British Journal of Radiology (2008) 81, e26-e30
© 2008 British Institute of Radiology
doi: 10.1259/bjr/15812414
PET scanning and Gamma Knife® radiosurgery in the early diagnosis and salvage "cure" of locally recurrent nasopharyngeal carcinoma
H E O'Donnell, MA, MRCP, FRCR1,
P N Plowman, MA, MD, FRCP, FRCR1,
M K Khaira, MRCP1 and
G Alusi, PhD, FRCS2
Departments of 1 Radiotherapy, 2 Ear, Nose and Throat, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
Correspondence: Dr Helen O'Donnell, MA, MRCP, FRCR, Department of Radiotherapy, St Bartholomew's Hospital, 25 Bartholomew's Close, West Smithfield, London EC1A 7BE, UK. E-mail: hodonnell{at}doctors.org.uk
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Abstract
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"Gamma Knife® radiosurgery" is high-dose conformal radiation therapy used for the treatment of small target lesions in the head. It is a minimally invasive technique of multiple fixed, precisely aimed cobalt beams, and relies upon strict patient immobilization via a pinned stereotactic frame to deliver treatment to a precisely located target within a coordinated mapping system. This technique has been widely validated for the treatment of intra-cranial neoplasms and arteriovenous malformations. In this manuscript, two cases of early diagnosed, locally recurrent (persistent) nasopharyngeal carcinoma, successfully treated by Gamma Knife®, are described. In one of these, early diagnosis by PET scanning may have improved the chance of cure.
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Introduction
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Nasopharyngeal carcinoma (NPC) is uncommon in the UK but its frequency is higher in China. There is an association with Epstein Barr virus infection, which is not related to the geographical variation. The disorder is more common in men and patients tend to be younger than those with other forms of head and neck cancer. The clinical presentation of NPC is variable: a neck mass is the most common presentation owing to the extensive lymphatic drainage of the nasopharynx, but nasal stuffiness, otitis media and facial pain are not uncommon. Central nervous system symptoms occur in up to 25% of cases owing to skull base invasion, which is typically caused by cranial nerve involvement in the cavernous sinus resulting from cranial growth through the foramen lacerum.
Definitive primary treatment of NPC is by radiotherapy. The addition of chemotherapy has now become standard following the Phase III randomized trial published by Al-Sarraf et al in 1998 [1]. External beam radiotherapy is delivered in a fractionated course with concurrent platinum chemotherapy. The radiotherapy dose delivered is limited by the tolerance of the surrounding normal tissues, and typically the maximum dose delivered is 60–70 Gy. Recurrences are often treated with palliative chemotherapy, whereas apparently isolated local recurrences are treated by further resection or re-irradiation, with moderately successful results. In a series of over 4000 patients with NPC, 21% had re-irradiation for recurrence following standard irradiation (15.6% for local recurrence and 5.5% had for regional recurrence) [2]. To date, re-irradiation has involved brachytherapy or further external beam radiation. Gold grain implant brachytherapy offers good palliation and reasonable local control in recurrent head and neck cancers for lesions less than 2.5 cm and is best for slow-growing tumours [3].
The nasopharynx is situated immediately below (caudal to) the skull base, and with developments in stereotactic radiation methods now lies within stereotactic space. In this manuscript, two cases of locally recurrent (persistent) NPC are described that were diagnosed early and treated by Gamma Knife® (Leksell Gamma Knife; Elekta, Sweden) radiosurgery. We comment on the advantages of this treatment modality after radical external beam radiotherapy. The usefulness of PET in the early diagnosis of this problem is also illustrated and discussed.
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Case 1
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In February 2000, a 47-year-old Malaysian Chinese woman presented with headaches, nasal stuffiness and occasional epistaxis. A CT scan of the brain at this time was normal. She was subsequently referred to ear, nose and throat (ENT) surgeons with bilateral otalgia. Grommets were inserted and biopsies were taken from the postnasal space. These revealed poorly differentiated nasopharyngeal carcinoma. CT and MRI showed a large tumour in the posterior nasopharynx measuring 5x2.5 cm. It invaded the base of the sphenoid, inferior clivus and foramen lacerum. Lymph nodes were not enlarged by CT/MRI criteria (T3NxM0 UICC 2002).
She was treated with radical chemoradiation that was completed in November 2000. 64 Gy was delivered to the primary tumour and nasopharynx and 50 Gy to the lower neck, with concurrent weekly cisplatin chemotherapy (40 mg m–2). She had an excellent symptomatic response and ENT examination 3 months after completion of treatment did not reveal any evidence of persistent or recurrent tumour. Post-treatment MRI in March 2001 confirmed a good response to treatment but raised some concerns over disease in the prevertebral space, with possible involvement of the strap muscles and soft tissue, extending to the carotid space. Further assessment with fluorodeoxyglucose–positron emission tomography (FDG–PET) confirmed uptake in this area and the patient was further treated with six cycles of cisplatin and 5-flurouracil chemotherapy. During chemotherapy, a second opinion revealed no evidence of disease on either PET or indeed biopsy of the above area of concern. Following completion of six cycles of chemotherapy in September 2001, no evidence of disease was found on clinical or radiological review over the ensuing 3 years.
In February 2004, the patient complained of recurrent epistaxis and left-sided facial pain. MRI and nasendoscopy at this time were normal. However, a PET scan (Figure 1
) demonstrated a focal area of marked FDG uptake in the roof of the nasopharynx in keeping with recurrent disease. This was confirmed with biopsies of the PET-positive area in May 2004. Staging investigations did not reveal any other areas of local recurrence or metastatic disease.
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Figure 1. A positron emission tomography(PET)-CT scan performed in March 2004. Fluorodeoxyglucose (FDG)-PET and CT axial images through the nasopharynx demonstrate increased FDG uptake in an area corresponding to the roof of the nasopharynx. The area of uptake shown was subsequently biopsied and confirmed as an area of persistent/recurrent nasopharyngeal carcinoma.
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Gamma Knife® radiosurgery was delivered in August 2004. A standard pinned stereotactic frame was employed and the head was imaged using MRI. The additional PET data allowed mapping of the recurrent lesion measuring 3.3 cm3. Computer programs used the brain images to develop a treatment plan outlining the 
-ray dose and location within the patient as shown in Figure 2. A single radiation dose of 14 Gy was prescribed to the 50% isodose line, which circumscribed the lesion; 95% of the lesion received 
14 Gy. The procedure was well tolerated.
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Figure 2. An axial MRI slice through the nasopharynx. The MRI scan is acquired with the patient secured in the stereotactic frame. Computer programs use these images to develop a treatment plan. Outlined in red is the target volume delineated using the MRI and PET-CT data. In yellow is the 50% isodose that conforms to the target, with 95% of the target receiving at least 14 Gy.
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A subsequent PET scan in December 2004 gave rise to suspicions of persistent disease in the pharyngeal wall but biopsies from this area were negative. A further PET scan was performed in May 2006 (Figure 3); this was negative for recurrent disease in the nasopharynx and elsewhere, and the patient remains well up to the present time.
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Figure 3. A CT-PET (positron emission tomography) scan performed in May 2006 demonstrating no areas of focal fluorodeoxyglucose uptake through the level corresponding to the previous area of recurrence.
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Thus, PET scanning diagnosed this biopsy proven local recurrence of NPC in 2004 at a time when the patient was asymptomatic. The patient was successfully treated with Gamma Knife® radiosurgery, and she remains well and PET-negative 2 years after her recurrence.
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Case 2
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A 69-year-old man presented in Albania in April 2002 with cervical lymphadenopathy and subsequently underwent a right neck dissection. No obvious primary was discovered and he was treated with six cycles of chemotherapy (5-flurouracil, cyclophosphamide and doxorubicin). He arrived in the UK in December 2002 and was reviewed in the ENT clinic. Nasendoscopy revealed granular tissue in the posterior aspect of the nasal cavity, a biopsy of which confirmed non-keratinising NPC (Type 2). A CT scan demonstrated tumour within the nasopharynx extending anteriorly into the nasal cavity. There was no lymph node enlargement (T3NxM0 UICC 2002).
He was treated with chemoradiation and received conventionally fractionated radiotherapy delivering 66 Gy to the nasopharynx and 60 Gy to the lower neck with weekly platinum chemotherapy (40 mg m–2). Treatment was completed in April 2003. On regular ENT review, there was no suspicion of recurrence until November 2004, when biopsies from an irregular area in the posterior nasal septum were positive for recurrent/persistent carcinoma. MRI revealed abnormal soft tissue in the post-nasal space, asymmetry of the nasopharynx and occlusion of the left eustachian tube owing to presumed nodal enlargement. He proceeded to a nasopharyngectomy via a mid-facial de-gloving approach in January 2005. Clinical follow-up was unremarkable but post-operative MRI was unable to distinguish residual/recurrent disease from post-radiation fibrosis. PET confirmed activity in a small discrete area behind the antrum. Gamma Knife® radiosurgery was delivered to this area in October 2005. The patient remains well after 1 year, with no clinical or MRI evidence of recurrent disease.
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Discussion
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Treatment with external beam conformal radiotherapy for NPC involves irradiation of the primary tumour, the potential routes of spread, and the entire lymphatic drainage system of the neck. Local control rate after radical radiotherapy is approximately 80% for tumours confined to the nasopharynx, but only 50% for those with erosion of the skull base. Survival improves with locoregional control, as does freedom from distant failure (71% versus 59%) [4]. Results have improved since the introduction of platinum-based concomitant chemotherapy [1].
Persistence of the primary tumour is the main cause of treatment failure [4]. Primary tumour volume of more than 60 cm3 is associated with a lower likelihood of local control after radiotherapy [5]. For small tumour recurrence in the nasopharynx, salvage options are re-irradiation therapy, brachytherapy or surgery. The salvage option depends upon the size and location of the tumour, as well as the expertise available, and the long-term effects of these treatment modalities must be considered. The majority of recurrences occur within 2 years and have traditionally been managed with surgical resection or brachytherapy where possible. In a series of 903 patients with NPC treated with radical external beam radiotherapy (1984–1989), 176 patients had local failures. Of the 166 (truly) locally recurrent NPC (10 also had distant metastases on CT staging), 123 were treated with either re-irradiation to high dose or nasopharyngectomy, with or without radical neck dissection. Median follow-up was 20 months after recurrence; the actuarial 5-year overall survival and further relapse-free survival rates were 9.4% and 11.5%, respectively [6]. Results favoured surgery over re-irradiation perhaps because of selection bias; there was also significant morbidity with re-irradiation, e.g. temporal lobe necrosis, trismus and deafness. In another series of 891 patients with recurrent NPC, 70% had local failure only at the time of detection of recurrence. The prognosis for patients with recurrent NPC is very poor; overall 5- and 10-year actuarial cancer-specific survival rates are 14% and 9%, respectively. There is also a high incidence of late complications secondary to re-irradiation [7]. These poor results are probably caused, in part, by the late diagnosis of recurrence with conventional imaging in the period this patient group was analysed (1976–1985).
Local recurrences are not easily accessible, making surgical and brachytherapy treatment approaches technically difficult. Nasopharyngectomy with or without neck dissection has been shown to be associated with better survival and local control than re-irradiation with external beam radiotherapy. Brachytherapy using gold grain implants has been employed for the treatment of local relapse of head and neck cancer. The best results are achieved for lesions <2.5 cm, with most success in slow-growing tumours such as adenoid cystic tumours, rather than nasopharyngeal tumours [3]. Often, treatment of recurrence is palliative, using further platinum-based chemotherapy with modest responses.
FDG-PET is increasingly being used for detection of recurrent or residual disease in many tumour types. The majority of malignant tumours have increased glucose, amino acid and DNA metabolism. By using suitable tracers, malignant tumours can be differentiated from benign lesions. This is of particular importance in the brain and other sites where lesion access is a problem. Areas of tumour recurrence can be distinguished from radiation fibrosis, necrosis and post-surgical changes. Often, CT or MRI studies cannot make this distinction, necessitating the patient to undergo invasive biopsies. In NPC, the use of PET has been studied in the decision for salvage treatment in locally persistent disease. PET resulted in treatment reduction strategies, excluding those who were unlikely to benefit from salvage treatment, reducing the target volume and improving treatment accuracy in others [8]. In a retrospective analysis of 64 patients, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of PET in the diagnosis of recurrence or metastases in NPC were 92%, 90%, 92%, 90% and 91%, respectively [9].
In the first case presented here, PET detected subclinical disease (as the facial pain and epistaxis were not readily attributable to this area of recurrence) at an early stage than could have been achieved by anatomic cross-sectional imaging.
The Gamma Knife® is a medical instrument that emits 201 finely collimated beams of cobalt-60 -radiation. These beams intersect at the precise location of the stereotactically mapped lesion and treat with minimal effect on surrounding normal tissue. Safe delivery of a single high dose of radiation relies upon a sharp dose fall-off and, for this reason, lesions for treatment must be small (usually up to a maximum diameter of 3.5 cm). This steep dose gradient is particularly crucial in cases involving re-treatment following external beam radiotherapy. The surrounding tissues including critical structures (e.g. brain stem, optic chiasm) have already received their accepted radiotherapy dose; therefore, there is little tolerance of further radiation. The use of the stereotactic frame allows fixation of the patient and, therefore, the target to within 1 mm. With low fixation of the frame, the extra-cranial targets that were hitherto beyond stereotactic space become accessible, and this manuscript demonstrates this for locally persistent NPC — a technique that we believe will prove superior to previous salvage radiation therapy options.
Stereotactic radiotherapy has occasionally been employed for NPC recurrence; the majority of cases have used linear accelerator-based methods. In such a series of three patients, one remained disease-free 1 year after radiosurgery, one had neurological deterioration 6 months after treatment, and one had recurrence 6 months after radiosurgery [10].
Gamma Knife® radiosurgery has previously been used in a small number of patients with NPC both at recurrence and as a primary treatment. Treatment was found to be effective for a short period of time but reported follow-up periods are brief [11].
The 2-year follow-up of our first patient treated with Gamma Knife® has been event free. No clinical evidence of recurrence has manifest and, reassuringly, a recent PET scan has not shown any FDG uptake in the nasopharynx, or indeed elsewhere, to suggest recurrent disease. In the second case presented, treatment also appears successful, albeit with shorter follow-up.
The data presented illustrate the usefulness of FDG-PET in the early diagnosis of local relapse of NPC, and it is hypothesized that such early diagnosis will allow local salvage treatment and improved chance of cure. When coupled with focal radiation therapy such as Gamma Knife®, the combination may offer an improved treatment for this group of patients.
Received for publication August 12, 2006.
Accepted for publication September 15, 2006.
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References
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- Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, et al. Chemotherapy-radiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomised intergroup study 009. J Clin Oncol 1998;16:1310[Abstract/Free Full Text]
- Lee AW, Law SC, Ng SH, Chan DK, Poon YF, Foo W, et al. Retrospective analysis of nasopharyngeal carcinoma treated during 1976–1985: late complications following megavoltage irradiation. Brit J Radiol 1992;65:918–28.[Abstract]
- Ashamalla H, Rafla S, Zaki B, Ikoro NC, Ross P. Radioactive gold grain implants in recurrent and locally advanced head and neck cancers. Brachytherapy 2002;1:161–6.[CrossRef][Medline]
- Lee AW. Contribution of radiotherapy to function preservation and cancer in primary treatment of nasopharyngeal carcinoma. World J Surg 2003;27:838–43.[CrossRef][Medline]
- Chua DDT, Sham JST, Kwong DLW, Tai KS, Wu PM, Lo M, et al. Volumetric analysis of tumour extent in nasopharyngal carcinoma and correlation with treatment outcome. Int J Radiat Oncol Biol Phys 1997;39:711–9.[CrossRef][Medline]
- Teo PM, Kwan WH, Chan AT, Lee WY, King WW, Mok CO. How successful is high-dose (>or = 60Gy) reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 1998;40:897–913.[CrossRef][Medline]
- Lee AW, Law SC, Foo W, Poon YF, Cheung FK, Chan DK, et al. Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976-1985: survival after local recurrence. Int J Radiat Oncol Biol Phys 1993;26:773–82.[Medline]
- Zheng XK, Chen LH, Wang QS, Wu FB. Influence of flurodeoxyglucose positron emission tomography on salvage treatment decision making for locally persistent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;65:1020–5.[CrossRef][Medline]
- Yen RF, Hong RL, Tzen KY, Pan MH, Chen TH. Whole-body 18F-FDG PET in recurrent or metastatic nasopharyngeal carcinoma. J Nucl Med 2005;46:770–4.[Abstract/Free Full Text]
- Buatti JM, Friedman WA, Bova FJ, Mendenhall WM. Linac radiosurgery for locally recurrent nasopharyngeal carcinoma: rationale and technique. Head Neck 1995;17:14–9.[CrossRef][Medline]
- Dong RH, Gao ZU, Hu ZQ, XU WM, Pan L. Preliminary application of Gamma Knife in the treatment of nasopharyngeal carcinoma. Stereotact Funct Neurosurg 1996;66(Supp1):201–7.
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Abstract
Introduction
