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Nasopharyngeal Cancer
121
References
Perez CA, Devineni VR, Marcial-Vega V, et al: Carcinoma of the nasopharynx: factors
affecting prognosis. Int J Radiat Oncol Biol Phys 1992; 23:271-280.
Teo P, Shiu W, Leung SF, et al: Prognostic factors in nasopharyngeal carcinoma investigated
by computer tomography: an analysis of 659 patients. Radiother Oncol 1992; 23:79-93.
9. Prognostic Factors
• N stage. Advanced N-category and adenopathy in the lower neck were independent
adverse prognostic factors for the development of distant metastases, while advanced
T- and N-category were independent adverse prognostic factors for disease-specific
survival.
• Tumor volume. Primary tumor volume is an independent prognostic factor of local
control and is more predictive with the AJCC/UICC staging system than with Ho’s T
stage classification. Validity of tumor volume has been confirmed in patients with T3
and T4 tumors.
However, tumor volume is not an independent prognostic factor in early-stage
nasopharyngeal carcinoma treated by radiotherapy alone.
• Anemia. It is an independent adverse effect for nasopharyngeal cancer treated with
radiation therapy. In a randomized phase III trial, comparing induction chemotherapy
followed by radiotherapy with radiotherapy alone, showed that Hb level during
radiotherapy was an important prognostic factor with respect to local control and
survival.
Patients with Hb levels <11 g/dL during radiation had significantly poorer local
control than patients with higher Hb levels.
• EBV DNA. High posttreatment levels of EBV DNA may reflect microscopic
residual tumor, and provide an even greater estimate of the chance of disease
recurrence and death than pretreatment EBV DNA.
• T stage. T classification of the AJCC staging system overall is of prognostic
significance; however, T1 and T2a categories do not differentiate prognosis .
Paranasopharyngeal extension (T2b) is an independent prognostic factor correlated
with adverse local tumour
References
Perez CA, Devineni VR, Marcial-Vega V, et al: Carcinoma of the nasopharynx: factors
affecting prognosis. Int J Radiat Oncol Biol Phys 1992; 23:271-280.
Teo P, Shiu W, Leung SF, et al: Prognostic factors in nasopharyngeal carcinoma investigated
by computer tomography: an analysis of 659 patients. Radiother Oncol 1992; 23:79-93.
Gustavo Arruda Viani
122
Trials
Description
Al sarraf et
al (1999)
Randomized 147 cases of stage III–IV (1988 AJCC system) NPC to compare RT
versus concurrent chemoradiation therapy (CRT) followed by adjuvant
chemotherapy.
RT in 2 arms used identical regimens of 70 Gy in 2 Gy per daily fraction.
CRT used 3 cycles of cisplatin (100 mg/m2 bolus, day 1, weeks 1, 4, and 7);
adjuvant chemotherapy used 3 cycles of cisplatin (80 mg/m2 bolus, day 1, weeks 11,
15, and 19) plus 5-FU (1 g/m2/24 h infusion, days 1–4, weeks 11, 15, and 19).
3-Year OS (78 versus 47%) and progression-free survival ([PFS] 69 versus 24%)
favored CRT arms over RT alone Local control improved with CRT over RT (not
reported).
Wee J et al.
(2005)
Randomized 284 cases of stages III–IV (1988 AJCC system) NPC to compare RT
versus CRT, followed by adjuvant chemotherapy
RT in 2 arms used similar regimens of 70–74 Gy in 2 Gy per daily fraction.
CRT used 2 cycles of cisplatin (20 mg/m2/day) plus 5-FU (400 mg/m2/96 h
infusion) during weeks 1 and 5 of RT
5-Year OS (72.3 versus 54.2%, p = 0.0022), PFS (71.6 versus 53%, p = 0.0012), and
local control (96.8 versus 92.1%) favored CRT arms over RT alone.
Lin Jc et al
(2003)
Randomized 221 cases of stages II (N+), III, and IV (1997 AJCC system) NPC to
compare RT (70 Gy in 7 weeks by using conventional RT) versus CRT followed by
adjuvant chemotherapy (same RT regimen).
CRT used 3 cycles of cisplatin (25 mg/m2/day, days 1–4 or 30/30/40 mg/m2/day,
days 1–3, weeks 1, 4, 7); adjuvant chemotherapy used 3 cycles of cisplatin (20
mg/m2/day, days 1–4, weeks 10, 14, and 18) plus 5-FU (1 g/m2/24 h infusion, days
1–4, weeks 10, 14, and 18).
5-Year OS (80 versus 65%, p = 0.006) and disease-free survival ([DFS] 72 versus
53%, p = 0.02) favored CRT arms over RT alone
10. Treatment
• Radiotherapy (RT) remains the primary treatment modality for NPC.
• The use of neoadjuvant and concomitant chemotherapy are increasingly applied,
because it is a radiosensitive tumor and because its anatomic location limits a
surgical approach.
• Early (stage I) cancers are treated with RT alone with good locoregional control.
Stage II disease, an intermediate risk group, is often considered for combined
modality treatment strategies that are used in stage III-IV disease, because of
elevated distant failure rates seen with stage II disease.
• Despite the limited supporting data, CRT has been considered for patients with
intermediate stage nasopharyngeal cancer rather than RT alone. Based on the results
of a series of randomized clinical studies and meta-analysis published in recent years
(see below), concurrent chemotherapy (CRT) has been used in patients with
locoregionally advanced head and neck cancer to sensitize tumor to the effects of RT
and to thereby improve tumor control.
• The United States Intergroup 0099 trial was the first to demonstrate a benefit from
CRT for the management of locoregionally advanced nasopharyngeal cancer (table-
5).
Table 5. Randomized clinical trials supporting cheoradiation and radiation
aone for nasopharyngeal cancer
Nasopharyngeal Cancer
123
Trials
Description
Chang at et
al.
(2005)
Randomized 350 NPC cases of Ho stages N2–3 or any node ≥4 cm to compare RT
(66 Gy followed by a parapharyngeal boost in ~70% of patients) versus CRT (same
RT regimen) CRT arm used cisplatin (40 mg/m2 weekly)
5-Year OS (70.3 versus 58.6%, p = 0.049) favored CRT arms over RT alone.
Subgroup analysis revealed no difference in OS between arms for T1–T2 disease (p
= 0.74), but a diff erence between T3–T4 disease (p = 0.013) favoring CRT over RT
alone
Chemotherapy timing
5-year survival
Odds ratio [OR], 95% CI OS
Overall survival
Disease free survival
Neoadjuvant alone
0.65 (0.51-0.84)
0.63 (0.51-0.79)
Concurrent alone
0.72 (0.40-1.30)
0.68 (0.46-0.99)
Concurrent + adjuvant
0.30 (0.16-0.55)
0.30 (0.17-0.53)
Adjuvant alone
0.49 (0.18-1.31)
0.60 (0.34-1.04)
All
0.65 (0.51-0.83)
0.59 (0.51-0.68)
References
Al-Sarraf M, LeBlanc M, Shanker Giri et al (1998) Chemo-radiotherapy versus radiotherapy
in patients with advanced NPC. Phase III randomized intergroup study 0099. J Clin
Oncol 16:1310–1317
Wee J, Tan EH, Tai BC et al (2005) Randomized trial of radiotherapy versus concurrent CRT
followed by adjuvant chemotherapy in patients with AJCC/UICC stage III and IV NPC
of the endemic variety. J Clin Oncol 23:6730–6738
Lin JC, Jan JS, Hsu CY et al (2003) Phase III study of concurrent CRT versus radiotherapy
alone for advanced NPC: positive effect on overall and progression-free survival. J Clin
Oncol 21:631–637
Chan AT, Leung SF, Ngan RK et al (2005) Overall survival after concurrent cisplatin-
radiotherapy compared with radiotherapy alone in locoregionally advanced NPC. J Natl
Cancer Inst 97:536–539
Meta-analyses of randomized controlled trials concluded that the addition of any
chemotherapy (concurrent, induction, or adjuvant) to definitive radiation therapy (RT)
reduces the risk of death by 18 %t and increases overall five-year survival by 4 to 6%. Most
of this survival benefit is due to a reduction in distant failure; concurrent CRT as opposed to
induction chemotherapy or adjuvant chemotherapy demonstrated the most pronounced benefit
(table 6). Thus, concurrent CRT, with or without adjuvant chemotherapy, now is the standard
of care for patients with advanced (stage III, IVA, and IVB) nasopharyngeal carcinoma.
Table 6. Meta-analysis of CRT compared to RT alone for stage III/IV
nasopharyngeal cancer
Gustavo Arruda Viani
124
Reference
Thephamongkol, K, Zhouo, J, Browman, G, et al. Proc Am Soc Clin Oncol 2004; 23:491a
(abstract 5522).
• There are no trials directly comparing concurrent CRT plus adjuvant chemotherapy
with CRT alone. Whether adjuvant chemotherapy adds benefit to concurrent CRT
remains uncertain. The results of randomized trials that added adjuvant
chemotherapy to concurrent CRT are similar to trials in which concurrent CRT was
used alone. Trials that compared the addition of adjuvant chemotherapy to RT alone
showed no significant reduction in the risk of locoregional recurrence and/or distant
metastases and no significant improvement in overall survival.
• Adjuvant chemotherapy after concurrent CRT is difficult to complete . As an
example, in the Intergroup Study 0099, only 55 % of patients actually completed
three cycles of adjuvant chemotherapy. Based upon the results of the Intergroup
Study 0099, some experts give three cycles of adjuvant chemotherapy as used in this
trial, especially for patients who are fit and have good performance status. However,
the role of adjuvant chemotherapy is currently under debate.
• Sequential therapy, the administration of induction chemotherapy followed by
concurrent CRT, appears promising and may represent an alternative to concurrent
CRT with adjuvant chemotherapy, mainly, to advanced disease, reducing treatment
radiotherapy volume. Furthermore, induction chemotherapy preceding concurrent
CRT is more likely to be successfully administered than adjuvant chemotherapy
following concurrent CRT.
• Another alternative treatment for NPC would be to use an alternative RT schedule.
Although RT is typically given on a schedule of five treatments per week (70 Gy/ 35
fractions) in the western contries, there is increasing evidence that outcomes in head
and neck squamous cell carcinoma may be improved with alternative fractionation
schedules, including hyperfractionation and accelerated fractionations regimens.
11. Radiotherapy Technique
Patients are treated supine with head and shoulders immobilised in a thermoplastic mask.
The chin is elevated to spare the oral cavity and orbit, but the spine should be kept as straight
as possible if posterior neck nodes are present, to facilitate matching of an electron boost
(figure-6).
CT scan slices measuring 3 mm are obtained from 2 cm above the superior orbital ridge
(to include the skull base) to the arch of the aorta inferiorly. Intravenous contrast is used to
help definition of cervical nodes. 3D conformal or an IMRT technique is preferred because
local extent of disease can be better determined. The GTV is first contoured on the planning
CT using diagnostic images and clinical information.
Particular attention should be given to the parapharyngeal space and to the lateral
pharyngeal lymph nodes. Retropharyngeal nodes >=5 mm and cervical nodes >=10 mm in
short axis diameter are contoured as GTV. Three CTVs are defined: a high dose CTV70
Nasopharyngeal Cancer
125
reflecting the clinically apparent disease; a high risk CTV60 reflecting the high risk of local
spread in and adjacent to the nasopharynx; and a prophylactic CTV44 to treat at risk but
clinically uninvolved nodes.
Figure 6. CT simulator and thermoplastic mask for radiotherapy treatment.
The GTV is expanded isotropically by 5 mm to form the CTV70, which is then edited to
reflect natural tumour barriers. In particular, the posterior margin can be reduced if the
vertebral column is not involved, and this will help minimize brainstem dose. The CTV70 is
copied to form the CTV60 which is expanded to reflect possible local spread in the
nasopharynx. It should include the whole nasopharynx, adjacent retropharyngeal lymph nodal
regions, parapharyngeal space, pterygoid plates, pterygomaxillary fissures, floor of the
sphenoid sinus, foramen lacerum and the posterior part of the nasal cavity (5 mm anterior to
the GTV) (Figure-7).
Figure 7. Coronal view of isodose distributions from IMRT for nasopharyngeal cancer.
Gustavo Arruda Viani
126
OAR
Dose
Complication
Brain stem
Dmax < 54 Gy
Neuropathy
Parotid gland
Dmax < 25 Gy
Xerostomy
Optic chiasm
Dmax < 55 Gy
Optic neuropathy
Temporal lobes
Dmax < 70 Gy
Necrosis
Mandibular Temporal articulation
Dmax < 70 Gy
Joint dysfunction
Spinal cord
Dmax < 50 Gy
Mielopathy
Lens
Dmax < 54 Gy
Cataract
Coclea
Dmax < 45 Gy
Sensorium hearing loss
Retina
Dmax < 45 Gy
blindness
If a T1 primary tumour is small and well defined on imaging, some of these sites can be
excluded from the CTV60 (e.g. contralateral parapharyngeal space). The CTV60 is copied to
form the CTV44. This is expanded to include bilateral level Ib and II–V nodes. In N0 disease,
level Ib can be omitted bilaterally. In N1 disease, the contralateral level Ib can be omitted. If
level IV or low level V nodes are involved the supraclavicular nodes on that side should be
included in the CTV44. A CTV-PTV margin is applied (usually 5 mm) based on measured
set-up errors assuming no tumour motion. The brainstem and spinal cord should always be
defined. The parotid glands, pituitary gland, temporomandibular joints (TMJs), optic
apparatus, temporal lobes and middle ear apparatus should also be contoured as critical
structures if IMRT is used, as dose sparing may be possible (figure-8).
Figure 8. Coronal, sagittal and axial view of isodose lines using IMRT for nasopharyngeal cancer.
The recommended dose to the PTV 70 (i.e., CTV 70 with margin) is 70 Gy in 35
fractions. The high risk PTV 60 (CTV 60 + margin) will receive 60 Gy in 30 fractions at 2 Gy
per fraction. The PTV54 (CTV54 + margin) will receive 54 Gy at 2 Gy per fraction.
Treatment should be delivered once daily, five fractions per week. All targets should be
treated simultaneously. Dose limitations for organs at risk due to radiotherapy treatment for
nasopharyngeal cancer is summarized in table-7.
Table 7. Dose limitations for OAR
Nasopharyngeal Cancer
127
References
Chau RMC, Teo PML, Choi PHK et al. Three-dimensional dosimetric evaluation of a
conventional radiotherapy technique for treatment of nasopharyngeal carcinoma.
Radiother Oncol 2001;58: 143–53.
Jen Y-M, Shih R, Lin YS et al. Parotid gland-sparing 3-dimensional conformal radiotherapy
results in less severe dry mouth in nasopharyngeal cancer patients: a dosimetric and
clinical comparison with conventional radiotherapy. Radiother Oncol 2005;75: 204–9.
Lee AWM, Poon YF, Foo W et al. A retrospective analysis of 5037 patients with nasopharyn-
geal carcinoma treated during 1976–1985, overall survival and patterns of failure. Int J
Radiat Oncol Biol Phys 1992; 23: 261–70.
Liu L-Z, Zhang GY, Xie CM et al. Magnetic resonance imaging of retropharyngeal lymph
node metastasis in nasopharyngeal carcinoma: patterns of spread. Int J Radiat Oncol Biol
Phys 2006;66: 721–30.
Wolden SL, Chen WC, Pfister DH et al. Intensity-modulated radiation therapy (IMRT) for
nasopharyngeal cancer: update of the Memorial Sloan-Kettering experience. Int J Radiat
Oncol Biol Phys 2006; 64: 57–62.
Conclusion
• Nasopharyngeal cancer is a relatively rare tumor in Western countries.
• Radiotherapy treatment remains as standard treatment for early disease. On the other
hand, chemoradiation is considered the best option for locally advanced disease.
• Recent advances in radiotherapy treatment, like IMRT and IGRT, associated with
new chemotherapy agents, can improve treatment outcomes. The algorithm below
summarized the treatment options.
Algorithm for treating nasopharyngeal cancer.
Salivary Gland Cancer
Salivary malignancies are rare and involve less than 0.3% of all
malignancies, and 6% of head and neck cancers.
Malignant salivary neoplasms present as a painless mass in approximately
75% of patients. Rarely, patients are initially seen with pain or facial nerve
palsy.
Approximately 50% of submandibular tumors are benign while the other
50% are malignant; most tumors of the sublingual glands are malignant.
The initial evaluation for salivary gland cancer should include imaging
studies
Histological diagnosis is necessary to treatment decisions. Histological
diagnosis may be by FNA.
Surgical resection is the first option treatment for patients with resectable
tumors.
Elective neck dissection of levels Ib-III is indicated for patients with lymph
node clinically negative, but with high-risk of local failure. High risk
patients for local failure included: high-grade tumors, advanced age, T3 /T4
tumors, and facial nerve palsy.
Adjuvant radiotherapy is recommended for patients with high risk for local
failure, or for low grade tumors with perineural, vascular, and lymphatic
invasion, lymph node involvement, extracapsular spread or positive
margins.
Chapter 9
Abstract
Introduction
Neoplasms from the salivary glands are relatively rare, and they represent a wide variety
of both benign and malignant histologic subtypes. Although researchers have learned much
from the study of this diverse group of tumors over the years, the diagnosis and treatment of
salivary gland neoplasms remain complex and challenging problems for the head and neck
surgeon and radiation oncologist. In this chapter we will discuss several apects of diagnostic
and treatment of this disease.
Gustavo Arruda Viani
130
Variable
Description
Smoking
Cigarette smoking has a strong association with Warthin’s tumor, a benign tumor of the
parotid gland.
Ionizing
radiation
Risk factor mostly for mucoepidermoid carcinomas and Warthin’s tumors. An increased
risk has also been observed for adenocarcinomas among Hodgkin’s lymphoma survivors.
Exposure to ionizing radiation has been implicated both in survivors of the atomic bomb
explosion at Hiroshima and in individuals who received low-dose irradiation to the head
and neck in childhood.
Genetic
factors
Genetic factors are suggested by the increased incidence of salivary carcinoma in Eskimo
families.
1. Epidemiology
• The major and minor salivary glands of the head and neck can give rise to a
heterogeneous group of both benign and malignant neoplasms.
• Salivary malignancies are rare and involve less than 0.3% of all malignancies, and
6% of head and neck cancers.
• While most parotid neoplasms are benign, about half of submandibular tumors are
malignant, and an even higher proportion of minor salivary neoplasms will be
malignant (figure 1).
• Patients with malignant tumors typically present after age 60 years, whereas those
with benign lesions usually present when older than 40 years.
• Approximately 80% of all salivary gland tumors are benign, and 20% are malignant.
• The age-adjusted incidence rate for 2006 was 1.4 per 100,000 in the Surveillance,
Epidemiology, and End Results (SEER) Program US database.
• Approximately 80% of all salivary gland neoplasms originate in the parotid gland.
Figure 1. Distribution of malignancy tumors according to salivary gland.
Reference
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin.
2005;55(2):74.
2. Risk Factors
Several risk factors have been identified for salivary gland cancer, as described in table-1.
Table 1. Risk factors for larynx cancer