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© 2000 American Society for Clinical Oncology Surveillance for Recurrent Head and Neck Cancer Using Positron Emission TomographyFrom the Departments of Nuclear Medicine, Otolaryngology, Head and Neck Surgery, Hematology/Oncology, Radiation Oncology, Pathology, and Radiology, St Louis University; and Department of Health Administration, Washington University, St Louis, MO. Address reprint requests to Val J. Lowe, MD, PET Imaging, Section of Nuclear Medicine, Charlton 1N-215, Mayo Clinic, Rochester, MN 55905; email vlowe{at}mayo.edu
PURPOSE: Earlier detection of head and neck cancer recurrence may improve survival. We evaluated the ability of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) to detect recurrence in a prospective trial using sequential PET scans. PATIENTS AND METHODS: Serial posttherapy FDG-PET was prospectively performed in 44 patients with stage III or IV head and neck cancer. PET was performed twice during the first posttreatment year (at 2 and 10 months after therapy) and thereafter as needed. After therapy, patients were grouped, based on tissue biopsies, into those who achieved a complete response (CR) and those who had residual disease (RD). Patients who achieved a CR were further grouped into those without evidence of disease and those who had recurrence by 1 year after completion of therapy. Disease status as determined by physical examination (PE), PET, and correlative imaging was compared. RESULTS: Eight patients were lost to follow-up and six had RD after therapy. Of the remaining 30 patients with a CR, 16 had recurrence in the first year after therapy. Five of these 16 patients had recurrence detected by PET only, four by PET and correlative imaging only, five by PE and PET only, and two by PE, correlative imaging, and PET. Only PET detected all recurrences in the first year. PET performed better than correlative imaging (P = .013) or PE (P = .002) in the detection of recurrence. CONCLUSION: PET can detect head and neck tumor recurrence when it may be undetectable by other clinical methods. FDG-PET permits highly accurate detection of head and neck cancer recurrence in the posttherapy period.
STANDARD TREATMENT for advanced (stage III and IV) head and neck cancer is surgery followed by postoperative radiation therapy. A number of investigators have achieved organ preservation by using induction chemotherapy and radiation therapy, with surgical salvage.1,2 Despite this accomplishment, survival has remained constant.3 Earlier and more accurate detection of recurrence may improve survival. Positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG) as a metabolic tracer can identify cancer. Cancer cells have increased glucose metabolism,4 and because FDG is an analog of glucose, FDG accumulates at increased rates in highly metabolic, malignant cells.5 After phosphorylation, FDG-6-PO4 does not proceed further in the metabolic pathway and for the most part remains trapped within cells, allowing for PET imaging. High FDG accumulation is thereby a marker of high metabolic activity, and the growth rate of tumors correlates with their FDG uptake.6 We postulated that FDG-PET could permit early detection of tumor recurrence. Previous reports have shown the high accuracy of PET in staging head and neck cancer and in identifying tumor recurrence.7-11 However, in prior tumor recurrence studies, patients were commonly enrolled if recurrence was suspected. The advantage of a test that can detect subclinical recurrence is thereby unlikely to be demonstrated. Bias is introduced, because there is a high likelihood of recurrence in such patients. We evaluated the ability of FDG-PET to identify tumor recurrence prospectively in patients seen routinely and sequentially for a 1-year period after completion of therapy for locally advanced head and neck cancer.
Patients Serial posttherapy FDG-PET was prospectively performed in 44 patients with stage III or IV head and neck cancer who were being treated according to a neoadjuvant organ-preservation protocol that included chemotherapy, radiation therapy, and surgical salvage. PET was performed twice during the first posttreatment year (at 2 and 10 months after therapy) and thereafter as needed. Patients were grouped, based on tissue biopsies at the original tumor site, into those who achieved a complete response (CR) and those who had residual disease (RD) after chemotherapy. If there was RD at the primary tumor site, patients had salvage primary tumor surgery and neck dissection. If patients had a CR at the primary tumor site, only neck dissection was performed, in the case of patients with pretreatment stage disease greater than N0. All patients had subsequent radiation therapy. After therapy, patients with a CR were then subcategorized into those with no evidence of disease (NED) and those who had recurrence at least 1 year after completion of radiation therapy. Patients’ physical examination (PE), PET imaging, and correlative imaging findings during the first year were recorded and compared. All patients gave informed consent to participate in this study, which was approved by our institutional review board. FDG-PET studies were scheduled for all patients 2 and 10 months after completion of radiation therapy. Computed tomographic (CT) scans of the head and neck and chest radiographs were obtained at 2 and 10 months during the period. Additional imaging was performed only when it was deemed clinically necessary. All patients fasted before PET studies, and serum glucose levels were measured in each patient. Biopsies were performed when there was clinical suspicion of disease. Because of a change in protocol during the recruitment period, some patients underwent random biopsies of the regions of the primary tumors at 2 months after therapy.
PE PE findings were considered negative when no evidence of disease was found or when physical complaints or nonspecific findings could be ascribed to another cause (such as an upper respiratory infection) or when the examining physician noted that he or she believed that there was no evidence of disease and no additional specific action was taken to assess for recurrence. PE findings were considered positive when the clinician noted recurrence or suspicion of recurrence given the findings, even if recurrence was not confirmed until later or was not confirmed by a confirmatory test.
PET Imaging The F-18 fluoride was produced by an RDS 112 Cyclotron (Siemens) located on-site. The F-18 fluoride ions were transferred to an automated system for synthesis of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) by the Hamacher method. FDG was tested for sterility, pyrogenicity, and radiochemical purity on each production run. PET images included the areas from the inferior orbit to the lower abdomen and were obtained 50 minutes after intravenous injection of 370 MBq of FDG. In patients with nasopharyngeal cancer, the imaging field was extended to the supraorbital region. Attenuation correction of the images was used in selected cases. PET images were reconstructed using filtered back-projection with a Hann window of 5.0-mm width. Emission data were corrected for scatter, random events, and dead-time losses using the manufacturer’s software.
Conventional Correlative Imaging
Pathology
Chemotherapy
Radiation Therapy In patients who had undergone surgery, the total dose to the primary tumor site was reduced to 60 Gy but the same dose to the neck was maintained.
Surgery Neck dissections were offered as part of surgical salvage on the basis of the presenting amount and location of cervical metastases. Limited neck disease (stage N0 or N1) was treated with a selective neck dissection (supraomohyoid or lateral neck dissection) that spared the jugular vein, spinal accessory nerve, and sternocleidomastoid muscle. In the case of stage N2A or greater disease, a modified radical or radical neck dissection was performed that spared some or none of the cervical structures just mentioned, respectively. Patients who achieved a CR underwent neck dissections only, and only if needed. Patients with neck disease of pretreatment stage greater than N0 were treated with modified radical or radical neck dissection as just described. Patients with stage N0 neck disease had no neck dissection performed. Patients with RD and those with a CR then received postoperative radiation therapy, 4 to 6 weeks after surgery. Patients with distant metastasis or whose disease was deemed unresectable after chemotherapy were not offered salvage surgery.
Data Analysis Sensitivity and specificity of PE, PET, and correlative imaging for recurrent disease in the first posttherapy year were determined. Statistical comparisons were made using the McNemar test, a nonparametric test for equality of proportions for paired data.
Of the 44 patients who began the initial organ-salvage treatment, six had RD at the completion of radiation therapy or postoperatively or died during therapy. Eight patients did not complete the treatment because they did not return for scheduled appointments for testing and examination. The remaining 30 patients were considered to have NED at the end of radiation therapy. Fourteen of these 30 patients still had NED at the end of the 1-year posttherapy follow-up period. Sixteen of the 30 patients were found to have recurrent disease in the first year after therapy. Of the 16 patients found to have recurrent disease in the posttherapy year, two of 16 recurrences were identified by PE, correlative imaging, and PET; four of 16 patients had recurrence detected by correlative imaging and PET only; five of 16 patients had recurrence detected by PE and PET only; and five of 16 had recurrence detected by PET only (Figs 1 - 4; Table 1). The sensitivities and specificities were calculated to be 44% and 100% for PE, 38% and 85% for correlative imaging, and 100% and 93% for PET (Table 2). Significant differences (P = .002) in the performance of PET versus PE were seen. Conventional imaging and PE performance showed no statistical difference in this group (P = .763).
The specificity of 93% for PET was due to the existence of one false-positive PET result in a patient (of 14 patients) who later had confirmed recurrent disease after the 1-year test period. This result was considered to be false-positive because evidence of clinical progression was less than clear during the 1-year posttherapy period before subsequent pathologic confirmation, and because surgical exploration at the time of the positive PET finding was unable to confirm the finding. Pathologically proven recurrence was documented in 15 of 16 patients with recurrence. One case, in a patient with suspected lung metastasis, was considered a case of recurrence because of the increasing size of lung lesions as seen on CT scans. Recurrence was documented by concurrent needle biopsy in 13 of 15 patients with pathologically proven recurrences. One of the other two of 15 recurrences was documented by concurrent wedge resection of a lung lesion. In the other of these two cases, the patient had a confirmatory needle biopsy of the area in question 1 year after PET detection of recurrence. This case was considered positive because of the clinical progression of the lesion (Fig 2). PET imaging findings, although negative in the early posttreatment scan, were positive in the 9-month posttherapy PET scan (Fig 2A). CT scans of this patient after therapy had continued to show soft tissue fullness in the right parapharnyx relative to the original mass, and although the mass had shown regression with therapy, it had not changed over four posttherapy serial CT scans up to 14 months after therapy. These findings were thought to represent not recurrence but stable posttherapy abnormalities. The fourth CT scan, from 14 months after therapy, is shown with the corresponding PET scan in Fig 2B. The patient had confirmatory positive MRI findings (Fig 2C) 8 months after the PET scan with positive findings. Findings of an initial biopsy had also been negative on April 30, 1997, but the biopsy was described as being of the right parapharnyx, and the PET finding may have been missed. Biopsy of the right parapharnyx was repeated after the positive MRI findings and disease was demonstrated. Ten of the 16 recurrences were found on the early PET scan, and nine (90%) of the 10 were local recurrences (Table 1). Six of the 16 recurrences were found on the later PET scan, and three (50%) of the six were distant recurrences. In the six patients with recurrence detected by PET at 10 months, there was no other suspicion of recurrence on PET, correlative imaging, or PE before this time, except in one patient (no. 17) with tonsil cancer who presented with a nodule and pain on the tongue 3 months after the completion of radiation therapy. PET and correlative imaging findings were negative at this time. Findings of a biopsy at this time were negative. The documented recurrence at the 10-month period was on the soft palate. Retrospective review did not demonstrate abnormalities on the 2-month PET scans of these six patients.
Recurrence of head and neck cancer has a poor prognosis. With earlier detection of recurrence, it is possible that survival could be improved. Previous reports have shown the high accuracy of PET in staging head and neck cancer and in identifying tumor recurrence.7-11 In prior trials, the objective was to assess the ability of PET to visualize a recurrence that was already highly suspected. The goal of performing PET in such a situation was to provide data that PET is at least equivalent to standard techniques for assessing recurrence. We evaluated the ability of FDG-PET to identify tumor recurrence prospectively in patients seen routinely and sequentially for a 1-year period after completion of therapy for locally advanced head and neck cancer. This was done in an attempt to demonstrate any subclinical recurrent disease. Such detection may precede detection of other clinical signs or symptoms, and therefore there may be reasonable cause for using PET routinely in such patients. In this study, we demonstrated sensitivities and specificities, respectively, of 44% and 100% for PE, 38% and 85% for conventional imaging, and 100% and 93% for PET. PET had a statistically significant advantage over other techniques. If one combines all cases in which recurrence was detected by correlative imaging or PE, one finds that only 63% of the cases of recurrence were discovered. One false-positive PET result was noted in a patient who later had confirmed recurrent disease after the 1-year test period. This result was considered to be false-positive because evidence of clinical progression was less than clear before subsequent pathologic confirmation. Two patients who had false-positive correlative imaging results had NED at 200 weeks and 66 weeks after therapy. There were no false-positive PE findings. PET imaging has been evaluated by both visual and semiquantitative methods, with equivalent accuracy in some tumors. The normal metabolism of head and neck structures provides specific challenges for PET image interpretation. Some normal structures in the region such as oral mucosa, palatine tonsils, and mylohyoid muscle routinely show increased FDG accumulation. This finding can create considerable difficulty in defining a cutoff between normal and abnormal semiquantitative values. For this reason, we chose to evaluate the PET data visually. Some published data on posttherapy PET scans have indicated significant hypermetabolism in association with treatment-related inflammatory changes without the presence of residual tumor.12 It seems, however, that the same confounding hypermetabolism was not a major difficulty in our patient group. We did not perform PET imaging until at least 2 months after the completion of radiation therapy. In fact, when PET scan findings were positive, the PET study was highly indicative of tumor. Only one (7%) of 14 patients considered to have NED throughout the first year had a positive PET finding. In this patient, results of two biopsies were negative; one biopsy was performed at the time of the positive PET findings that showed sialadenitis, and the other biopsy was performed 4 months after the PET scan that did not demonstrate tumor. In the same patient, at 6 months after the positive PET findings, results of a biopsy of the same region were positive. It is unknown whether this patient had subclinical disease detected by PET but not confirmed until 6 months later. Eight patients were lost to follow-up in our group. Two of these patients would not allow PET imaging in the posttherapy period because they found the long scan-time uncomfortable. Newer-generation PET scanners require one half to one third the time for scans, and in the future it is likely that fewer patients will find PET scanning unbearable. Six other patients did not keep follow-up clinic appointments, for unknown reasons. Data from this group of patients with advanced-stage head and neck cancer imply that routine surveillance PET imaging of patients in the first year after therapy will allow detection of recurrent disease that may otherwise go undetected. Additional therapy for patients with recurrence has traditionally not been effective. However, this should not strictly imply that therapy for patients detected earlier by PET would not fare better. We believe that patient no. 25, in whom PET detected an early lung metastasis, was spared significant morbidity, because of the PET findings. Although other test findings were not clearly indicative of disease, the PET scan led to a limited wedge resection of a presumed lung metastasis. Because of this limited resection at an early stage, this patient continued to be gainfully employed. Had the disease progressed, more morbid surgery might have been necessary. Another patient was still alive more than 2 years after therapy. Three of the other five patients whose disease was detected initially by PET alone did not survive. Much of the care of these patients was assisted by subsequent PET scans, care including adequate placement of brachytherapy catheters, in one patient, and management of chemotherapy response, in another patient (this patient had a recurrence in the posterior nasopharynx/base of skull, a region where it is difficult to obtain biopsy specimens). Given these data, PET imaging of treated, advanced-stage head and neck cancer is recommended when PET is available for surveillance of recurrent disease. Most cases of PET-only detected recurrence occurred in the early imaging phase; therefore, PET imaging should be performed at least by 4 months after the completion of therapy. These data indicate that recurrent malignancy that is difficult to detect by conventional means or PE may be discovered using PET imaging and the use of PET for prospective assessment during posttreatment periods in patients with other malignancies may be warranted. In conclusion, PET can detect head and neck tumor recurrence when it may be undetectable by PE or conventional imaging methods. Conventional imaging and PE perform comparably in detecting recurrent disease. PET performs significantly better than conventional imaging and PE in detecting recurrent disease in patients with advanced-stage head and neck cancer.
We thank Penny Yost, Sue Paulik, Timothy Westermeyer, Ranajit Bera, PhD, and Rita Gentilcore of the St Louis University PET Imaging Center for their contributions in the performance of the PET imaging and PET radiopharmaceutical production needed for this study.
Presented at the Forty-Fourth Annual Meeting of the Society of Nuclear Medicine, Toronto, Ontario, Canada, June 6-11, 1998.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
