Suat W. Loo and Tom Roques
Case history
A 60-year-old white man presented with a 6-week history of epistaxis, nasal obstruction, headache, diplopia, and left neck swelling. On clinical examination, there was left-sided sixth cranial nerve palsy and a palpable cervical node in the left level II neck measuring 4cm in maximum dimension. Flexible nasoendoscopy showed a mass in the left nasopharynx. Biopsy confirmed a moderately differentiated non-keratinizing carcinoma. MRI revealed a soft tissue mass centred on the left nasopharynx with extension into the oropharynx and ipsilateral parapharyngeal space. There was marrow infiltration of the skull base with involvement of the left cavernous sinus (Fig. 2.1). Enlarged bilateral level II cervical nodes were present, the largest measuring 4.5cm in its greatest dimension. Computed tomography showed erosion of the skull base with no evidence of distant metastatic disease.
Fig. 2.1 MRI scan shows left side nasopharyngeal cancer with left cavernous sinus and paraoesophageal invasion, and enlarged upper deep cervical nodes
Questions
1. What is the histological classification of this patient’s nasopharyngeal carcinoma according to the World Health Organization (WHO)?
2. What is the stage of this patient’s nasopharyngeal carcinoma?
3. What is the optimal management?
Answers
1. What is the histological classification of this patient’s nasopharyngeal carcinoma according to the World Health Organization (WHO)?
The WHO grading system divides nasopharyngeal carcinoma into keratinizing squamous cell carcinoma (WHO type I) and non-keratinizing carcinoma. The latter is in turn subdivided into differentiated (WHO type II) and undifferentiated carcinomas (WHO type III). Lymphoepithelioma is a WHO type III nasopharyngeal carcinoma characterized by a lymphoid infiltrate. Thus, this patient has a WHO type II nasopharyngeal carcinoma. Approximately 95% of affected patients from southern China have either WHO type II or III nasopharyngeal carcinoma whereas a quarter of those from the United States have WHO type I disease. The Epstein–Barr virus is associated with type II and III tumours. Undifferentiated nasopharyngeal carcinomas respond better to radiotherapy than differentiated ones; however, they have a higher rate of distant metastasis compared with their differentiated counterparts.
2. What is the stage of this patient’s nasopharyngeal carcinoma?
There are two major staging systems in use for nasopharyngeal carcinoma: the 1997 revised American Joint Committee on Cancer (AJCC) TNM system (Fleming et al. 1997) and the Ho system (Ho 1978). The AJCC system is preferred in Europe and the United States. According to the AJCC TNM classification, this patient has T4N2M0 or stage IVA disease in view of the intracranial disease extension and the presence of bilateral involved cervical nodes less than 6cm in size. The majority of patients with nasopharyngeal carcinoma present with either stage III or IV disease.
3. What is the optimal management?
Radiotherapy to a curative dose is the cornerstone of management in nasopharyngeal carcinoma. The Intergroup 0099 Phase III Study (Al-Sarraf et al. 1998) showed improved survival with the addition of chemotherapy to radiotherapy in advanced-stage disease. In this study, patients with advanced-stage nasopharyngeal carcinoma were randomly assigned to receive either radiotherapy alone to 70Gy or the same radiotherapy schedule with three cycles of concurrent cisplatin followed by three cycles of adjuvant cisplatin and 5-fluorouracil (5-FU) chemotherapy. There was a statistically significant improvement in the 3-year survival rate from 47% to 78% with the addition of chemotherapy to radiotherapy. Based on the results of this study, the optimal management of this patient should be radiotherapy to a curative dose with concurrent platinum-based chemotherapy. The addition of induction chemotherapy is preferred, as the toxicities of concurrent chemoradiotherapy may preclude delivery of adjuvant chemotherapy. This treatment paradigm results in local tumour control rates of approximately 50–70% in T4 tumours and regional control rates of 70% in N2 disease. Neck dissection is reserved for those with persistent nodal disease following chemoradiotherapy. Although chemoradiotherapy is effective in nasopharyngeal carcinoma, it can also result in long-term treatment-related toxicities due to close proximity of the tumour to adjacent organs such as the major salivary glands, pituitary gland, temporal lobes, and the middle and inner ear. Xerostomia is one of the major late complications of chemoradiotherapy for nasopharyngeal carcinoma due to the high radiation doses received by the parotid glands. Consequently, techniques such as intensity-modulated radiotherapy have been explored in an attempt to improve the therapeutic ratio. By producing highly conformal dose distributions around the tumour volume with sparing of the adjacent uninvolved organs, intensity-modulated radiotherapy has the potential to reduce the long-term toxicity of treatment. Indeed, there is now randomized evidence to show that intensity-modulated radiotherapy reduces the incidence of severe late xerostomia compared with two-dimensional non-conformal techniques in patients with nasopharyngeal carcinoma treated with high-dose radiotherapy.
The patient was treated with three cycles of induction cisplatin and 5-FU chemotherapy followed by intensity-modulated radiotherapy to a dose of 66Gy in 33 fractions over 6.5 weeks with concurrent weekly carboplatin, achieving a complete response. Post-treatment MRI showed no evidence of persistent disease. Endoscopy and biopsies confirmed the absence of residual tumour. Four years following completion of treatment the patient re-presented with nasal obstruction and trismus. Flexible nasoendos-copy showed a lesion in the post-nasal space. Repeat imaging revealed local recurrence of tumour within the left nasopharynx with involvement of the ipsilateral medial ptyergoid muscle and skull base. Biopsies demonstrated recurrent nasopharyngeal carcinoma. 18FDG PET-CT scan showed tracer uptake in the left nasopharynx with anterior extension into the pterygoid region with no evidence of nodal relapse or distant metastasis. His ECOG performance status remained 0 and he had no residual toxicity from his previous chemoradiotherapy.
Question
4. What is the optimal management of this patient’s recurrent disease?
Answer
4. What is the optimal management of this patient’s recurrent disease?
Despite the effectiveness of chemoradiotherapy, a significant proportion of patients with advanced-stage nasopharyngeal carcinoma will develop local recurrence of tumour. These patients have a poor prognosis if left untreated. Early stage local recurrences can be managed with salvage nasopharyngectomy, intracavity brachytherapy, or interstitial implants. Unfortunately more than half of all local recurrences present as rT3 or rT4 tumours. In these cases, surgery or brachytherapy are of limited benefit. Re-irradiation with external beam radiotherapy represents the only potentially curative treatment option (Fig. 2.2). However, it is associated with a significant risk of damage to normal tissue due to the close proximity of the recurrent tumour to adjacent critical organs. Several factors therefore need to be taken into consideration when considering re-irradiation for this group of patients. These include the time interval from the initial radiotherapy treatment, the radiation dose already delivered to the adjacent critical structures, the severity of existing late complications from previous radiotherapy, and the ECOG performance status of the patient. The risk of long-term treatment-related complications should be carefully discussed and appropriate consent obtained. During re-irradiation, the radiation dose to the adjacent critical structures should be kept as low as possible. This is best achieved using highly conformal techniques such as intensity-modulated radiotherapy. Available data from the published literature suggest that the toxicity from re-irradiating locally recurrent nasopharyngeal carcinoma is acceptable. In a patient series reported by Qiu et al. (2012), moderate to severe late toxicity was noted in 35.7% of patients treated with re-irradiation using intensity-modulated radiotherapy. Of these, 15.7% had posterior nasal space ulceration, 24.3% experienced cranial nerve palsy, 17.1% developed trismus, and 17.1% experienced deafness. There are now an increasing number of published single-institution reports on the use of intensity-modulated radiotherapy in the re-irradiation of radio-recurrent nasopharyngeal carcinoma showing promising survival outcomes. With careful patient selection, 5-year survival rates of up to 42% for rT3 and 17% for rT4 tumours can be achieved. As a result, re-irradiation is now considered to be standard practice in the management of radio-recurrent nasopharyngeal carcinoma. The patient in this case study has locally advanced recurrent nasopharyngeal carcinoma with extension into the masticator space and skull base. He is thus unsuitable for salvage surgery or brachytherapy. Despite his recurrent disease, his ECOG performance status remains excellent. Moreover, it is 4 years since his initial radiotherapy and he has no residual toxicity from his previous treatment. The optimal management is thus re-irradiation with intensity-modulated radiotherapy.
Fig. 2.2 (See also colour plate section)
Treatment details and outcome of the case
The patient was re-irradiated using intensity-modulated radiotherapy to a dose of 60Gy in 30 fractions with concurrent weekly cisplatin. He tolerated treatment well with minimal acute toxicity. Unfortunately, he died of persistent local disease 4 months following completion of treatment.
Further reading
Al-Sarraf M, Leblanc M, Giri S, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup Study 0099. Journal of Clinical Oncology1998; 16: 1310–1317.
Chang JT, See LC, Liao CT, et al. Locally recurrent nasopharyngeal carcinoma. Radiotherapy and Oncology 2000; 54: 135–142.
Fleming ID, Cooper JS, Henson DE, et al. (eds) AJCC cancer staging manual, 5th edn. Philadelphia: Lippincott-Raven, 1997; 33–35.
Ho JH. Stage classification of nasopharyngeal carcinoma: a review. In: Nasopharyngeal carcinoma: etiology and control, IARC Scientific Publication No. 20, 1978; 99–113.
Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. International Journal of Radiation Oncology Biology Physics 2006; 66: 981–991.
Qiu S, Lin S, Tham IW, Pan J, Lu J, Lu JJ. Intensity-modulated radiation therapy in the salvage of locally recurrent nasopharyngeal carcinoma. International Journal of Radiation Oncology Biology Physics2012; 83: 676–683.
Shanmugaratnam K, Sobin LH. Histological typing of tumors of upper respiratory tract and ear. In: International histological classification of tumours, 2nd edn (ed. Shanmugaratnam K, Sobin LH). Geneva: WHO, 1991; 32–33.