1. GENERAL INFORMATION
Cancer of nasopharynx (NPC) is rare in Europe, with an annual incidence of less than 1 per 100,000 (Parkin 2002). The highest European incidence rates (world age-adjustusted) is in Malta (2.62 per 100,000 in men). In Spain (Asturias, Albacete, Tarragona), Italy (Varese, Parma, Ragusa) and France (Haut-Rhin, Doubs), incidence rates are, in men, higher than 1. The lowest incidence is found in Norway, Denmark, Finland and Sweden and some areas of the UK (0.2-0.3 per 100,000 men). On the world scale, NPC accounts 65,000 new cases per year, or 0.6% of all cancers (Stewart 2003). The highest risk areas in the world for developing NPC are found in South East Asia, North Africa and southern China (Figure 1). In Hong Kong NPC is the second most frequent tumour after lung cancer. North African immigrant populations account for a significant part of the incidence especially the first generation (Jeannel 1993). Incidence remains high also for chinese people who have immigrated to North America, but is lower among chinese people born in North America. These results favor a critical role of environmental factors in the risk of NPC (Hanley 1995). NPC occurs predominantly in males: the European male-to-female ratio for incidence is 4.5: 1.4 (Ferlay 2001). The age-specific incidence curves for NPC are unlike those for other cancers in this region of the body: NPC occurs in younger patients, including children under five years old, but the peak incidence is seen in people aged between 55 and 64 years (Ferlay 2001). Recent epidemiological studies show a decrease of 30% in incidence of NPC in Hong Kong over the past 20 years ( Lee 2003).
The prevalence of NPC, that is the number of people living with a diagnosis of NPC, is only known for Italy (Micheli 1999), where in 1992 the average prevalence was 14 per 100,000 (22/100,000 for men and 7/100,000 for women). The great majority (83%) were long-term survivors, that is people living with a diagnosis made 5 or more years before the survey date.
In Europe the relative survival rate for NPC was 73% at one year and 43% at five years in adults (Berrino 2003). Survival was slightly higher for women (49%) than for men (41%). The effect of age on survival is marked. Survival at five years was 57% for the youngest age group (15-45 years) and 19% in the oldest group of patients (75 years old and over). There was a slight improvement in 5-year survival since the early 1980s, from 37% to 42%, the increment was more pronounced in patients with 45-65 years of age (Roazzi 2003). Patients with squamous cell carcinoma, the most common form of the disease in Europe, had a 10-30% worse survival than those with undifferentiated carcinoma (Jiong 1998). This is because undifferentiated tumours are more sensitive to radiotherapy and chemotherapy – the standard treatments for NPC. Stage is an important prognostic indicator, but unfortunately data on stage were only available in a few cancer registries. Data from the English registries show that spread to adjacent structures, involvement of regional lymph nodes, and metastasis occurs in about 70% of cases (Coleman 1999).
2. PATHOLOGY and BIOLOGY
2.1 Histological types2.1.1
|TYPE 1||Keratinizing squamous cell carcinoma (M8071/3)|
|TYPE 2||Non keratinizing carcinomas (8072-3/3)|
|· Differentiated non keratinizing carcinoma (8072-3/3)|
|· Undifferentiated carcinoma (undifferentiated carcinoma of nasopharyngeal type) (M8020/3)|
|TYPE 3||Basaloid squamous cell carcinoma (8083/3)|
Carcinomas account for about 85% of the histological varieties of nasopharyngeal malignant tumours. The following histotypes, listed according to the World Health Organization (WHO 1991) classification, are considered in this chapter. The ICD-O (“International Classification of Diseases for Oncology”) morphology code is provided in brackets (ICD-O 2000).
Carcinomas considered in this chapter arise from the ectodermic tissues of the nasopharyngeal walls and supporting structures. Poorly or undifferentiated carcinoma is characterized by a lymphoid infiltration, which accounts for the description of lymphoepithelioma. The WHO-type 1 histotype is identified in one-third to one-half of nasopharyngeal cancers occurring in low risk populations, such as North Americans.
Squamous cell carcinomasand undifferentiated carcinomas display distinct clinical behaviours and therefore the clinical decision making process is essentially dictated by the WHO classification (as reported at 2.2.1.).
Basaloid squamous cell carcinomas are morphologically identical to the tumours occurring in other head and neck sides and are very rare neoplasms.
2.2 Biological data
2.2.1 Epstein-Barr virus expression
The association between Epstein-Barr virus (EBV) and nasopharyngeal carcinomas has been extensively studied. EBV is linked with WHO type 2 and 3 histology, while more debatable is the association with type 1 (keratinizing squamous cell carcinoma), especially in non endemic regions, where this histotype is more frequent (Raab-Traub 2002). EBV has been identified in a clonal pattern in pre-invasive lesions of the nasopharynx, that contain EBV RNAs characteristics of latent infection (Pathmanathan 1995). The viral proteins, latent membrane protein 1 and 2 (LMP1 and 2), act on cellular gene expression and cellular growth, causing the highly invasive, malignant growth of the neoplasm ( Raab-Traub 2002). LMP-1 has also been associated with metastatic cascade, reducing tumor cell adhesion, promoting extracellular matrix and basement membrane degradation and enhancing neovascularization (Yoshizaki 2002). EBV-encoded RNA (EBER) positivity is commonly present in undifferentiated carcinomas: its pathway works through induction of IGF-1, that acts as an autocrine growth factor (Iwakiri 2005). EBER positivity is a predictor for improved overall survival (Shi 2002).
2.2.2 Genetic alterations
Several genetic markers of the HLA system have been investigated in patients with nasopharyngeal carcinoma in China and other parts of Asia. Evidence for positive associations between nasopharyngeal cancer and HLA alleles A2, B14 and B46 has been reported, while negative associations exist with alleles HLA A11,B13 and B22 (Goldsmith 2002 ). The deletion of the short arm of chromosome 3 is the karyotypic defect most often associated with nasopharyngeal cancer. Homozygous deletion of the p16 locus and chromosome 9p21-22 were found in most of the studied cases (Huang 1994; Lo 1995). No specific cellular oncogene has been found activated through mutation, translocation or amplification, except for an overexpression of c-myc and Int-2 recently reported (Fan 2000), and a more dubious amplification of c-erbB-2 (Yazici 2000). In the advanced disease VEGF expression is significantly increased in respect to early disease (Guang-Wu 2000). c-KIT immunohistochemical determination has been shown positive in one third of cases in a small study, linked to EBV-positive, WHO type 2 and 3 histology (Bar-Sela 2003). EGFR expression is frequent in NPC, reported in more than 80% of analysed cases (Chua 2004; Leong 2004; Ma 2003). Deregulation of cell cycle plays an important role in pathogenesis, mainly by the inactivation of the p16/INK4A gene and the overespression of cyclin D1 (Lo 1995). Inibition of apoptosis is another step in cancerogenesis, with overespression of bcl2 and inactivation of p53 as main mechanisms (Yang 2001). Although p53 immunohistochemical overexpression is frequent in this neoplasm (Agaoglu 2004), a gene mutation is rarely observed (Effert 1992), and its function could be abrogated by other pathways. Telomerase reactivation may play a role in the carcinogenesis of nasopharyngeal cancer (Chang 2000b). Complex gene profiling reveals a pattern of growth, survival, and invasion-promoting genes aberrant expression (Sriuranpong 2004).
2.2.3 Other viruses
The smaller group of keratinized squamous cell carcinomas seems to be only infrequently associated with EBV. Recent studies, based on polymerase chain reaction, demonstrate that a percentual ranging from 25% to 44% of squamous cell carcinomas of the nasopharynx (WHO-type 1) harbor Human Papillomavirus (HPV) genomic sequences, of type 11 or 16. These putatively oncogenic HPV types may thus be involved in the carcinogenesis of some EBV-negative keratinizing carcinomas of the nasopharynx ( Hording 1994).
2.3 Accuracy and reliability of pathological diagnosis
2.3.1 Accuracy and reliability of pathological diagnosis
Keratinized and non keratinized cell carcinomas are the main two forms of nasopharyngeal carcinomas. While the keratinized form is easily diagnosed, the diagnosis of the non-keratinized carcinomas may be difficult (Weiland 1985). This latter form is characterized either by cells with well-defined cell margins that form a stratified pattern but do not produce keratin, or by cells with indistinct cell margins and a syncytial pattern. In the lymphoepithelioma group – which is considered as a subgroup of the non keratinized carcinomas – lymphocytes may obscure the true histo-morphologic features (Moss 1989). Among the malignancies that occur in the nasopharynx, the most likely to be confused with nasopharyngeal cancer is non-Hodgkin’s lymphoma. These problems may be solved by the use of histochemical and immunohistochemical techniques. Serology may help in specific cases.
2.4 Particular histological types considered elsewhere
Lymphomas account for 10% of the malignant lesions of the nasopharynx. They usually are of B-cell type with large cells in a diffuse pattern. They rarely invade the base of the skull and usually involve bilateral neck nodes. Spread to the gastrointestinal tract occurs in 10 to 15% of cases.
2.4.2 Other histotypes
Other malignant diseases of this anatomic site include adenocarcinomas and adenoid cystic carcinomas (of minor salivary gland origin), sarcomas, plasmocytomas, melanomas and other malignancies which defy classifications.
3.1 Signs and symptoms
Due to the anatomical structure and location of the nasopharynx, nasopharyngeal tumours may initially grow without producing any signs or symptoms. The most frequent early local symptoms are unilateral hearing loss, bleeding, nasal obstruction, or cervical adenopathies. Later signs are headache, cranial nerve palsies, or bilateral bulky cervical nodes which become fixed to the surrounding structures.
3.2 Diagnostic strategy
In the majority of cases the diagnosis of nasopharyngeal cancer is made at a late stage. If the first sign is solely an enlarged neck node, then the primary tumour may be very small. General anaesthesia is only required for a local clinical examination if the examination is impossible for anatomical reasons, if it is part of a panendoscopic search for a primary tumour, or to avoid patient’s distress. When enlarged cervical nodes are present, even without direct evidence of a primary tumour, panendoscopy is recommended. If the panendoscopic search is negative a fine needle aspiration of the node is recommended. before nodal biopsy, since it has been reported that such biopsy may result in a detrimental effect on survival (Tang 1990).
3.3 Pathological Diagnosis
Biopsy is mandatory for a pathological diagnosis of NPC. If an early or a submucosal lesion is present a CT scan may help as a guide to the biopsy site. Biopsy is generally performed under local anaesthesia. The entire nasopharynx is inspected endoscopically and the biopsy of the suspicious area should be taken under direct vision. Bleeding is rare and the procedure is generally well tolerated. Multiple biopsies under general anaesthesia are sometimes requested in doubtful cases, especially in the presence of neck metastases of undetermined origin.
4.1 Staging Classification
Several classification systems for nasopharyngeal cancer have been formulated. The most popular in Western countries is the UICC-AJCC classification, while in Eastern countries the most utilised is Ho’s classification. The value of this classification mainly lies in its higher efficiency in utilising nodal involvement as a prognostic indicator. Only in the recent UICC-AJCC classification have important prognostic factors (such as node level) been adopted and its validity confirmed ( Ozyar 1999). The value of the UICC-AJCC in comparison to the Ho classification is still to be defined (Heng 1999; Lee 1999a). No modifications have been introduced in the 2002 6th edition of AJCC classification. Stage grouping for either classification is probably an inproper way of bringing together clinical prognostic factors, which had already been considered in the original classification without adding any real advantage in terms of prognostic efficacy. For these reasons the use of stage grouping for the planning of individual treatment is not advisable.
4.1.1 TNM Classification (UICC 2002)
Primary Tumour (T)
T1 Tumour is confined to the nasopharynx
T2 Tumour extends to soft tissues of oropharynx and/or nasal fossa
T2a without parapharyngeal extension
T2b with parapharyngeal extension
T3 Tumour invades bony structures and/or paranasal sinuses
T4 Tumour with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx or orbit
Regional Lymph nodes (N)
NX Regional lymph nodes can not be assessed
N0 No regional lymph node metastasis
N1 Unilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossa
N2 Bilateral metastasis in lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular fossa
N3 Metastasis in lymph node(s)
N3a greater than 6 cm in dimension
N3b extension to the supraclavicular fossa
Distant metastasis (M)
—MX Distant metastasis can not be assessed
—M0 No distant metastasis —M1 Distant metastasis
4.1.2 Stage Grouping (UICC 2002)
Stage Grouping (UICC 2002)
|T3||N0, N1, N2||M0|
|Stage IVA||T4||N0, N1, N2||M0|
|Stage IVB||Any T||N3||M0|
|Stage IVC||Any T||Any N||M1|
4.1.3 Staging system of Ho
T: Primary tumour
T1: Tumour confined to nasopharynx (space behind choanal orifices and nasal septum and above posterior margin of soft palate in resting position)
T2: Tumour extended to nasal fossa, oropharynx, or adjacent muscles or nerves below base of skull
T3: Tumour extended beyond T2 limits and subclassified as follows:
T3a: bone involvement below base of skull (floor of sphenoid sinus is included in this category)
T3b: involvement of base of skull
T3c: involvement of cranial nerve(s)
T3d: Involvement of orbits, laryngopharynx (hypopharynx), or infratemporal fossa
N: Regional lymph nodes
N0: No node palpable or nodes thought to be benign
N1: Node(s) wholly in upper cervical level, bounded below by the skin crease extending laterally and backward from or just below thyroid notch (laryngeal eminence)
N2: Node(s) palpable between crease and supraclavicular fossa, the upper limit being a line joining the upper margin of the sternal end of the clavicle and the angle formed by the lateral surface of the neck and the superior margin of the trapezius
N3: Node(s) palpable in the supraclavicular fossa and/or skin involvement in the form of carcinoma en cuirasse or satellite nodules above the clavicles
M0: No hematogenous metastases
M1: Hematogenous metastases present, and/or lymphnodal metastases below the clavicle
I T1, N0
II T2 and/or N1
III T3 and/or N2
IV N3 (any T)
4.2 Staging procedures
4.2.1 Staging Imaging is required for the correct staging of and treatment planning for nasopharyngeal malignancies. Computed Tomography (CT) and/or Magnetic Resonance Imaging (MRI) are recommended for the diagnostic process and evaluation of tumoural extent at primary site and neck nodes. These techniques are able to detect bone erosion (Cheung 1994), and also to delineate subclinical tumour extensions to the para-and retropharyngeal spaces, the oropharynx, and the orbit (Sham 1991). The limitations of CT scanning are due to its relative lack of sensitivity in detecting skull base erosion, perineural infiltration and early intracranial spread. MRI appears to be better than CT for visualizing soft tissue invasion outside the nasopharynx, for demonstrating involved retropharyngeal nodes and for identifying skull base involvement (Chong 1996; Olmi 1995 ).
However it remains unclear if the early changes in the skull base images represent tumour infiltration or reactive changes. Positron Emission Tomography (PET) examination recently showed higher sensitivity in detecting distant metastases than conventional workup (chest X-ray, liver ultrasound echography, bone scan) (Chang 2005). Since asymptomatic distant metastases are frequent (up to 40% in patients with bulky involved nodes), this diagnostic tool is suitable for individual clinical use in N2-N3 NPC, on a type 3 level of evidence. Relatively low specificity of PET could increase the number of subsequent invasive procedures. Bone marrow aspiration is recommended in the case of blood count abnormalities. Besides these staging examinations, an X-ray study of the mandible and upper alveolar ridge (OPT) is recommended. Since radiotherapy is the predictable treatment for every case, dental care is mandatory before starting radiotherapy. Regarding follow up after radiation therapy, limitations of MRI and CT include a relatively low sensitivity and moderate specificity in recognising tumour recurrence or post treatment changes both in soft tissues and bone. PET has been evaluated in comparison with CT scans and MRI for the diagnosis of persistent or locally recurrent nasopharyngeal cancer ( Kao 1998; Yen 2003). Sensitivity, specificity and accuracy have been demonstrated to be superior with PET than with CT scanning or MRI, thus its application in this context is suitable for individual clinical use on a type 3 level of evidence.
The typical anti-EBV serologic profile of nasopharyngeal cancer patients consists of rises in IgG and IgA against virus capsid antigen (VCA) and early antigen (EA), as well as rises in IgG anti-Epstein-Barr virus nuclear antigen (EBNA). The sensitivity and specificity of IgA anti-VCA and anti-EA are particularly high, and this may prove especially useful in cases of anaplastic tumours which histologically mimick lymphomas or sarcomas. The role of ZEBRA (Z Epstein-Barr Replication Activator), and EBV replication activator protein in switching the virus from latent to productive could be helpful in diagnosis (Mathew 1994 ; Joab 1991). Quantitative analysis of cell-free Epstein-Barr Virus DNA in plasma of patients has been studied, and suggests a possible value of this tool in screening, predicting outcome and monitoring treatment (Lo 1999). In particular, combining serum EBV-DNA and IgA against VCA could improve screening accuracy (Leung 2004), while the presence of anti-EBV DNase antibodies and the presence of IgA against VCA are strong predictors of the risk of developing nasopharyngeal carcinoma (Chien 2001). Plasma EBV DNA concentration measured before therapy is a strong predictor of outcome and it could help in identifying early-stage patients with a greater risk of developing distant metastasis (Lin 2004; Leung 2003). Plasma EBV DNA concentration after chemo-radiotherapy predicts the likelihood of relapse and correlates significantly with overall and relapse-free survival (Lin 2004 ; Chan 2004; Chan 2002).
5.1 Natural history
5.1.1 General data
The natural history of nasopharyngeal cancer is dependent on local growth and metastatic potential. Infiltration is predominant in local growth. Keratinizing squamous cell carcinomas (WHO – type 1) have a more aggressive local tumour growth than non keratinizing and undifferentiated carcinomas (WHO-type 2), while lymphatic and hematogenous metastatic spread is more frequent for the latter types (Perez 1992).5.1.2 Local infiltration
Nasopharyngeal carcinoma grows either by infiltration or by expansion. Infiltration is often predominant and patients may present with symptoms related to the growth of the tumour into the surrounding anatomical structures. When nasopharyngeal carcinomas originate from the postero-superior wall, they tend to invade and destroy the base of the skull (25-35% of cases). Intracranial tumour spread is present in approximately 12% of patients. This may happen either by direct extension or by spread through the foramen lacerum which gives access to the cavernous sinus. The first phase of invasion is characterized by the involvement of the trigeminal nerve, whereas in late stages of infiltration the tumour invades the cavernous sinus with involvement of the abducens and the oculomotor nerves, and the carotid artery. When the tumour arises from the postero-lateral wall of the nasopharynx, it invades the parapharyngeal space and infiltrates the pterygoid space, the pterygoid muscles, and the lingual, inferior alveolar and auriculo-temporal nerves. In patients with more advanced disease, the post-styloid space, internal jugular vein, carotid artery and cranial nerves IX through XII can be involved ( Mendenhall 1994; Kwong 1994). Inferior extension along the oropharyngeal walls is also a common spread pattern found in up to one third of the patients and is often associated with the presence of bulky retropharyngeal nodes.5.1.3 Lymph node metastases
Lymph node metastases are observed in 75% of patients with nasopharyngeal carcinoma ( 60% of WHO-type 1 histotype and 85 to 90% of WHO-type 2). The first nodes to be involved are those in the parapharyngeal spaces (retropharyngeal space- post-styloid compartment) and then the cervical chains (jugular- spinal accessory). Invasion of the upper and middle spinal nodes (posterior chain) is typical of nasopharyngeal cancer.
5.1.4 Distant metastases
Distant dissemination of nasopharyngeal cancer is frequent, with autopsy studies showing 38-87% cases with distant metastases ( Ahmad 1986). The most frequently involved sites are bone (70-80%), lung (18%), liver (30%) and extraregional nodes (axillary, mediastinal, but also pelvic and inguinal) (Cvitkovic 1993).
At diagnosis, distant metastases are found in about 5 to 7% of patients. Within the first three years following treatment, the overall incidence of metastases is approximately 25%-30%, increasing with advanced stages of disease and in patients with undifferentiated nasopharyngeal tumours. While metastases will occur in about one fourth of the patients with type I carcinomas, the incidence can exceed 35% for undifferentiated nasopharyngeal tumours and even 55% in patients with bulky involved nodes (N3). The most common sites of involvement include bone, lung and liver (Ahmad 1986).
The incidence of metastatic disease is correlated with the nodal stage. A careful, prospective, pre-therapeutic workup of patients with bulky involved nodes (N3) showed a high rate of subclinical distant metastasis (40%) with the added distinctive feature of bone marrow invasion ( Micheau 1987). This was seen in 23% of cases and is related to bone metastasis (Cvitkovic 1993).
Death from NPC is usually due to the progression of loco-regional disease in patients with type I squamous cell carcinoma; the cause of failure is more often linked to distant metastases in the undifferentiated group. Loco-regional relapse also appears to be a significant risk factor for the development of distant metastases, especially during the first two years after primary treatment. In patients with loco-regional recurrence the incidence of distant metastases at 5 years exceeds 40%, whereas the corresponding figure for controlled tumours is only 30% (Kwong 1994; Mesic 1981).
Five year survival rates are 80-90% for stage I and II and 60-70 % for stage III and IVa-IVb. The prognosis of patients with early disease (T1-2, N0) is good, with approximately 85% local control and <10% distant failure at 10 years. Patients with more advanced disease have a different probability of local control and distant failure in relation to the extent of the tumour: T3-4, N0-1 has a high risk of local relapse (40%), but a low incidence of distant metastases (10%), T1-2, N2-N3 has a low risk of local recurrence (15%) and a high risk of distant relapse (40%), while T3-4, N2-3 has both a high risk of local recurrence (50%) and a high probability of developing distant metastases (40%). Loco-regional control and overall survival rates obtained after definitive radiotherapy have improved (roughly by 5 to 10%) throughout the last decades, mainly because of the progress in imaging and irradiation techniques ( Lee 1992); further 5 years survival benefit of 20% has been obtained in advanced disease since when concomitant chemotherapy was adopted (Langendijk 2004). The 5-year survival rate for undifferentiated carcinomas is roughly 20-30% higher than for squamous cell carcinomas (Mesic 1981; Fletcher 1980; Hoppe 1976; Sanguineti 1997). Incidence of second primaries appears to be inferior to the one of non nasopharyngeal squamous cell head and neck cancers (Cooper 1991).
5.2 Prognostic factors
5.2.1 Locoregional disease
Large node size is inversely related to survival in NPC and decreases the regional disease control rate (Kaasa 1993; Leung 1993).
Other node characteristics, such as mobility and level according to Robbin’s classification are associated with greater risk of distant metastases and worse outcome ( Ma 2001b). Advanced T-stage, oropharyngeal invasion, parapharyngeal and/or skull base involvement, squamous histology, more differentiated tumours and the presence of cranial nerve deficits (in particular II-VI nerve) are poor prognostic factors for local control (Sanguineti 1997). Number of involved sites within the nasopharynx, determined by multiple biopsies, has not been recognized as an independent prognostic factor (Sham 1992). Primary tumor volume measured by CT scan may predict outcome in advanced stages, while more questionable is its role as prognostic factor in early stage cancer (Chua 1997; Chua 2004a; Chang 2003).
5.2.2 Metastatic disease
Liver involvement and/or bone marrow invasion are correlated with a very poor prognosis (Cvitkovic 1993). Limited bone involvement may be associated with long term survival with systemic treatment (Fandi 2000). NPC metastatic to lung alone showed a better survival profile among a group with other different metastatic sites (Hui 2004). Poor performance status, anaemia and a disease free interval less than 6 months are unfavourable prognostic factors (Toh 2005; Ong 2003).
5.2.3 Molecular and biochemical prognostic factors
A strong expression of c-erbB-2, as well as intense tumour angiogenesis correlates with poor prognosis (Roychowdhury 1996). LDH values above the cut off value of 410 U/L has been associated with increased probability of distant metastases (Cheng 1998). EBV DNA pretreatment and post-treatment values predict progression-free and overall survival. There are conflicting results about a possible prognostic role for EGFR over-expression (Leong 2004; Ma 2003; Chua 2004a).
5.3 Predictive factors
5.3.1 Predictive factors for response to radiotherapy and chemotherapy
The histological type of nasopharyngeal carcinoma clearly has an impact on outcome. Usually, no difference is found between squamous cell carcinoma and undifferentiated carcinoma of the nasopharyngeal type (UCNT) in Chinese studies, but in this population cases of type I carcinoma are rare (<5%). For series in which both types of tumour are well discriminated, patients with squamous cell carcinoma (WHO – type 1) fare worse than patients with undifferentiated nasopharyngeal carcinoma (WHO – type 2) in terms of local control and overall survival (Kaasa 1993; Gallo 1991).
A retrospective study shows a much higher proportion (80%) of well vascularized (functional angiogenesis) involved metastatic nodes in nasopharyngeal cancer patients than in other head and neck epidermoid cancers (30%). This observation may explain the good chemo- and radio-sensitivity of the disease. An isodensity of the tumour relative to muscle, demonstrated by contrast-injected CT scan, is highly predictive of a positive outcome when primary cisplatin-based chemotherapy is used in head and neck cancer ( Munck 1991). In a retrospective study of patients treated with radiotherapy alone the pattern of nasal mucosa involvement (infiltrating versus exophytic protruding) was found to be prognostic in favour of the latter (Lin 1999). EBV DNA quantification in predicting outcome was already discussed. Midradiation haemoglobin levels have been related to outcome in terms of survival and local control of disease (Chua 2004b).
6.1 Early disease (Stage I and II)
6.1.0 General strategy
These patients are curable. The recommended treatment, on a type C basis, is radiotherapy at the T level and at bilateral neck nodes. In the future intensity-modulated radiotherapy (IMRT) will probably substitute conventional radiation. Few selected patients at stage II may benefit from the combination of chemotherapy.
6.1.1 Stage I
In patients with T1 N0 nasopharyngeal cancer the treatment of choice, on a type C basis, is definitive radiation therapy of the primary site and prophylactic radiotherapy on the whole neck, based on a conventional fractionation delivered 5 weekly fraction of 1.8 – 2.0 Gy each (Lee 1992; Fletcher 1980; Hoppe 1976; Lee 1989). Brachytherapy as boost treatment is suitable for individual clinical use on a type 3 level of evidence (Chang 1996; Teo 2000b). Radiosurgical techniques as boost treatment are investigational (Cmelak 1997; Tate 1999). More frequent acute complications are fibrinous mucositis, xerostomia, or dental caries. Serous otitis of the middle ear is an uncommon event (Altun 1995). Parotid-sparing intensity-modulated radiotherapy (IMRT) achieves good survival results, with partial recovery of salivary flow; its use is suitable for individual clinical use on a type 3 level of evidence ( Kwong 2004a).
6.1.2 Stage II
Treatment strategy of stage II is similar to that of stage I, consisting of definitive radiation dose to primary site and prophylactic dose to the whole neck, as a standard option on a type C basis. A small study, including stage II patients with a greater burden of disease treated with concomitant chemo-radiotherapy and two adjuvant cycles of chemotherapy achieved similar survival rate compared to stage I patients receiving radiotherapy alone. On these bases, the use of chemotherapy plus radiotherapy for stage II disease is suitable for individual clinical use on a type 3 level of evidence (Cheng 2000). Stratifying stage II according to risk factors (parapharyngeal extension – positive nodes – high EBV DNA plasma level (Ma 2001a; Chua 1997; Leung 2003), the use of chemotherapy in adjunct to radiotherapy might be considered as investigational.
6.2 Advanced disease (Stage III and IVa-IVb)
6.2.0 General strategy
This patients are curable. The standard option, on a type 1 level of evidence, in theses cases is the combination of cisplatin containing chemo and radiation.
6.2.1 Stage III and IV
A recent meta-analysis of full published randomised studies including mainly advanced stages showed a significant benefit for combination of radiotherapy and concurrent chemotherapy over radiotherapy alone (Langendijk 2004). An absolute survival benefit of 20% after 3 years was found with the adjunct of chemotherapy. Another meta-analysis more recently published confirmed these data, even though it did so with a smaller beneficial effect for chemotherapy (Baujat 2006). In this context the recommended treatment is a combination of chemoradiation, on a type 1 level of evidence with cisplatin containing chemotherapy. An Asiatic randomised trial, with almost all WHO type 2-3 histology, adopted a scheme of concurrent chemotherapy with uracil and tegafur, including also adjuvant chemotherapy (Kwong 2004b). A borderline statistically significant survival benefit of concomitant chemo-radiotherapy was observed. Other randomised studies adopting platinum-based concurrent chemotherapy (almost all comprised in Langendijk meta-analysis) showed better overall survival for combined treatment arm (Al Sarraf 1998 ; Al Sarraf 2001; Chan 2005b; Lin 2003; Wee 2005). Benefit of concurrent chemo-radiation treatment has been demonstrated both for endemic and non-endemic nasopharyngeal cancers. Another recent preliminary report of an Asiatic study observed a better loco-regional relapse free survival when chemotherapy is added to radiotherapy, but this gain does not reflect into a survival benefit (Lee 2005). The role of neoadjuvant chemotherapy has been investigated in several randomised studies: some trials detected a benefit in disease control (loco-regional or distant one) for induction chemotherapy arm, however no overall survival advantage was shown ( VUMCA 1996). Induction chemotherapy provides ome improvement in distant metastases control and by tumor shrinking away from critical structures when defining gross tumour volume for radiation treatment (Sanguineti 2003). In this context neaodjuvant chemotherapy can not substitute concurrent chemotherapy which remain the mainstay of treatment of advanced disease. Neoadjuvant chemotherapy can be however added to concurrent chemo-radiation and this could be considered suitable for individual clinical use on a type 2 level of evidence (Oh 2003; Rischin 2002; Al Amro2005). Adjuvant chemotherapy after radiation treatment alone failed to show any benefit in randomised studies (Rossi 1988; Chi 2002) thus its use is not recommended. Few data regarding altered fractionation radiotherapy are available. This field regards studies of accelerated fractionation (i.e. six fractions of radiotherapy per week instead of five), hyperfractionation (based on twice-a-day fractionation schemes, delivering 1.2 Gy per fraction with a minimum 6-hour interval between treatments), accelerated hyperfractionation and combination of these with chemotherapy. Questions about altered fractionation regard side effects. One randomised study demonstrated an increased damage to the central nervous system without significant improvement when accelerated hyperfractionation along with conventional radiation was given, compared with conventional radiation treatment ( Teo 2000a). In another study an unexpected incidence of temporal lobe necrosis with altered fractionation was observed (Lee 1999c). On the other hand a phase II study demonstrated the feasibility of giving a concomitant boost of radiotherapy with cisplatin and suggested a survival advantage when compared with historical controls treated with standard radiotherapy (Wolden 2000). Improvement in local control with hyperfractionation and chemotherapy has been demonstrated for T3-T4 lesions (Jian 2002). Similar results in another phase II studies have been achieved with hyperfractionation, obtaining a survival advantage for selected patients (with N2-N3 disease) (Wang 1989). Accelerated fractionation showed a better progression free survival over standard radiotherapy in T3-T4 tumours, in a retrospective analysis (Lee 2001). the use of these altered fractionated schemes is to be considered suitable for individual clinical use in selected patients on a type 3 level of evidence. Evidences in favour of intensity modulated radiotherapy (IMRT) in nasopharyngeal cancer are cumulating, even if not yet strengthened by randomised studies. This technique allows an increased dose of radiotherapy delivered to target area, improving dose-differential between the tumour and the dose-limiting areas and reducing toxicities due to salivary glands irradiation. Preliminary data derived from phase II studies are encouraging for what concerns outcome and toxicities ( Hsiung 2002; Lee 2002; Kwong 2004a; Kam 2004). IMRT is suitable for individual clinical use on a type 3 level of evidence. Hopefully the better irradiation precision and normal tissue sparing offered by IMRT techniques will allow the combination of radiotherapy with more intensive chemotherapy regimes, without increasing significantly the acute and late toxicities of a therapeutic management based on chemo-radiation.
6.3 Treatment of relapsed disease
6.3.0 General strategy
In patients with squamous cell carcinomas of the nasopharynx, most recurrences are diagnosed within 3 years. In every case of disease relapse treatment is indicated, the nature of which depends mainly on prior treatment.
6.3.1 Local recurrence
When a recurrence has been radiologically and, if possible, histologically documented and the lesion is limited to the nasopharynx, adjacent sphenoid sinus or base of the skull, reirradiation can be considered. Timing of the pathological postradiotherapy evaluation is critical, since late remissions are observed ( Kwong 1999). Retreatment with external irradiation or brachytherapy is suitable for individual clinical use in selected patients on a type 3 level of evidence. A total dose of 60 Gy is required, usually consisting of 45-50 Gy with external beam and then a boost to the nasopharynx with an intracavitary implant with an addition of 10-15 Gy (Cmelak 1997). The magnitude of benefit varies markedly among series: in some selected cases with localized recurrence survival rates of 40%-45% and of 25%-40% have been reported at 5 and 10 years, respectively (Buatti 1995; Goffinet 1993; Pryzant 1992; Wang 1987) but eradication of the recurrent tumour occurs in only 10-30% of such patients. Extension of local recurrence seems to affect local control (Lee 1997a). Survival after retreatment is adversely affected by advanced initial disease (5-year survival is around 15% for T3-T4) and by a short disease-free interval (5-year survival is 13% for recurrence occurred within 2 years versus 66% for those occurred after 2 years). The prognosis is more favourable in patients initially staged T1 or T2 (5-year survival is around 40%) and retreated with high doses (60 Gy) ( Wang 1987) and in the cases with long latency (lee 1999b). Possible complications after reirradiation include xerostomy, osteoradionecrosis, dental caries and neurological complications such as brain necrosis or visual impairment. They are found in 10 to 30% of the re-irradiated cases (Pryzant 1992). Conformal reirradiation may reduce these complications (Chang 2000c). Use of IMRT has been recently adopted, with an acceptable toxicity profile and good tumour response (Lu 2004). Stereotactic radiosurgery (median dose 12,5 Gy) showed good results in recurrent or persistent early stage disease in a small series of 18 patients. Late toxicities were reported in one patient, developing a radiologically confirmed temporal lobe necrosis (Chua 2003). This treatment is suitable for individual clinical use on a type 3 level of evidence. Generally, half of the failures after retreatment are due to distant metastases. Brachytherapy alone is suitable for individual clinical use in selected patients (localized, discrete lesions limited to the mucosa) on a type 3 level of evidence ( Altun 1995). Surgical excision is suitable for individual clinical use in patients with small recurrences on a type 3 level of evidence (Fee 1991; Tu 1988; Shu 1999; King 2000). Possible complications of this therapy depend on the surgical approach, consisting in particular in infections, loss of functions of cranial nerves and development of fistulas. Local control of 43% have been obtained. If the disease is not amenable to further radiotherapy or to surgery, a cisplatin-based combination chemotherapy is suitable for individual clinical use on a type 3 level of evidence.
6.3.2 Regional recurrence or residual nodal disease
Neck node dissection or nodal excision is suitable for individual clinical use in patients with operable neck recurrence on a type 3 level of evidence ( Tu 1988). This salvage procedure is able to achieve approximately 50%-60% of long term survival. Number of involved nodes and extracapsular nodal extension is an unfavourable prognostic index (Yen 1997; Wei 2001). In some selected cases, such as unresectable relapses, a carefully planned reirradiation is possible. The timing of nodal surgery for residual disease after primary treatment is not known since delayed complete remission may be achieved in some cases. In patients with regional recurrence cisplatin-based chemotherapy after nodal dissection is suitable for individual clinical use on a type R basis, considering the high chemosensitivity of the tumour. Administration of chemotherapy before neck dissection is suitable for individual clinical use on a type R basis, because of the opportunity to test in vivo the chemotherapy activity and because of a better compliance for preoperative chemotherapy over the postoperative one.
6.3.3 Locoregional recurrence and/or metastatic disease
In patients with locoregional recurrence and/or metastatic disease combination chemotherapy offers a good palliative treatment choice, with a small but constant (10%) proportion of long-term disease-free survivors even in patients with metastases (Fandi 2000). The outcome for patients with isolated locoregional relapse of undifferentiated carcinoma is better than for patients with type I squamous cell carcinoma. Objective responses reach 75% and remissions of long duration are observed especially in reirradiated patients (Fandi 2000; Altun 1995; Gandia 1993). Combination cisplatin-based chemotherapy is a standard treatment on a type C basis (Altun 1995) followed by reirradiation of locoregional disease. In the case of few metastatic bone deposits irradiation after induction chemotherapy is suitable for individual clinical use on a type 3 level of evidence ( Altun 1995). A cisplatin-based chemotherapy can achieve a high response rate raging from 100% to 47%, with a lower complete response rate (approximately 20%) (Azli 1995). The choice of the regimen should be based on previous chemotherapy, total dose of cisplatin and disease free interval. Chemotherapy including platinum compounds and paclitaxel reached response rates varying from 57% to 75% (Fountzilas 1997; Chi 1997) and should be considered as investigational. A trial of cisplatin and docetaxel in chemotherapy naive recurrent or metastatic nasopharyngeal cancer aborted because of low response rate (22% partial responses) (McCarthy 2002). Adding gemcitabine to cisplatin resulted in 64% of overall responses (14% complete responses) in a small group of 14 patients (Ma 2002), while it provided 73% of responses (20% complete responses) in another series of 44 patients (Ngan 2002 ); gemcitabine alone reached 34% of overall responses (6% complete responses) in a group of 18 heavily pre-treated patients (Ma 2002). Also its use should be considered investigational. Combination of carboplatin, paclitaxel and gemcitabine in metastatic setting obtained an overall response rate of 78%, with high hematologic toxicities (Leong 20005). In platinum refractory patients a combination of ifosfamide and doxorubicin reached 33% of partial responses (Altundag 2004). In a phase II study including cisplatin pre-treated patients ifosfamide, fluorouracil and leucovorin, a 56 % response rate was observed showing a good tolerability (Chua 2000). Monochemotherapy with irinotecan (CPT-11) obtained 14% of partial responses (Poon 2005), and capecitabine alone reached 23% of overall responses (Chua 2003). The role of radiotherapy is limited to the palliative irradiation of skeletal metastases, either to arrest severe bone destruction or to allieviate painful bone metastases. Less commonly subcutaneous or connective tissue metastases may require radiation therapy for symptoms palliation.
6.3.4 Targeted therapies, immunotherapy and other therapies
A recent phase II study of cetuximab (monoclonal antibody against EGFR) in combination with carboplatin in platinum refractory patients has been performed, with 12% of partial responses and 48% of stable disease (Chan 2005b). Target therapy with cetuximab should be considered investigational. Immunotherapy with cytotoxic T lymphocytes (CTL) infusion showed an acceptable toxicity profile in a phase I study. (Straathof 2005). Use of antiviral Cidofovir as enhancer of radiosensitivity (Abdulkarim 2003) and cell therapy with EBV targeted autologous CTLs (Comoli 2005) as well as high dose chemotherapy with autologous periferal blood stem cells transplantation (Airoldi 2001) are all investigational procedures.
6A Radiotherapy: target volumes
It is recommended on a type C basis that the planned target volume of irradiation is delineated. This can be defined as follows:
Primary: Nasopharynx proper and
- laterally: pharyngeal walls down to the mid-tonsillar fossa; pterygoid fossa
- anteriorly: posterior third of the nasal cavity
- postero-superiorly: floor of the sphenoid sinus and clivus.
- retropharyngeal, parapharyngeal and bilateral cervical nodes (including spinal accessory and supraclavicular chains).
- Adjustment of the target volume to cover disease extensions:
- anteriorly: nasal cavity
- laterally: parapharyngeal space (pre- and post-styloid components)
- superiorly (T4) : skull base +/- intracranial extensions.Boost target volume encompasses gross disease sites.Field arrangement
Primary tumour and upper neck nodes:
- Irradiation through 2 lateral photon beams of 6 MV or less is recommended. In patients with T1-2 lesions, a posterior tilt of a few degrees can be calculated to reduce the dose to ipsilateral external auditory canal and contralateral posterior orbit and eye. In T3 lesion with extension into nasal cavity, irradiation can be completed with an appositional anterior field.
Lower neck and supraclavicular nodes:
- Irradiation through an anterior field. A posterior field can be applied to spinal accessory nodes too. Off-cord reduction is mandatory once spinal cord reduction is reached (45 Gy ): spinal accessory chain is then treated either through direct electron beams or glancing photon fields.
- It has been repeatedly substantiated that there is a dose-control relationship for this group of patients. Therefore, it is recommended to deliver the following doses:
|T1N0-1:||64-66 Gy in fractions of 1.8 to 2 Gy each. Initial target volume: 50 Gy; boost: 14-16 Gy.|
|T2-3 or any T N<5 cm:||70-72 Gy, with the same fractionation. Initial target volume: 54 Gy; boost: 16-18Gy.|
|T4 or any T N3:||70-72 Gy, with the same fractionation. Initial target volume: 54 Gy; boost: 16-18Gy.|
It is recommended that a 5% reduction in dose is applied for undifferentiated carcinomas because of their greater radiosensitivity as compared with that of squamous cell carcinomas. Similarly, a 10% dose reduction may be applied for children.
6B Chemotherapy schedules
6B.1 Chemotherapy in locally advanced disease
BEC regimen (neoadjuvant chemotherapy)
Bleomycin 15 mg/m2 push i.v day 1 then 16 mg/m2 /day, continuous infusion day 1 to 5
Epirubicin 70 mg/m2 i.v. day 1
Cisplatin 100 mg/m2, 1 hour infusion, day 1 (or day 5)
Every 3 weeks for three courses pre RT
TC regimen (neoadjuvant chemotherapy)
Carboplatin AUC 6 i.v. day 1
Docetaxel 80 mg/m2 i.v. day 1
PF regimen (concomitant chemoradiation)
Cisplatin 100 mg/m2 i.v. day 1, 22, 43 during RT
Cisplatin 80 mg/m2 day 1
5FU 1000 mg/m2/day, continuous infusion day 1 to 4
Every 3 weeks for three courses after RT
Cisplatin 100 mg/m2 i.v. day 1
5FU 1000 mg/m2/day, continuous infusion day 1 to 4 in relapsed patients
5FU 1000 mg/m2/day, continuous infusion day 1 to 5 in chemonaive patients
Cisplatin 100 mg/m2 i.v. day 1
Epirubicin 70 mg/m2 i.v. day 1
Every 3 weeks
6B.2 Chemotherapy in metastatic and/or recurrent disease
Cisplatin 100 mg/m2 i.v. day 1
5FU 1000 mg/m2/day, continuous infusion day 1 to 4
Every 3 weeks
Bleomycin 15 mg/m2 push i.v day 1 then 16 mg/m2 /day, continuous infusion day 1 to 5
Epirubicin 70 mg/m2 i.v. day 1
Cisplatinum 100 mg/m2, 1 hour infusion, day 1
Every 3 weeks
Bleomycin 15 mg/m2 push i.v day 1 then 16 mg/m2 /day, continuous infusion day 1 to 5
5FU 650 mg/m2/day, continuous infusion day 1 to 5
Cisplatin 100 mg/m2, 1 hour infusion, day 1
Every 3 weeks
5FU 800 mg/m2/day, continuous infusion day 1 to 4
Epirubicin 70 mg/m2 i.v. day 1
Cisplatin 100 mg/m2, 1 hour infusion, day 1
Mitomycin 10 mg/m2 i.v. day 1 every other cycle
Every 3 weeks
Cisplatin 100 mg/m2 i.v. day 1
Epirubicin 70 mg/m2 i.v. day 1
Every 3 weeks
Gemcitabine 1000 mg/m2 i.v. day 1, 8, 15
Cisplatin 70 mg/m2 i.v. day 2
Every 4 weeks
Ifosfamide 2500 mg/m2 i.v. day 1-3
Doxorubicin 60 mg/m2 i.v. day 1
Every 3 weeks
Irinotecan 100 mg/m2 i.v. day 1,8,15
Every 4 weeks
Capecitabine 1,25 g/m2 per os twice daily day 1 to day 14
Every 3 weeks
Gemcitabine 1000 mg/m2 i.v. day 1, 8, 15
Every 4 weeks
7. LATE SEQUELAE
7.1 Treatment late effects and sequelae
7.1.1 Radiotherapy late effects and sequelae
Although radiotherapy techniques have improved over the last years, late effects and sequelae in adequately treated patients continue to be a problem produced by the large volume of irradiation that is usually applied to these tumours. These effects involve the mucous membranes, muscle, bone and subcutaneous tissues, and the central nervous system. However, the frequency of severe (RTOG grade 4-5) late complications has steadily decreased over the years: the 10-year actuarial incidence of side effects was 14% in 1954-1971 (with a 3% mortality) versus 5% in 1983-1992. This reduction is due to improvements in treatment technique and the wider use of CT planning. The 10-year incidence of moderate-severe complications (RTOG grade 3-5), using the T: lat/lat technique employing custom blocks, is around 16%. Radiation doses (>60 Gy) to the primary site as well as tumour stage are not significant factors in the development of grade 3-5 late effects ( Sanguineti 1997). Mucosal dryness is always present and the severity of xerostomy is increased by the irradiation volume and dose, and by the addition of cytostatic drugs to radiation therapy. Dental problems can be reduced by prophylactic care based on daily fluorine applications. Trismus occurs to varying degrees and is related more to fibrosis and contracture of the pterygoid muscles rather than temporomandibular joint fibrosis. Severe trismus might require surgical correction. Otitis, secondary to auditory canal obstruction, can be treated with middle ear drainage. Chronic sinus disease and dysphagia have been reported (Chang 2000a; Wu 2000). Delayed bone age and growth failure may be observed in young patients developing pituitary insufficiency following irradiation of the base of the skull (Fletcher 1980).7.1.2 Neurological late effects and sequelae
The risk of neurological late effects is increased after irradiation of locally advanced diseases (T3 -T4) which require large volumes of irradiation both at the primary site and in the neck. Brain necrosis in the temporal lobe is uncommon when doses delivered through opposed lateral portals range between 60 and 70 Gy. Nevertheless some patients may experience a transitory central nervous system syndrome a few months after radiotherapy, with spontaneous resolution of the symptoms. Radiation necrosis of the brain stem and cervical cord is the most severe neurological complication following nasopharyngeal irradiation. Nevertheless, in the literature the incidence of myelitis does not exceed a few percent and is more frequent in the treatment of locally advanced cases. Severe spinal cord injuries were reported in 2.4% of cases treated before 1970 (Sanguineti 1997). Persistent sensorineural hearing loss develops in 24% of irradiated patients; age (older than 50), sex (males) and postirradiation serous otitis media are negative prognostic factors for persistent sensorineural hearing loss. Ciplatinum-based chemotherapy and the radiation dose or how it is fractionated make no significant contribution to hearing loss ( Kwong 1996). Retrobulbar optic neuritis or retinopathy may occasionally be observed in patients with anterior tumour extension towards the nasal cavities, and after full dose irradiation of the posterior region of the orbits (Fletcher 1980).7.1.3 Chemotherapy late effects and sequelae
Chemotherapy, especially bleomycin, often results in an increased incidence of neck fibrosis (Lee 1992; Peters 1988).
7.1.4 Quality of life after definitive treatment
Overall mean quality of life score of patients treated for nasopharyngeal cancer is good (Talmi 2002). Major problems affecting survivors regard dry mouth, difficulty in chewing and ear diseases. Better definition of target radiotherapy volumes could help in reducing toxicities and so improving quality of life after therapy.
7.2 Related and secondary tumours
No second primary tumours have been reported in nasopharyngeal cancer patients. Radiation-induced malignancies (osteosarcomas, nasal cavity cancers and oral cavity cancers) have been reported (Chen 2000; Teo 1999b). Postirradiation osteosarcoma is a very rare complications, occurring in 0.037% of treated patients treated (Wei 2005).
8.1 General principles and objectives
It is primarily the task of the physician to look for signs of local persistence or local-regional relapse on a type R basis. The risk of recurrence will be the highest during the three years immediately following the completion of treatment. The follow-up should include careful clinical observation both of the primary site, since reirradiation can be useful in a significant number of patients with local recurrence, and along the neck node chains, since isolated lymph node recurrences may be salvaged by neck dissection. Radiological investigations (CT, MRI) are recommended for the evaluation of treatment results, particularly for those tumours invading the skull base, since any persistence or local tumour relapse may benefit from further treatment. Unfortunately in some cases it will be difficult to assess whether neoplastic tissue is present or not since fibrosis due to irradiation may mimic tumour infiltration. For tumours extending beyond the skull base a biopsy may not be recommended. In these cases a careful and shorter interval follow-up is mandatory. The diagnostic anticipation of secondary dissemination with chest X-rays, liver ultrasound and bone scans has no certain clinical benefit. Use of PET and of EBV DNA quantification in follow up after radiation are to be considered suitable for individual clinical use on a type 3 level of evidence.
Laboratory testing will aim at monitoring treatment-related late effects such as possible endocrine hypofunction of the thyroid and pituitary gland after radiotherapy.
8.2 Suggested protocols
A first complete evaluation should be performed 2 to 3 months after completion of treatment. The next evaluations should be scheduled every three months for the first two years, every six months for the next two years and on a yearly basis thereafter.
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Prof. Jean Pierre Armand (Author)
Institut Gustave Roussy – Villejuif, France
Prof. Jacques Bernier (Author)
Ospedale San Giovanni – Bellinzona, Switzerland
Dr. Paolo Bossi (Author)
Istituto Nazionale Tumori – Milan, Italy
Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
Dr. Lisa Licitra (Editor)
Start Clinical Editor – Istituto Nazionale Tumori – Milan, Italy
Prof. Roberto Molinari (Reviewer)
Istituto Ortopedico Galeazzi – Milan, Italy