Kaohsiung Medical University Institutional Repository:Item 310902000/15416

452 Kaohsiung J Med Sci October 2005 • Vol 21 • No 10 Radiation therapy is considered effective in nasopharyngeal

carcinoma (NPC) and other head and neck malignancies. However, it is not without morbidity, and complications can develop as a result of damage to neighboring structures. The irradiation field of head and neck neoplasms may include brain tissue, which may result in brain radiation necrosis. Reported cases of cerebral radionecrosis are still rare in Taiwan. We present seven cases that were clinically diagnosed as cerebral radionecrosis among NPC patients in our institute. We also review cases of extracranial malignancies, diagnostic modalities and treatment from the literature.

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Ying-Che Hsu, Ling-Feng Wang, Ka-Wo Lee, Kuen-Yao Ho, Chih-Jen Huang,1 and Wen-Rei Kuo Departments of Otolaryngology and 1Radiation Oncology, Kaohsiung Medical University

Chun-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

This study involved seven patients with cerebral radionecrosis following radiation therapy for nasopharyngeal carcinoma (NPC). Their charts were reviewed and the relationship of extracranial malignancies to cerebral radionecrosis was investigated. The radiation dose ranged from 70 to 135 Gy, and the latency was from 6 to 39 months. Two of seven patients died of NPC-related complications during follow-up. The crude incidence of cerebral radionecrosis in patients with NPC was 0.93% in our series. Improvement of symptoms could be achieved by corticosteroid therapy, with or without surgery. In a review of the literature, there were 306 cases of cerebral radionecrosis in extracranial malignancies. The nasopharynx is the most common primary site in cerebral radionecrosis of extracranial malignancies, followed by the scalp and sinonasal tract. The 3-year overall survival rate in our series was 68.57%, as provided by the Kaplan-Meier product limited method. Cerebral radionecrosis in NPC patients should be differentiated from tumor recurrence, in order to apply the appropriate treatment.

Key Words: radionecrosis, nasopharyngeal carcinoma (Kaohsiung J Med Sci 2005;21:452–9)

Received: April 24, 2005 Accepted: August 11, 2005

Address correspondence and reprint requests to: Dr. Wen-Rei Kuo, Department of Otolaryngology, Kaohsiung Medical University,

100 Tzyou 1st _{Road, Kaohsiung 807, Taiwan.}

E-mail: [email protected]

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From 1991 to 2001, 775 patients with newly diagnosed NPC received complete radiotherapy at Kaohsiung Medical University Hospital. By May 2004, seven patients had a clinical diagnosis of cerebral radionecrosis. Their charts were retrospectively reviewed. There were four male and three female patients. The mean age at diagnosis of cerebral radionecrosis was 52.7 years (range, 34–74 years).

Four of seven patients had received neoadjuvant or adjuvant chemotherapy with a cisplatin-based regimen (cisplatin, 5-fluorouracil, and leucovorin). None had concurrent chemoradiotherapy. One patient had diabetes mellitus. Five patients with documented recurrence had been re-irradiated. All patients were treated with 6 MV photons using the same technique of two lateral-opposed fields, supplemented by an anterior field. The radiation dose per course was 65–70 Gy, delivered in 2-Gy fractions

via the lateral portal once daily for 5 days per week, and 1.5-Gy (6 patients) or 1.8-Gy (1 patient) fractions 10 times via the anterior portal. The total radiation dose ranged from 70 to 135 Gy (mean, 111 Gy), and the mean latent period from the end of the last radiation to the diagnosis of cerebral radionecrosis was 26.3 months (range, 6–39 months).

Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain was performed in all patients. The diagnosis of cerebral radionecrosis was confirmed by surgical intervention in two cases and clinically diagnosed based on CT or MRI in five cases. Five patients had a further MRI perfusion-diffusion weighted scan. One had a Tc99m-hexamethyl-propyleneamine oxime (HMPAO) single photon emission CT (SPECT) scan of the brain.

A search of the English-language literature was undertaken in PubMed (http://www.ncbi.nlm.nih.gov/).

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The incidence of cerebral radionecrosis in NPC in this series was 0.93% (7/755). Clinical symptoms and signs included epilepsy, change in consciousness, memory impairment, vertigo/dizziness, and headache (Table 1A and 1B). Epilepsy was the main presenting symptom for Patient 5, while Patient 4 only had vague symptoms and

developed epilepsy 19 months after the diagnosis of cerebral radionecrosis by CT scan. Two patients (2 and 7) had consciousness change as the initial manifestation. Patient 3 had severe vertigo that made her normal daily activity impossible. Patients 1 and 6 complained of headache as their main symptom. Six of the seven patients had an associated optic neuropathy.

Cerebral radionecrosis was mainly in the temporal lobe of the brain. In five patients, diffusion-perfusion weighted MRI of the intracranial lesion showed a high signal in the diffusion-weighted image, and a low signal in the perfusion-weighted image. Patients 1 and 2 had initial surgical treatment with surgicopathologic documentation, while the other patients were treated conservatively. Patient 7 received betamethasone (0.75 mg/day), Patients 1, 3, 5, and 6 were given prednisolone (15 mg/day), and Patient 2 was treated with cortisone (25 mg/day).

Patient 1 formed a brain abscess 20 months after the diagnosis of cerebral radionecrosis and underwent craniotomy. Patient 3 developed intracranial hemorrhage 17 months after diagnosis and presented with epilepsy. The follow-up period lasted for a mean of 21.3 months (range, 4–36 months). Six patients had a favorable response to corticosteroids, with or without surgery, while one (Patient 4) was treated only with an anti-epileptic agent. Two patients eventually died of NPC-related complications during follow-up.

Table 1A. Patient data

Patient Sex Age at TNM Tumor Total C/T Latency Lesion site

diagnosis of recurrence dose (Mo)

radionecrosis (Yr) (Gy)

1 M 34 T4N0M0 Yes 135.0 2 course adj 18 Bil T

2 M 60 T4N1M0 Yes 131.5 6 course adj 14 LT R cerebral

3 F 58 T2N2M0 No 72.5 N 38 Bil T

4 M 45 T3N2M0 Yes 121.0 N 38 Bil T

5 M 50 T4N0M0 Yes 126.0 2 course neoadj 6 Bil T LF

6 F 52 T4N0M0 No 70.0 9 course adj 31 RT

7 F 74 T2N1M0 Yes 121.0 N 39 Bil T

C/T = chemotherapy; adj = adjuvant chemotherapy; Bil T = bilateral temporal; neoadj = neoadjuvant chemotherapy; LF = left frontal; RT = right temporal; TNM = tumor-node-metastasis staging.

T

able 1B.

Patient data

Patient

Clinical symptoms and signs of cer

ebral radionecr osis Systemic Tr eatment Duration of Clinical Epilepsy Consciousness Memory V ertigo/ Headache Associated disease Sur gery Corticoster oid follow-up after outcome change impairment dizziness optic neur opathy therapy diagnosis of cer ebral radionecr osis (Mo) 1 – – + + ++* + – Y es Y es 25

Brain abscess formation 20 months later

2 – +* + + – + – Y es Y es 15

Death at 15 months follow–up

3 – – – ++* + + DM No Y es 31

Bilateral intracranial hemorr

hage 17 months later 4 + – – + + + – No No 26

Epilepsy developed 19 months after diagnosis by CT scan

5 +* – + – – + – N o Y es 12 Impr oved 6 – – – + +* + – N o Y es 36 Impr oved 7 – +* + + – – – N o Y es 4

Death at 4 months follow–up

*Initial pr

esenting symptom for diagnosis of cer

ebral radionecrosis; – = none; + = mild to moderate; ++ = sever

e; DM = diabetes mellitus; CT = computed tomography

Chemotherapy r

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The incidence of NPC is higher in Southeast Asia than in the West. Radiation therapy is the main treatment modality, and the irradiation field inevitably covers the medial and inferior temporal lobes of the brain, owing to the close proximity to the skull base. In addition, the radiation dose is usually 65–70 Gy, which exceeds the tolerance of brain tissue.

Radionecrosis is a late complication of radiotherapy. The first case of extracranial neoplasm with cerebral radionecrosis was described by Fischer and Holfelder in 1930 [1]. In 1984, Glass et al reported nine cases of cerebral radionecrosis and reviewed another 65 cases in the literature [2]. Since then, another 232 patients have been reported, including our series (Table 2) [2–31], giving a total of 306 cases of cerebral radionecrosis in extracranial malignancy. The most common primary site of malignancy is the nasopharynx (mainly NPC), followed by the scalp and the sinonasal tract.

In our institute, cerebral radionecrosis was detected in seven cases, giving a crude incidence of 0.93%. The reported incidence of radionecrosis in NPC patients ranges from 0.40% to 18.60% with different radiation regimens [3,32,33]. Lee et al reported that 64 Gy at the conventional fraction of 2 Gy daily would lead to a 5% necrotic rate in 10 years [32]. Hence, the incidence of radionecrosis in NPC in our patients is thought to be underestimated. This may be because the fractional dose via the anterior portal was low (1.5 or 1.8 Gy) compared to the normal fractional dose (1.8–2.0 Gy). Other anatomic sites reported in the literature are summarized in Table 2.

The period between the last irradiation and the diagnosis of cerebral radionecrosis in our series ranged from 6 to 39 months (mean, 26.3 months). Latency has been reported at 1 month to 16 years after the end of irradiation [34], with approximately 80% occurring within 3 years after the last dose of radiotherapy [2]. The mechanism is thought to be endothelial cell damage, resulting in brain tissue ischemia in long-term follow-up [35,36].

The radiation dose in our series ranged from 70 to 135 Gy (mean, 111 Gy). The average dose was higher in our series because five of our seven cases had documented recurrent disease. A dose of 60 Gy delivered in 1.8–2-Gy fractions represents the upper limit of the “safe dose” to brain tissue [37]. To treat NPC, the radiation dose inevitably exceeds this limit. The irradiation field used to treat NPC and other malignancies of the sinonasal tract and scalp may include a part of the brain tissue. The ratio of brain tissue irradiated may be higher for scalp tumors than those in the nasopharynx, which makes the scalp the second most frequent tumor site associated with cerebral radionecrosis. The threshold for injury may be lowered by hypertension [38] or concomitant chemotherapy [39,40], although the effect of induction or adjuvant chemotherapy has not been reported. Old age or systemic illness may play a role in developing radionecrosis. Lee et al analyzed their irradiation regimen and concluded that the most significant factor was the fractional dose [32]. Prolonging the treatment time offered little protective effect [32], and yet, the overall treatment time had a significant impact [41]. The age at the time of radiotherapy also appeared to affect the volume of radionecrosis [42].

The clinical symptoms of cerebral radionecrosis are variable. It may manifest major symptoms, such as changes in consciousness and seizures, or minor complaints, such as dizziness, vertigo or memory impairment. In our series, consciousness change was detected in two cases, headache in two, epilepsy in one and vertigo in one. One patient had vague symptoms. If a patient has neurologic or psychiatric symptoms, an encephalopathy must be ruled out [4]. Patients with temporal lobe radionecrosis have significant impairments in memory, language, motor ability, and executive function, compared with those without radionecrosis [5]. Asymptomatic patients are sometimes found by follow-up imaging studies.

Distinguishing radionecrosis from tumor is a challenge in traditional imaging studies. The general characteristics of cerebral radionecrosis and tumors are summarized in Table 3. Differentiating radionecrosis from recurrent tumor is difficult with CT or MRI findings alone because of similar

Table 2. Primary malignancy site of cerebral radionecrosis in extracranial malignancy Location n Nasopharynx In the literature [2–17] 220 This series 7 Total 227 Scalp [2,18–22] 32 Sinonasal tract [2,17,23–28] 23 Ear [2,17] 9 Oropharynx [2] 2 Lacrimal gland [2] 4 Submandibular gland [2] 1 Parotid gland [2,29,30] 5

Glomus jugulare tumor [2] 1

Orbit [2,31] 2

imaging characteristics. Scintigraphic studies, such as

18

F-fluorodeoxyglucose positron emission tomography or

201

Tl chloride SPECT, have been reported to sensitively distinguish recurrent tumor from radionecrosis [43]. Recent MRI techniques, such as perfusion- and diffusion-weighted scans or MR spectroscopy to detect the brain N-acetylaspartate/choline ratio, may also help distinguish the lesion [7,8,44]. However, pitfalls in scintigraphic imaging have also been reported [18,23,24].

The standard diagnosis of radiation necrosis is histologic verification, and two of our seven patients had initial surgical treatment. The pathologic features of radionecrosis were fibrinoid and coagulation necrosis of the brain tissue. Even though surgery is an invasive procedure, it should be undertaken if the diagnosis is unclear. The surgical exploration rate may be reduced and the diagnostic rate may be increased by combining imaging studies and clinical characteristics. The clinical diagnosis of cerebral radionecrosis without pathologic proof in NPC patients has been discussed [6], and one study reported direct biopsy

under local anesthesia via a left temporal craniotomy by the neurosurgeon [30].

Treatment includes conservative management with corticosteroid or invasive procedures, such as craniotomy to clean necrotic tissue or brain lobectomy [9]. Six of our seven cases showed clinical improvement after corticosteroid therapy, with or without surgical treatment. The reported regimen is dexamethasone 4–16 mg/day for 4–6 weeks, which is gradually tapered off [3,10]. Tsui et al point out that a perfusion and diffusion mismatch might imply injured tissue, such as edema and potentially salvageable brain tissue, and this may be used to predict response to treatment [8]. Lee et al reported a mortality rate of 8% due to uncontrolled sepsis, with a 44% associated side-effect rate in corticosteroid treatment [3]. Hyperbaric oxygen therapy has also been reported [45].

Patient 3 developed a brain abscess 17 months after the diagnosis of cerebral radionecrosis. She underwent craniotomy and her symptoms improved, which stabilized her condition for the following 5 months of follow-up.

Table 3. Diagnostic tools and general characteristics of recurrent nasopharyngeal carcinoma and cerebral radionecrosis

Diagnostic tool Recurrent nasopharyngeal Cerebral radionecrosis Note

carcinoma

Angiography Avascular space-occupying lesion

CT [4] Low-density, Digitiform or round hypodense lesion Reported detection rate: 50%

post-contrast enhancement Post-contrast enhancement Detection rate < MRI

PET-18 FDG B uptake ? uptake Expensive and limited availability

SPECT B uptake ? uptake No significant differences in

sensitivity or specificity for

FDG-PET and 201_{Tl SPECT}

MRI [6] Low signal in T1W, Low signal in T1W, Poorly differentiated from

high signal in T2W High signal in T2W tumor with only T1W, T2W

Heterogeneous contrast Heterogeneous contrast Superior sensitivity to

enhancement enhancement CT scan

Irregular or cystic shape Lesions best shown on T2W

MRI perfusion-weighted High signal Low signal

scan (rrCBV map)

MRI diffusion-weighted Low signal High signal

scan (ADC map) [7]

MR spectroscopy [44] B NAA/Cr ratio B Choline peak and ? NAA/Cr ratio

CT = computed tomography; MRI = magnetic resonance imaging; PET-18 FDG = 18

F-fluorodeoxyglucose positron emission tomography; SPECT = single photon emission computed tomography; T1W = T1 weighted; T2W = T2 weighted; rrCBV = relative regional blood volume; ADC = apparent diffusion coefficient; NAA/Cr = N-acetylaspartate/choline ratio.

Cheng et al reported six cases complicated by brain abscess formation in 28 patients with temporal lobe radionecrosis following radiotherapy for NPC [46]. Cerebral radiation necrosis is a predisposing cause of brain abscess formation, as is the use of corticosteroids. Surgical excision is the recommended treatment.

Six of our patients had optic neuropathy, possibly because of the higher radiation dose due to tumor recurrence. One patient with a lower irradiation dose had diabetes mellitus (Patient 3), which may exacerbate the impairment of microcirculation caused by radiotherapy. The patient developed intracranial hemorrhage 17 months after the diagnosis of cerebral radionecrosis (55 months after the end of radiotherapy). Cheng et al reported five cases of acute hemorrhage in late radiation necrosis of the temporal lobe [47]. The interval between the onset of hemorrhage and cranial irradiation was long (mean, 7.8 years), and rupture of the thin-walled new blood vessel is the hypothesized hemorrhage mechanism.

Clinical improvement has been reported in the treatment of cerebral radionecrosis using anti-coagulation therapy with heparin and warfarin [48]. Anti-platelet treatment with pentoxyfyllin, aspirin, and ticlopidine has also been used, but the potential risk of bleeding from these agents must be considered [49].

The follow-up time after diagnosis of cerebral radionecrosis ranged from 4 to 36 months (mean, 21.3 months). Two of our seven patients died. The 3-year overall survival rate in our series was 68.57%, as provided by the Kaplan-Meier product limited method. Lee et al found a 5-year survival rate for cerebral radionecrosis in NPC of 59%, with or without treatment [33]. The weak points of our sampling were the relatively short follow-up time and the limited numbers of cases.

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Patients with NPC comprise the majority of those with cerebral radionecrosis following treatment for extracranial malignancies. Differential diagnosis with tumor recurrence is needed. Since advances in the treatment of NPC have resulted in an accumulation of long-term survivors, cerebral radionecrosis may become a major clinical concern. Several studies have shown that a promising first-line treatment is with corticosteroids [3,4, 10,11]. The consequences of cerebral radionecrosis, which include brain abscess and acute hemorrhage, are also of chief concern.

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