**4.1 Difference between clinical CN palsy and MRI-detected CN involvement**

Clinical findings were not consistent with the MRI findings of CN involvement in some cases. Nerves are resistant to tumor, and perineural tumor spread is an insidious and often asymptomatic process. The incidence of MRI-detected CN involvement is high in NPC; patients are often asymptomatic [10]. According to our observation, the incidence of MRIdetected CN involvement was much higher than that of clinical presentation of CN palsy in NPC patients.

With improvement in imaging techniques, direct visualization of smaller nerves and proximal nerve branches have become possible. MRI allows contrast between the nerve fibers and the surrounding cerebrospinal fluid, perineural vascular plexus, and fat pads. Involvement of cranial nerves may be direct or perineural; proposed MRI criteria of cranial nerve involvement in our study include both possibilities. MRI, including the contrastenhanced fat suppression technique, is particularly helpful in detection of direct and perineural invasion of the nerve in patients with NPC, so we often identified cranial nerve involvement on gadoliniumenhanced T1-weighted images. Perineural spread, in which pathologic conditions spread along the connective tissues of the perineurium, is often associated with malignant disease of the head and neck. The imaging hallmark of this process has been discussed in detail in a previous articles [1-3].

Without contrast between the nerve and the surrounding structures, CNs in the parapharyngeal space could not be identified on MRI; therefore, parapharyngeal space invasion was not defined as evidence of CN involvement in our study. A small number of symptomatic patients with only carotid sheath or retropharyngeal lymph node invasion along the course of ipsilaterally paralyzed CNs were regarded as MRI negative but clinically positive in our series.

Because NPC is a nonsurgical disease, the limitation of our study is that there was no pathologic correlation of CN involvement with MRI findings. Another limitation is the slice thickness of 5 mm used in our study, which may limit the sensitivity of detecting cranial nerve involvement. Ideally, slice thickness should be 3 to 4 mm in future studies; this may lead to earlier identification of CN involvement.

#### **4.2 Prognosis of clinical CN palsy in MRI-detected CN involvement**

We observed that most CN palsies had 1 or more MRI findings of intracranial or orbital CN involvement; this may be a reason for the adverse prognostic significance of CN palsies, and patients with CN palsies are determined to be at stage T4 [4].

Several investigators have reported that the perineural tumor spread in patients with nonnasopharyngeal carcinoma of the head and neck is associated with an increased incidence of recurrence [11-14]. However, in our series, MRI-detected CN involvement was not associated with the 3-year LRFS rate in NPC patients with local advanced disease. The primary treatment modality for NPC was radiation therapy, whereas that of other carcinomas of the head and neck was surgery. Lawrence and Cottel reported that postoperative radiotherapy of squamous cell carcinoma with perineural invasion resulted in a much improved survival probability when compared with that observed after

MRI-Detected Cranial Nerve Involvement in Nasopharyngeal Carcinoma 131

and high-risk clinical target volume. A higher radiation dose improved tumor control and survival in NPC. We suggest that an adequate dose should be determined for these patients

Prognosis may depend not only on the extent of disease on MRI but also on the effectiveness of treatment. Variability of treatment may be one of the limitations of our study. In our series, most patients with stage III and IV disease received chemotherapy, but some did not receive chemotherapy (patients with advanced age, heart disease, diabetes, and patients in the control group in a clinical trial). Although 3-DCRT/IMRT techniques were reported to provide excellent locoregional control for NPC, distant metastases are still the main cause of treatment failure [21]. In our series, only a small percentage of patients were treated with IMRT/3-DCRT because of resource limitations; however, when included as a covariate, radiation technique was not an independent prognostic factor for either distant failure or

The incidence of MRI-detected CN involvement in NPC is high and is often observed in asymptomatic patients, and the incidence of MRI-demonstrable trigeminal nerve involvement is much higher than other nevers. Disease with MRI-detected CN involvement has a poor prognosis, independent of lesion localization and symptoms in local advanced

[1] Williams LS, Mancuso AA, Mendenhall WM. Perineuralspread of cutaneous squamous

management and prognosis. Int J Radiat Oncol Biol Phys. 2001;49:1061-1069. [2] Gebarski SS, Telian SA, Niparko JK. Enhancement along the normal facial nerve in the facial canal: MR imaging and anatomic correlation. Radiology. 1992;183:391-394. [3] Curtin HD, Wolfe P, Snyderman N. The facial nerve between the stylomastoid foramen and the parotid: computed tomographic imaging. Radiology. 1983;149:165-169. [4] Lin JC, Jan JS. Locally advanced nasopharyngeal cancer: long-term outcomes of radiation

[5] Jun Ma, Lizhi Liu, Linglong Tang, et al. Retropharyngeal lymphadenopathy in

[6] Zhao C, Han F, Lu LX, et al. Intensity modulated radiotherapy for local-regional

[7] Wei L, Xiaowu D, Taixiang L. Dosimetric evaluation for 3 dimensional radiotherapy

[8] Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat

advanced nasopharyngeal carcinoma. Ai Zheng. 2004;23:1532-1537.

[9] Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187-220.

nasopharyngeal carcinoma: prognostic value and staging categories. Clin Cancer

plans for patients with early nasopharyngeal carcinoma. Ai Zheng. 2004;23:605-608.

therapy. Radiology. 1999;211:513-518.

Res. 2007;13: 1445-1452.

Assoc. 1958;53:457-481.

and basal cell carcinoma: CT and MR detection and its impact on patient

with MRI-detected CN involvement.

**4.4 Limitations of our study** 

death in multivariate analyses.

**5. Summary** 

**6. References** 

disease.

conventional surgical excision [13]. Radiation therapy (relatively large treatment volume) provided better LRFS to patients with perineural spread. Early results of improved treatment strategies for nasopharyngeal carcinoma, including the boost technique of 2 dimensional radiation therapy, use of IMRT, and combinationof chemotherapy with radiotherapy, has shown considerable improvement in LRFS [15-16]. Improved treatment might result in no significant difference with regard to the 3-year LRFS rate in patients with T3-4 disease with or without MRI findings of CN involvement.

The LRFS in patients with intracranial or orbital CN involvement was so poor that there was little difference in the 3-year LRFS rate between T3 patients with MRI-detected CN involvement and T4 patients. This poor survival rate may be a result of difficulties encountered in designing a therapeutic strategy for these patients and limitations on the dose escalation for intracranial or orbital disease. Several studies have demonstrated that perineural tumor spread in other head and neck cancers may result in a higher incidence of distant metastases [17-18]. We found that MRI-detected CN involvement was associated with a greater propensity for distant metastasis and resulted in unfavorable outcome in OS. Batsakis reported that carcinoma proliferated along the nerves within the lymphatics of the epineurium and the perineural sheaths [19]. We presume that tumor proliferation within the lymphatics may increase the risk of distant metastasis. On the basis of our data, the pattern of treatment failure in the NPC patients with CN involvement is caused by distant metastases. This implies that tumors with perineural involvement are more aggressive and spread from the primary tumor site to distant organs. Understanding the perineural invasion at the molecular level is an important step toward identification of the prognostic markers and therapeutic targets for NPC treatment.

Both clinical CN palsy and MRI-detected CN involvement were significant and independent predictive factors for the DMFS and OS rates in local advanced disease. In patients with clinical CN palsy or MRI-detected CN involvement, there is no real difference in the OS and DMFS between symptomatic and asymptomatic patients. This implies that MRI-detected involvement of CN itself has a poor prognosis in high-risk NPC irrespective of the clinical symptoms caused by such an involvement. In current *AJCC Cancer Staging Manual*, that CN involvement be assessed by neurological evaluation is recommended, rather than by crosssectional imaging. Therefore, MRI-detected CN involvement should be involved in the future staging system.

#### **4.3 Clinical value of MRI-detected CN involvement in treatment**

Almost all the patients with MRI-detected CN involvement were classified as T3-4. Concurrent chemoradiotherapy has emerged as the treatment of choice for locoregionally advanced (T3-4) NPC. Therefore, all patients with MRI-detected CN involvement should receive concurrent chemoradiotherapy. According to our data, these patients had a high distant metastasis rate; therefore, more intensive chemotherapy regimes should be considered.

Chang et al demonstrated that MRI was associated with improved tumor control of patients with NPC and CN palsy [20]. Because MRI can be used to clearly detect the location and extent of CN invasion, MRI should be considered as a basic imaging modality in the delineation of the target volume, ensuring full coverage of the gross target target volume and high-risk clinical target volume. A higher radiation dose improved tumor control and survival in NPC. We suggest that an adequate dose should be determined for these patients with MRI-detected CN involvement.

#### **4.4 Limitations of our study**

Prognosis may depend not only on the extent of disease on MRI but also on the effectiveness of treatment. Variability of treatment may be one of the limitations of our study. In our series, most patients with stage III and IV disease received chemotherapy, but some did not receive chemotherapy (patients with advanced age, heart disease, diabetes, and patients in the control group in a clinical trial). Although 3-DCRT/IMRT techniques were reported to provide excellent locoregional control for NPC, distant metastases are still the main cause of treatment failure [21]. In our series, only a small percentage of patients were treated with IMRT/3-DCRT because of resource limitations; however, when included as a covariate, radiation technique was not an independent prognostic factor for either distant failure or death in multivariate analyses.

#### **5. Summary**

130 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

conventional surgical excision [13]. Radiation therapy (relatively large treatment volume) provided better LRFS to patients with perineural spread. Early results of improved treatment strategies for nasopharyngeal carcinoma, including the boost technique of 2 dimensional radiation therapy, use of IMRT, and combinationof chemotherapy with radiotherapy, has shown considerable improvement in LRFS [15-16]. Improved treatment might result in no significant difference with regard to the 3-year LRFS rate in patients with

The LRFS in patients with intracranial or orbital CN involvement was so poor that there was little difference in the 3-year LRFS rate between T3 patients with MRI-detected CN involvement and T4 patients. This poor survival rate may be a result of difficulties encountered in designing a therapeutic strategy for these patients and limitations on the dose escalation for intracranial or orbital disease. Several studies have demonstrated that perineural tumor spread in other head and neck cancers may result in a higher incidence of distant metastases [17-18]. We found that MRI-detected CN involvement was associated with a greater propensity for distant metastasis and resulted in unfavorable outcome in OS. Batsakis reported that carcinoma proliferated along the nerves within the lymphatics of the epineurium and the perineural sheaths [19]. We presume that tumor proliferation within the lymphatics may increase the risk of distant metastasis. On the basis of our data, the pattern of treatment failure in the NPC patients with CN involvement is caused by distant metastases. This implies that tumors with perineural involvement are more aggressive and spread from the primary tumor site to distant organs. Understanding the perineural invasion at the molecular level is an important step toward identification of the prognostic

Both clinical CN palsy and MRI-detected CN involvement were significant and independent predictive factors for the DMFS and OS rates in local advanced disease. In patients with clinical CN palsy or MRI-detected CN involvement, there is no real difference in the OS and DMFS between symptomatic and asymptomatic patients. This implies that MRI-detected involvement of CN itself has a poor prognosis in high-risk NPC irrespective of the clinical symptoms caused by such an involvement. In current *AJCC Cancer Staging Manual*, that CN involvement be assessed by neurological evaluation is recommended, rather than by crosssectional imaging. Therefore, MRI-detected CN involvement should be involved in the

Almost all the patients with MRI-detected CN involvement were classified as T3-4. Concurrent chemoradiotherapy has emerged as the treatment of choice for locoregionally advanced (T3-4) NPC. Therefore, all patients with MRI-detected CN involvement should receive concurrent chemoradiotherapy. According to our data, these patients had a high distant metastasis rate; therefore, more intensive chemotherapy regimes should be

Chang et al demonstrated that MRI was associated with improved tumor control of patients with NPC and CN palsy [20]. Because MRI can be used to clearly detect the location and extent of CN invasion, MRI should be considered as a basic imaging modality in the delineation of the target volume, ensuring full coverage of the gross target target volume

T3-4 disease with or without MRI findings of CN involvement.

markers and therapeutic targets for NPC treatment.

**4.3 Clinical value of MRI-detected CN involvement in treatment** 

future staging system.

considered.

The incidence of MRI-detected CN involvement in NPC is high and is often observed in asymptomatic patients, and the incidence of MRI-demonstrable trigeminal nerve involvement is much higher than other nevers. Disease with MRI-detected CN involvement has a poor prognosis, independent of lesion localization and symptoms in local advanced disease.

#### **6. References**


[10] Neel HB. Nasopharyngeal carcinoma: clinical presentation, diagnosis, treatment and prognosis. Otolaryngol Clin North Am. 1985;18:479-490.

**8** 

Ken Darzy

*United Kingdom* 

**Endocrine Complications Following** 

Long-term endocrine disorders are the most frequent complications in survivors of adult and paediatric nasopharyngeal carcinoma (NPC). The hypothalamic-pituitary (h-p) axis lies within the field of radiation therapy for NPC. Consequently, neuro-endocrine abnormalities due to radiation-induced damage of the h-p occur in the majority of patients followed long term. Similarly, radiation injury to the thyroid gland can result in primary thyroid dysfunction, particularly hypothyroidism as well as benign and malignant thyroid nodule. Chemotherapy-induced gonadal damage is another frequently seen complication in patients

Most of the endocrine complications are irreversible and progressive in nature. They may be of sufficient severity to have adverse impact on growth and pubertal development (in children), body image, sexual function, fertility, muscular and skeletal health and ultimately quality of life. It is mandatory that survivors of NPC undergo regular clinical, radiological and/or hormonal surveillance to ensure early diagnosis of these complications and appropriate and timely introduction of hormone replacement therapy and other therapeutic

Radiation damage is a potent cause of hypothalamic-pituitary (h-p) axis dysfunction. Deficiency of one or more of the anterior pituitary hormones may occur following radiotherapy for tumours of the head and neck when the h-p axis falls within the field of radiation. The pathophysiology of radiation-induced damage remains poorly understood. Neuronal cell death and degeneration due to the direct effects of radiation appear to play a major role (Hochberg et al., 1983); however, vascular damage has also been proposed

The onset and severity of radiation-induced hypopituitarism is primarily determined by the total radiation dose, the fraction size and the time allowed between fractions for tissue

**2. Radiation-induced hypothalamic-pituitary dysfunction** 

**1. Introduction** 

treated with chemotherapy.

interventions.

**2.1 Pathophysiology** 

(Chieng et al., 1991).

**Radiotherapy and Chemotherapy** 

**for Nasopharyngeal Carcinoma** 

*East & North Hertfordshire NHS Trust* 

