Head and neck cancers include cancer of the oral cavity, pharynx, larynx, sinonasal cavity, and salivary glands. More than 90% of all head and neck cancers are squamous cell carcinoma (HNSCC) [1
]. It is the sixth most common cancer worldwide and affects more than 50,000 people in a year in the United States [2
]. Patients with unresectable advanced disease have the worst prognosis; their 5-year survival rate is approximately 40–55% [5
]. Surgery, radiotherapy, chemotherapy, or a combination of these three are accepted standard treatment options for patients with HNSCC [6
]. Selection of the most appropriate treatment approach varies and depends on disease stage and primary site of cancer [8
]. Single-treatment modalities can be used for early-stage disease, but advanced-staged disease typically requires combination therapy [9
]. Posttreatment changes such as inflammation and fibrosis deform the anatomy and prevent accurate response assessment with conventional imaging [10
]. These therapy-related changes may lead to unnecessary treatment and increase mortality and morbidity [11
PET/CT performed in the early period after nonsurgical chemoradiotherapy can help differentiate residual tumor from treatment-related changes [11
]. In the case of patients treated with primary surgical resection, the timing of a PET/CT examination, the added value of PET/CT to clinical judgment, and the importance of PET/CT remain uncertain [8
]. The aim of this study is to evaluate the added value for clinical judgment and the impact of posttreatment PET/CT findings on the clinical outcome of patients with HNSCC treated primarily with surgical resection with or without adjuvant concurrent chemoradiation therapy.
Materials and Methods
This retrospective study was approved under a waiver of informed consent by the institutional review board. All patients with biopsy-proven HNSCC between 2000 and 2013 who underwent surgical resection as primary treatment and had a PET/CT scan in our center were identified. Unknown primary cancers were excluded. A total of 98 patients who underwent 18F-FDG PET/CT within 6 months after completion of treatment were identified and were included in this study. The median time interval for performing PET/CT after completion of postsurgical chemoradiation was 3.4 months and after surgery was 2.9 months (for those who underwent surgical resection only).
FDG PET/CT Protocol
PET/CT studies were performed according to institutional clinical head and neck protocol. All patients fasted for at least 6 hours before the PET/CT examination and had a blood glucose level lower than 200 mg/dL at the time of injection of FDG. An injection of an average of 5.55 MBq/kg (0.068 mCi/lb) of FDG was administered with an uptake time of approximately 60 minutes. Two PET/CT scanners (Discovery LS 2D and Discovery VCT 3D, GE Healthcare) were used. For body images, patients were scanned with arms up from midthigh to chin. The head and neck images were then acquired with arms down from carina to skull vertex. The acquisition time per bed position was 3 minutes, and the images were acquired in 128 × 128 matrix. Ordered-subsets expectation maximization (2D and 3D) was used to reconstruct all PET images. All PET data were reconstructed with and without CT-based attenuation correction. Helical CT images (120 kV; 20–200 mA; 8.0 noise index) were obtained with a 512 × 512 matrix. Beam collimation was 128 × 0.6 mm with a pitch of 0.8. Slice thickness was 3 mm, and the FOVs were 50 cm2 (body) and 30 cm2 (neck).
PET/CT Image Analysis
All FDG PET/CT images were interpreted by board-certified nuclear medicine physicians at the time of imaging in accordance with the routine clinical reporting. A nuclear medicine postdoctoral research fellow retrospectively read the scan reports and categorized them into three groups. When a report contained clear evidence of recurrence or metastasis, the scans were recorded as positive. When there was no evidence of recurrence or metastasis in a report, the scans were recorded as negative. Some scan reports had terminology such as “indeterminate” or “cannot exclude recurrence” in the impression, and these scans were categorized as indeterminate. For the purpose of analysis, indeterminate reports were grouped with the negative scan results because we found in previous studies [4
] that most indeterminate reports are true-negative for tumor.
Measures of Accuracy, Change in Management, and Outcome
The accuracy of the posttreatment PET/CT studies was established with either histopathologic confirmation of a suspected lesion (when biopsy was performed) or 6-month clinical follow-up findings from the date of the PET/CT study. Twenty-seven patients had biopsy confirmation (four image guided, 21 surgical excisional or endoscopic biopsies, two fine-needle aspiration of the neck mass without image guidance). Hospital electronic medical records and imaging records were carefully reviewed to establish the 6-month clinical follow-up findings. Change in management was recorded after each posttreatment PET/CT study. We also investigated the added value of PET/CT to clinical assessment. For each patient, the therapy-assessment PET/CT study was verified as to whether the requesting physician had previous clinical suspicion of residual disease at the time of the study. This was identified from the indication for the study as stated in the PET/CT reports and from careful review of the office and hospital visit and electronic medical records before the date of the PET/CT study. We further established the impact of PET/CT on the treatment strategy. The primary patient outcome measure evaluated in this study was overall survival. The survival status of patients was obtained from a public death registry (http://www.ancestry.com
) and review of electronic medical records at our institution. The survival data for patients who were alive were censored at the last date of follow-up at our institution.
Mean ± SD was used to present the descriptive features of variables. If data were not in normal distribution, the median with 25th and 75th centiles (interquartile range [IQR]) was reported. We evaluated the accuracy of therapy-assessment PET/CT scans obtained within 6 months of completion of primary treatment. The classic 2 × 2 table was used to calculate the sensitivity, specificity, positive and negative predictive values, and accuracy of PET/CT. Chi-square analysis was performed to evaluate the impact of PET/CT findings on treatment. The added value for clinical assessment and impact on management of PET/CT were calculated as fractions. Overall survival was estimated with Kaplan-Meier curves. Hazard ratios were calculated with the Cox proportional hazards model. Multivariate regression analysis was performed with variables that were significant in univariate analyses. All statistical analyses were conducted with two-sided tests with statistical significance considered p < 0.05. All analyses were performed with SPSS software (version 15.0, IBM-SPSS).
Assessment of treatment response with FDG PET/CT is a valuable tool after chemo-radiation therapy for HNSCC because residual tumor can be differentiated from treatment-related changes [11
]. Nevertheless, the value of PET/CT after surgical resection of HNSCC remains uncertain. This study evaluated the usefulness of postsurgical PET/CT in therapy assessment and prediction of survival of patients with HNSCC. Our results showed that posttreatment PET/CT has high accuracy and negative predictive value, adds value to clinical assessment, and impacts the subsequent treatment of patients. The scan findings are associated with the survival of patients with HNSCC treated primarily with surgical resection alone and with surgery followed by adjuvant radiotherapy with or without chemotherapy.
Previous studies [17
] assessed the value of posttreatment (surgery, chemotherapy, radiotherapy alone or in combination) PET/CT in HNSCC and showed that PET/CT was 90–97% accurate in assessment of therapy for HNSCC. Results of a meta-analysis [21
] suggested that posttreatment PET/CT has high accuracy after definitive chemoradiotherapy for HNSCC; however, positive predictive values were low (50–60%). In contrast, our results show that the sensitivity and specificity of PET/CT for assessment of therapy for HNSCC are high in both treatment groups (surgery alone and surgery followed by radiotherapy with or without chemotherapy), likely because of the improved specificity added by the CT component of PET/CT. Moreover, the positive predictive value in group A (surgery alone) (90.9%) was higher than that in group B (46.1%) (surgery followed by radiotherapy with or without chemotherapy). This difference may be explained by the larger number of false-positive PET/CT scans due to postradiation inflammation not present in patients treated with surgery alone.
Our results show that results of posttreatment PET/CT in patients treated with surgery alone were helpful in excluding tumor in 20% of patients with clinical suspicion of residual disease and helped identify suspected disease in 14.3% of patients with no prior clinical suspicion. Marcus et al. [22
] previously showed that therapy-assessment PET/CT scans of HNSCC patients treated with chemoradiation therapy were valuable in excluding tumor in 44.4% of patients with clinical suspicion of residual disease and helped identify disease in 19.5% of patients with no prior clinical suspicion of residual disease. Hence, PET/CT is a valuable tool for therapy assessment for patients with HNSCC, regardless of modality of treatment.
Our results show that therapy assessment with PET/CT has great impact on the treatment of patients with HNSCC. New treatment was initiated after 20.4% of scans because PET/CT results showed possible residual disease. In addition, PET/CT scans confirmed complete response to initial treatment in 77.6% of patients, and the patients underwent follow-up without further treatment. This finding is consistent with those of several previous studies showing the impact of PET/CT after chemoradiation therapy on therapeutic decision making [21
Kikuchi et al. [23
] evaluated the effect of posttreatment PET/CT on survival prediction in patients with HNSCC. They included all patients with definitive treatment (surgery, chemotherapy, radiation therapy) and excluded patients with nasopharyngeal and salivary gland carcinoma. Their results showed that the first posttreatment PET/CT (within 3.8 months after treatment) is useful for detection of subclinical lesions and for survival prediction in patients with HNSCC. Similarly, our results show that performing PET/CT a median of 3.4 months after surgical resection is valuable for both therapy assessment and outcome prediction in patients with HNSCC. Our results determined that posttreatment PET/CT is valuable to both patients treated with surgery alone and those who undergo adjuvant chemoradiation therapy after primary resection, especially when there is clinical suspicion of recurrence. The survival prediction value was observed in both early- and advanced-stage HNSCC.
We acknowledge limitations to our study. It was retrospective, and there is the possibility of inherent errors of confounding when exposure is not controlled. The clinical indication for PET/CT was retrospectively examined from the electronic medical records and the indication mentioned in the PET/CT reports. The exact perspective of the clinician requesting the study was not known. We included both PET/CT scans with IV contrast enhancement and those without enhancement. Use of unenhanced scans may have led to an increased number of indeterminate results. In addition, the biopsies that were performed to confirm residual disease were performed by surgical excision or under image guidance, and those performed with image guidance have limitations such as sampling error. Finally, a public registry and the patient medical records at our hospital were used to determine the dates of death of patients. There may have been lag time between death and public registry update, which may have resulted in loss of accurate mortality data. On the other hand, for patients who were alive, the overall survival was censored to their last date of follow-up at our institution, and this can affect the survival results.