis of patients with HNC. It is difficult, however, to determine an optimal cutoff value for each variable to risk stratification of patients, because different definitions (cutpoints) are proposed in determining high and low volumetric parameters among the studies.
VALUE OF FDG PET/CT – SUBSEQUENT TREATMENT STRATEGY Impact on Evaluation of Treatment Response Treatment monitoring with FDG-PET/CT imaging during early follow-up allows predicting the efficacy of treatments and outcome (Fig. 8). Recently, Marcus and colleagues23 proposed new interpretation criteria for therapy response assessment of HNCs based on the result of post-therapy FDG-PET/CT scan (Hopkins criteria). Therapy response is assessed based on the intensity (compared with the internal jugular vein [IJV] and liver activity) and pattern (focal or diffuse) of FDG-PET uptake in primary tumor and neck nodes and categorized into 5 scores as follows: score 1 (complete metabolic response, FDG uptake less than IJV), score 2 (likely complete metabolic response, focal FDG uptake greater than IJV and lesser than liver), score 3 (likely postradiation inflammation, diffuse uptake greater than IJV or liver), score 4 (likely residual tumor, focal uptake greater than liver), and score 5 (residual tumor, focal and intense FDG uptake). Scores 1, 2, and 3 are
18F FDG PET/CT and Head and Neck Cancer: Patient Management and Outcomes
Fig. 8. Therapy response assessment: axial fused FDG-PET/CT (A) image of a 48-year-old man with a recent diagnosis of a T2N2bM0, HPV-positive, SCC of the left tongue base, who underwent a staging FDG-PET/CT study. The study demonstrates metabolically active (SUVmax 9.9) left tongue base mass (midline arrow, A) and hypermetabolic (SUVmax 9.4), metastatic, cervical lymphadenopathy (left arrow, A). After the study he underwent CRT. The axial fused FDG-PET/CT image (B) of the study performed 2 months after treatment completion reveals no evidence of FDG avid residual or recurrent disease, consistent with complete response to treatment.
considered negative and scores 4 and 5 are considered positive for residual tumor. This qualitative assessment scoring system was shown to have substantial inter-rater reliability (k 5 0.69–0.79) and high specificity (92.2%) and NPV (91.1%).23 Studies suggest that FDG-PET/CT findings in post-therapy assessment of HNCs are time and therapy dependent. An increase in FDG uptake occurs in recently radiated tissues, which may last 12 to 16 weeks after RT or CRT (Fig. 9).4,7,56 To ensure a balance between the disadvantages of early and late imaging, the first post-treatment
FDG-PET/CT scan to assess response to treatment is generally recommended at approximately 12 weeks post-RT. A significant number of recurrences, however, occur later. According to the 2013 NCCN clinical practice guidelines,28 after either RT/or CRT, if clinical assessment is suspicious of a persistent disease or progression, CT scan needs to be performed within 4 to 8 weeks post-treatment as a guide to salvage surgery or neck dissection. If clinical assessment were negative for suspicion of a persistent cancer, PET/CT scan is suggested to
Fig. 9. Post-treatment inflammatory changes: axial CT (A) and fused FDG-PET/CT (B) images of a 42-year-old man with history of T4N2bMo SCC of the supraglottic larynx, post-total laryngectomy and CRT. The post-treatment PET/CT study, performed 7 weeks after treatment completion, demonstrates diffuse FDG uptake (SUVmax 4.0) in the right vallecula (red arrow, A, B), consistent with postradiation changes (Hopkins score 3).
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Sheikhbahaei et al be performed at minimum of 12 weeks after treatment for follow-up, and further management relies on the result of PET/CT scan.28 This guideline may help identify those patients who can be observed safely without surgery to the neck. Diagnostic performance of post-treatment FDG-PET/CT scan in early follow-up In post-therapeutic assessment, the diagnostic accuracy of functional imaging mostly depends on the time interval between the end of treatment and imaging scan. In a meta-analysis of 51 studies comprising 2335 patients, Gupta and colleagues15 evaluated the diagnostic performance of posttreatment FDG-PET/CT scan in HNC. The impact of timing of post-treatment FDG-PET/CT was also assessed before and after 12 weeks. The pooled sensitivity (79.9% and 72.7%), specificity (87.5% and 87.6%), NPV (95.1% and 94.5%), and positive predictive value (PPV) (58.6% and 52.1%) of FDG-PET/CT were reported for the primary site and the neck nodes, respectively. Sensitivity was higher in both primary tumor (91.9% vs 73.6%, P-value 0.12) and neck nodes (90.4% vs 62.5%, P-value
KEY POINTS 18F-Fluoro-deoxyglucose (FDG)-PET/computed tomography (CT) is considered a cost-effective imaging for the diagnosis and staging of head and neck cancer (HNC) and provides more accurate staging compared with conventional work-up; accurate staging improves therapy selection. High negative predictive value (NPV) of FDG-PET/CT in therapy assessment and follow-up can be used to individualize follow-up regimens in patients who have been treated for HNC. Patients with negative post-therapy or follow-up FDG-PET/CT have significantly longer survival than those with a positive post-therapy or follow-up FDG-PET/CT. The optimal timing for performing the first follow-up FDG-PET/CT scan could be approximately 6 months post-treatment; subsequent follow-up FDG-PET/CT can be tailored based on the findings and clinical context. The use of FDG-PET/CT during follow-up adds value to clinical assessment, detects recurrence, could alter patient management for salvage or palliative treatment, and could predict survival.
HNC accounts for 650,000 cases annually worldwide.1 The incidence of HNC has remained relatively stable over the past decade, with a decrease in the average age at diagnosis mostly due to a rise in disease associated with human papillomavirus (HPV).2,3 In the United States, there is an estimate of 55,000 new HNC cases every year and approximately 12,000 deaths each year.2 Head and neck squamous cell carcinoma (HNSCC) accounts for 90% of HNCs and is known
to have high rates of recurrence.4 The 5-year locoregional and distant failure rates in patients treated with induction chemotherapy (ICT) and chemoradiotherapy (CRT) are found to be 31% and 13%, respectively.5 The overall 5-year survival rate for all stages is approximately 60%.6 The survival depends on several factors, the most important of which is disease staging.4,7,8 The 5-year survival varies widely from 91% in stage I to less than 4% in metastatic stage IV patients.8 Moreover, follow-up and surveillance of patients with treated HNSCC is especially important,
The authors have nothing to disclose. a Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, JHOC 3230, 601 North Caroline Street, Baltimore, MD 21287, USA; b Department of Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins School of Medicine, 601 North Caroline Street, Baltimore, MD, USA; c Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, 624 North Broadway, Baltimore, MD 21205, USA * Corresponding author. Russel H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University, 601 North Caroline Street/JHOC 3235, Baltimore, MD 21287. E-mail address: [email protected] PET Clin - (2015) -–http://dx.doi.org/10.1016/j.cpet.2014.12.001 1556-8598/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
pet.theclinics.com
INTRODUCTION
2
Sheikhbahaei et al because significant morbidity and mortality in these cases are associated with recurrent disease.9 This underscores the need for better imaging modalities for staging, therapy selection, assessing response, and predicting outcome. FDG-PET/CT is a valuable imaging test for management of many human solid tumors.10–14 There is a growing body of evidence that indicates FDG-PET/CT has a significant impact on HNC staging, on therapeutic assessment, and during surveillance.6,7,9,15–25 The objective of this article is to review the value of FDG-PET/CT for patient management and outcome.
VALUE OF FDG PET/CT – INITIAL TREATMENT STRATEGY Impact on Staging and Therapeutic Planning FDG-PET/CT has been rapidly adopted for diagnosis and staging purposes of HNC since 2001.7 In a cohort of 436 HNC patients from 4 integrated health systems, VanderWalde and colleagues26 report an increasing trend in performing pretreatment FDG-PET/CT scan, from 12.5% in 2005 to 34% in 2008. The use of FDG-PET/CT in detecting
occult primary tumors, tumor size and stage, locoregional nodal spread, and distant nodal/ organ metastases has been well established.7,17,27 National Comprehensive Center Network (NCCN) clinical practice guidelines in HNC (updated version 2013) recommend performing PET/ CT in initial staging of patients who seem to have stages III and IV disease of oral cavity, oropharynx, hypopharynx, and larynx.28 They also suggest using PET/CT in evaluation of distant metastasis in nasopharyngeal carcinoma and mucosal melanoma as well as evaluation of occult primary tumors, particularly in patients presenting with a neck mass (Fig. 1).28 Furthermore, treatment protocols for HNCs depend mainly on primary tumor location and staging.4,7,27 The goal of HNC therapy is either cure or palliation, depending on disease severity or progression. The mainstay of treatment has evolved gradually from surgery to radiation therapy (RT)/CRT. Recommended treatment in early or localized disease (stages I–II) of oral cavity, pharyngeal, and laryngeal cancer is surgical resection or definitive RT. Patients with locally advanced disease (stages III–IV) are typically
Fig. 1. Impact of FDG-PET/CT on staging: anterior maximum-intensity projection (MIP) (A), axial fused FDG-PET. CT (B–E) images of a 57-year-old man who underwent a staging FDG-PET/CT study for a T4N2aM1, HPV-positive, SCC of the right tongue base. The staging PET/CT study revealed metabolically active (SUVmax 17.3) right tongue base mass (red arrow, B) with additional metastatic lesions in the brain (red arrow, C) (SUVmax 10.4), lungs (SUVmax 11.2), and paraspinal soft tissue (red arrow, E) (SUVmax 9.2).
18F FDG PET/CT and Head and Neck Cancer: Patient Management and Outcomes treated with concurrent CRT. Some patients with stages III to IVB disease can be treated with ICT to shrink a primary tumor in preparation for future surgery or RT. Current standard of treatment of patients with metastasis or recurrent disease is single-agent or combination palliative chemotherapy.8,27–30 The cost of treatment constitutes a large percentage of the overall expenses of care in patients with HNC.3 Therefore, an accurate staging improves decision making and helps in avoiding unnecessary interventions.3,17,31 FDGPET/CT provides more accurate staging in HNCs compared with conventional work-up and may alter management (Fig. 2). Several studies have corroborated this functionality.7,32–36
Studies by Wang and colleagues32 and Deantonio and colleagues33 showed that FDG-PET/CT scan results in staging changes in 57% (16 of 28) and 22% (5 of 22) of patients, respectively, compared with neck CT. Similarly, Abramyuk and colleagues34 conducted a retrospective study on 102 untreated HNC patients to evaluate the effect of FDG-PET/CT on stage modification and patients’ management compared with conventional staging. Histopathology confirmation considered as reference standard. Implementation of FDGPET/CT led to a significant change in tumor (T), nodal (N), metastasis (M), and clinical staging. In T staging, inclusion of FDG-PET/CT resulted in downstaging of 36 patients and upstaging of 10
Fig. 2. Change in stage and impact on treatment planning: axial CT (A, C) and fused FDG-PET/CT (B, D) images of a 56-year-old man who was clinically diagnosed with a T1N0M0 left tonsillar SCC, who underwent a staging FDGPET/CT study. The study revealed an intensely FDG avid (SUVmax 11.3) mass in the left tonsillar fossa (red arrows, A, B) and a metabolically active (SUVmax 8.7), metastatic, left level 2 cervical lymph node (red arrows, C, D), thereby changing the stage to T1N2bM0 and changing the treatment plan from single modality therapy to combined chemoradiation.
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Sheikhbahaei et al patients compared with conventional imaging. In N staging, 27 patients were downstaged whereas 8 were upstaged. In M staging, FDG-PET/CT shifted 13 of 102 patients from M0 to M1. Overall, by using FDG-PET/CT, 9 patients were upstaged and 18 patients were downstaged. The implementation of FDG-PET/CT also resulted in treatment change—RT modification—in 14 patients. Furthermore, in a multicenter prospective study on 233 newly diagnosed HNSCC patients, Lonneux and colleagues35 showed that FDG-PET/CT scan altered the staging in 43% of patients, 30% of whom were classified to a more advanced stage and 13% were classified as having a less advanced stage. In addition, FDG-PET/CT imaging altered the therapeutic plan in 32 (13.7%) patients. In another study conducted by Ha and colleagues,36 among 36 untreated HNSCC patients, FDG-PET/CT changed the treatment plan in 11 (31%) of cases. A recent systematic review evaluates the cost and economic burden associated with HNSCC.3 Although using a combined hybrid PET/CT scan seems expensive as an initial screening test, Wissinger and colleagues3 have indicated that the resultant reduction of unnecessary additional procedures or treatments offset the cost of FDG-PET/ CT for the health service. Thus FDG-PET/CT is considered a cost-effective screening imaging for the diagnosis and staging of HNSCC. Also, a prospective cost minimization analysis study in Australia showed that assessing nodal response with incorporation of FDG-PET/CT helped avoid the need for many unnecessary neck dissections, resulting in a considerable cost reduction for health service.31 These results suggest that implementation of FDG-PET/CT before treatment allows optimization of therapeutic goals in further management. In a recent study, however, VanderWalde and colleagues26 described the stage migration phenomenon during the PET era. In this retrospective cohort, a total of 958 patients diagnosed with HNC, identified via tumor registries, were included. Patients were categorized into pre-PET era (2000–2004, n 5 522) and PET era (2005– 2008, n 5 436). Based on the results, within the PET era, FDG-PET/CT implementation was significantly associated with increased diagnosis of locally advanced disease (odds ratio [OR] 2.86). Although use of PET was significantly associated with stage-specific survival benefit in patients with locally advanced disease (2-year survival in PET vs no PET: 52.2% vs 32.1%), there was no difference in overall survival (OS) in all patients (2-year survival in PET vs no PET: 53.2% vs 55.5%). They suggest that the improved survival in patients with locally advanced disease could
be a reflection of a selection bias or stage migration. Although the retrospective nature of the study, unknown intention and timing of PET scan, and nonrepresentative study population could have confounded the results, further research needs to be performed to determine whether the use of PET scan improves the OS in all patients with HNC.
Impact on Detection of Unknown Primary Tumors Cancer of unknown primary (CUP) is defined as the presence of histologic proved metastatic disease, with no identified primary tumor at presentation after a thorough conventional workup.7,37 Several studies indicated the usefulness of FDG-PET/CT scan in detection of unknown primary tumors (Fig. 3).37–39 In a meta-analysis of 16 studies comprising a total of 302 patients, Rusthoven and colleagues37 reported an overall sensitivity of 88.3%, specificity of 74.9%, and accuracy of 78.8% for FDG-PET/CT in the detection of primary tumors in patients with cervical metastases. FDG-PET detected 24.5% of tumors that were not apparent after comprehensive diagnostic work-up. Kwee and Kwee39 in another metaanalysis estimated the tumor detection rate and pooled sensitivity and specificity of FDG-PET/CT as 34%, 84%, and 84%, respectively, considering patients with cervical and extracervical metastatic CUP. The heterogeneity in the extent of subsequent diagnostic work-up among the included studies might overestimate their result. The detection of primary tumors in patients with CUP could be a decisive criterion in further management of patients and leads to RT planning modification, target volume delineation, and reduction in treatment-associated morbidities.7 Patients with known primaries in the head and neck receive site-specific treatment, whereas patients with persistent unknown primaries are treated with panmucosal RT or empirical chemotherapy.38
Impact on Detection of Second Primary Tumors Patients with HNSCC often harbor synchronous multiple primary cancers due to smoking and drinking habits.7,40,41 The most frequent site of secondary tumors is aerodigestive tract and head and neck (Fig. 4). Distant metastasis and second primary tumors are among the leading cause of treatment failure and death in patients with HNSCC.17,41 FDG-PET/CT has been increasingly used for the detection of synchronous tumors and considered to have a good diagnostic performance. A review of 12 studies published between
18F FDG PET/CT and Head and Neck Cancer: Patient Management and Outcomes
Fig. 3. Localization of primary tumor: axial CT (A, C) and fused FDG-PET/CT (B, D) images of an 80-year-old man who presented with a neck mass. Clinical evaluation revealed asymmetric appearance of the right hemilarynx. He underwent an FDG-PET/CT study for further evaluation. The study revealed an intensely FDG avid (SUVmax 12.6) right supraglottic mass (red arrow, C, D) with metabolically active (SUVmax 11.5), metastatic cervical lymphadenopathy (red arrow, A, B).
2000 and 2011 evaluated the utility of FDG-PET/ CT in detecting distant metastasis/second primary tumors in patients with HNC at initial staging, reporting pooled sensitivity and specificity of 88% (83–93%) and 95% (94–96%) for FDG-PET/CT, respectively.40 The ability of detection of malignancies by FDGPET/CT depends on the site and type of malignancies.17 Himeno and colleagues42 discussed the limitation of FDG-PET/CT in detection of Tis and T1a esophageal cancers. Hanamoto and colleagues43 conducted a study on 347 untreated HNSCC patients to evaluate the utility of FDGPET/CT in detection of synchronous tumors at initial staging. The sensitivities of FDG-PET/CT for detection of synchronous esophageal cancers were 0% in T1a, 60% in T1b, 0% in T2, 100% in T3, and 100% in T4, respectively. Similar studies also indicated the lower diagnostic sensitivity of FDG-PET/CT in early detection of synchronus tumors of upper gatrointestinal tract, especially esophageal cancer in patients with HNSCC.42,44
Overall, FDG-PET/CT has a good sensitivity and specificity compared with MR imaging or CT alone in HNC imaging (Fig. 5).45 Studies comparing the utility of FDG-PET/CT versus other conventional anatomic imaging in the staging of HNC suggest that FDG-PET/CT is often superior in detecting small regional lymph node metastases (20 cm3), TLG (>70 g), and ring-shaped uptake pattern significantly predicted patient outcome in
terms of disease-specific survival (DSS) and DFS. Even after correction for the stage and definitive therapy, MTV and uptake pattern remained significantly associated with DSS. In a prospective study on 52 patients with HNC, Apostolova and colleagues54 revealed that pretherapeutic SUVmax, MTV, and TLG are significant predictors of disease progression and OS. They propose a novel FDG-PET/CT marker, asphericity—the spatial heterogeneity of FGD uptake, as an independent prognostic factor in HNC survival. The combination of high MTV and asphericity showed a high HR for progression-free survival (HR 22.7) and OS (HR 13.2). Furthermore, Abd El-Hafez and colleagues55 prospectively studied 126 patients with oral cavity SCC who underwent pretreatment FDG-PET/CT scan. Patients were followed-up at least 24 months after surgery. Results showed that tumor TLG and nodal SUVmax are independently associated with 2-year DSS. In addition, they proposed a 3-point prognostic scoring system based on presence of neck node, high tumor TLG, and high nodal SUVmax. Patients with score-3 showed a 32-fold increased risk of cancer death compared with those without risk factors (2-year DSS: 26% vs 97%). There is strong evidence for the potential function of pretreatment FDG-PET/CT quantitative parameters in predicting survival and prognosis of patients with HNC. It is difficult, however, to determine an optimal cutoff value for each variable to risk stratification of patients, because different definitions (cutpoints) are proposed in determining high and low volumetric parameters among the studies.
VALUE OF FDG PET/CT – SUBSEQUENT TREATMENT STRATEGY Impact on Evaluation of Treatment Response Treatment monitoring with FDG-PET/CT imaging during early follow-up allows predicting the efficacy of treatments and outcome (Fig. 8). Recently, Marcus and colleagues23 proposed new interpretation criteria for therapy response assessment of HNCs based on the result of post-therapy FDG-PET/CT scan (Hopkins criteria). Therapy response is assessed based on the intensity (compared with the internal jugular vein [IJV] and liver activity) and pattern (focal or diffuse) of FDG-PET uptake in primary tumor and neck nodes and categorized into 5 scores as follows: score 1 (complete metabolic response, FDG uptake less than IJV), score 2 (likely complete metabolic response, focal FDG uptake greater than IJV and lesser than liver), score 3 (likely postradiation inflammation, diffuse uptake greater than IJV or liver), score 4 (likely residual tumor, focal uptake greater than liver), and score 5 (residual tumor, focal and intense FDG uptake). Scores 1, 2, and 3 are
18F FDG PET/CT and Head and Neck Cancer: Patient Management and Outcomes
Fig. 8. Therapy response assessment: axial fused FDG-PET/CT (A) image of a 48-year-old man with a recent diagnosis of a T2N2bM0, HPV-positive, SCC of the left tongue base, who underwent a staging FDG-PET/CT study. The study demonstrates metabolically active (SUVmax 9.9) left tongue base mass (midline arrow, A) and hypermetabolic (SUVmax 9.4), metastatic, cervical lymphadenopathy (left arrow, A). After the study he underwent CRT. The axial fused FDG-PET/CT image (B) of the study performed 2 months after treatment completion reveals no evidence of FDG avid residual or recurrent disease, consistent with complete response to treatment.
considered negative and scores 4 and 5 are considered positive for residual tumor. This qualitative assessment scoring system was shown to have substantial inter-rater reliability (k 5 0.69–0.79) and high specificity (92.2%) and NPV (91.1%).23 Studies suggest that FDG-PET/CT findings in post-therapy assessment of HNCs are time and therapy dependent. An increase in FDG uptake occurs in recently radiated tissues, which may last 12 to 16 weeks after RT or CRT (Fig. 9).4,7,56 To ensure a balance between the disadvantages of early and late imaging, the first post-treatment
FDG-PET/CT scan to assess response to treatment is generally recommended at approximately 12 weeks post-RT. A significant number of recurrences, however, occur later. According to the 2013 NCCN clinical practice guidelines,28 after either RT/or CRT, if clinical assessment is suspicious of a persistent disease or progression, CT scan needs to be performed within 4 to 8 weeks post-treatment as a guide to salvage surgery or neck dissection. If clinical assessment were negative for suspicion of a persistent cancer, PET/CT scan is suggested to
Fig. 9. Post-treatment inflammatory changes: axial CT (A) and fused FDG-PET/CT (B) images of a 42-year-old man with history of T4N2bMo SCC of the supraglottic larynx, post-total laryngectomy and CRT. The post-treatment PET/CT study, performed 7 weeks after treatment completion, demonstrates diffuse FDG uptake (SUVmax 4.0) in the right vallecula (red arrow, A, B), consistent with postradiation changes (Hopkins score 3).
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Sheikhbahaei et al be performed at minimum of 12 weeks after treatment for follow-up, and further management relies on the result of PET/CT scan.28 This guideline may help identify those patients who can be observed safely without surgery to the neck. Diagnostic performance of post-treatment FDG-PET/CT scan in early follow-up In post-therapeutic assessment, the diagnostic accuracy of functional imaging mostly depends on the time interval between the end of treatment and imaging scan. In a meta-analysis of 51 studies comprising 2335 patients, Gupta and colleagues15 evaluated the diagnostic performance of posttreatment FDG-PET/CT scan in HNC. The impact of timing of post-treatment FDG-PET/CT was also assessed before and after 12 weeks. The pooled sensitivity (79.9% and 72.7%), specificity (87.5% and 87.6%), NPV (95.1% and 94.5%), and positive predictive value (PPV) (58.6% and 52.1%) of FDG-PET/CT were reported for the primary site and the neck nodes, respectively. Sensitivity was higher in both primary tumor (91.9% vs 73.6%, P-value 0.12) and neck nodes (90.4% vs 62.5%, P-value
