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Part 1 General Principles of Head and Neck Radiotherapy
tumors progress by activating oncogenes and by silencing
tumor suppressor genes (TSGs), each producing a growth
advantage for a clonal population of cells, and that speci c
genetic events usually occur in a distinct order (multistep carcinogenesis) that is not necessarily the same for each tumor.
4
For head and neck carcinomas, Califano et al.
described a
preliminary tumor progression model using allelic loss or
imbalance as a molecular marker for oncogene ampli cation
or TSG inactivation. ey identi ed p16 (9p21), p53 (17p),
and Rb (13q) as candidate TSGs, and cyclin D1 (11q13) as a
candidate protooncogene. e results of this work support
the initial observations of the colorectal molecular progression model, in that clonal genetic changes occur early in the
histopathologic continuum of tumor progression. About one
third of histopathologically benign squamous hyperplasias
already consist of a clonal population of cells with shared
genetic anomalies characterizing head and neck cancer.
Identi cation of such early events facilitates discovery of
genetic alterations associated with further transformation
and aggressive clinical behavior.
e introduction of newer molecular assay techniques
has greatly increased the ability to detect genetic changes
and thereby improve the understanding of cancer biology in
general. An overview by Ha et al.
5
summarizes recent ndings on genetic alterations in HNSCC grouped by assay techniques, such as comparative genomic hybridization, in situ
hybridization, single nucleotide polymorphism, and microarray technology, and provides excellent illustrations of the
complexity of HNSCC and how that complexity will require
much more research to reveal the full picture. With further
validation, however, this knowledge will contribute a great
deal to the development of screening strategies focusing on
the earlier steps of genetic alterations required to generate
an invasive tumor phenotype and to the conception of early
pharmacologic or genetic therapy approaches.
Lifestyle-Related Risk Factors
Tobacco and alcohol exposure have long been recognized
as the dominant risk factors for HNSCC. Other risk factors
include low fruit and vegetable consumption and betel quid
chewing. In an overview, Petti6 estimated that, worldwide,
25% of HNSCCs are attributable to tobacco use, 7% to 19%
to alcohol consumption, 10% to 15% to dietary de ciency,
and, in regions of prevalence, >50% to betel quid chewing.
Carcinogenicity is dose-dependent and magni ed by exposures to multiple carcinogens.
Although tobacco and alcohol consumption is estimated to account for approximately three fourths of oral
and pharyngeal carcinomas in the United States,7 neoplasms
develop in only a small fraction of exposed individuals. is
intriguing information raised the notion of the contribution
of genetic susceptibility or predisposition and other cofactors (for examples of cofactors, see “Viral Etiology” section)
to carcinogenesis. e potential pathways are thought to
include genetic polymorphisms in uencing environmental
carcinogen absorption and detoxi cation, individual sensitivity to carcinogen-induced genotypic alterations, and so
on. ese ideas can now be tested more comprehensively
because of recent progress in molecular biology concepts
and assay methodology. For example, the ability to identify
smokers at high risk for developing cancer will have important practical clinical implications in selecting individuals
for more aggressive screening programs or for enrollment
into intensive chemoprevention trials.
Viral Etiology
Epstein-Barr Virus
NPC has been an excellent model for studying viral etiology
in human cancer. Although the association between
Epstein-Barr virus (EBV) and NPC has been recognized for
about four decades, major progress has been made in this eld
relatively recently. For example, the EBV genome was characterized (reviewed by Liebowitz8) to consist of a linear, 172-kb,
double-stranded DNA having ve unique sequences separated by four internal repeats and two terminal repeats. e
DNA circularizes by homologous recombination at random
locations within terminal repeats in the nucleus of infected
cells. e length of the terminal repeat is speci c for each
infected cell, and this is the basis for clonality assays, which
may be useful in determining the putative primary tumor in
patients presenting with nodal metastasis from an unknown
source. e genome encodes several families of proteins, such
as early antigens, Epstein-Barr nuclear antigens (EBNAs), and
latency membrane proteins (LMPs). Many of these proteins
control viral behavior and a ect cell proliferation regulatory
mechanisms, and are thought to play a role in transformation
and carcinogenesis and to in uence tumor response to therapy. EBNA-1 regulates viral genome replication during cell
division and was found to induce growth and dedi erentiation of an NPC cell line not infected by EBV.9 LMP-1 seems to
alter growth of epithelial cells and induce well-di erentiated
squamous carcinomas from human epithelial cell-line transfectants and is associated with bcl-2 expression in tumors.
More work has been done on the molecular genetics
of NPC. Many NPCs have been found to have deletions of
the short arm, or some regions of the short arm, of chromosomes 3 and 9, suggesting the possibility of the existence of TSGs in these regions.
12,13
For example, studies
revealed that the combined frequency for losses of chromosome 3p/9p (bearing p16 and RASSF1A) in the normal
nasopharyngeal epithelium among southern Chinese in
Hong Kong (a population at high risk for NPC) was 82.6%
as opposed to 20% in the low-risk populations. In contrast,
latent EBV infection was detected only in high-grade nasopharyngeal dysplasia or in NPC. Consequently, it was postulated that the abnormal genetic changes in chromosomes
10,11
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3p and 9 predispose nasopharyngeal cells to sustain latent
EBV infection, and this combination promotes a cascade of
events leading to malignancy.
Because the presence of EBV is ubiquitous, the question of
why this virus is associated with NPC in Southern China and
with Burkitt lymphoma in equatorial Africa but is not clearly
related to other neoplasms elsewhere in the world remains
puzzling. In reviewing the literature, Chang et al.16 could not
detect a clear link between EBV genotype, neoplasms, and
geographical factors. ey suggested that the extent of EBV
diversity is likely to be greater than is currently appreciated
and that carefully designed studies that are conducted in wellselected populations and are su ciently powered to provide
robust epidemiologic estimates are needed to further the
understanding of patterns of EBV genetic variation and their
association with malignancies in di erent regions.
Human Papillomavirus
e causal relation between HPVs and some human neoplasms has been established, particularly for carcinoma of
the uterine cervix. Nearly all cervical cancers contain integrated HPV-DNA, most commonly of high-risk types HPV16 and HPV-18n.
17
Cell culture studies clearly demonstrated
that the high-risk HPVs can transform and immortalize
epithelial cells from cervix, foreskin, and oral cavity.
18–20
In
contrast, HPV-6 and HPV-11, associated more o en with
benign lesions, do not possess this capability.
21,22
Expression
of the E6 and E7 open reading frames of HPV-16 or HPV-18
genome is su cient for immortalization.
23,24
e role of HPV in head and neck carcinogenesis has also
attracted attention (reviewed by Herrero25). Carcinomas of the
tonsil, oral tongue, and oor of mouth were found to have a
relatively high prevalence of HPV-DNA.
26–28
e evidence
implicating HPVs in carcinogenesis of tonsillar carcinomas is
quite strong because these tumors not only contain HPV-DNA
in most of the cells but also express readily detectable levels of
HPV-RNA.29 In a series of 253 patients, Gillison et al.30 detected
HPV in 25% of tumors, with HPV-16 present in 90% of the
positive neoplasms. e presence of HPV was most common
in oropharyngeal carcinoma occurring in individuals with no
history of smoking or alcohol consumption whose tumors were
of a basaloid subtype without TP53 mutation. Laboratory data
showing the persistence of transcriptionally active, integrated
HPV-16 DNA in an oral carcinoma cell line with features indis-
31
tinguishable from those of the primary tumor
provide strong
evidence that HPV has an active role in carcinogenesis.
e question of how high-risk HPV induces cell transformation has been studied mostly in cervical cancer, and the
ndings have been summarized in several review articles.
32–35
In a nutshell, two viral oncoproteins, E6 and E7, are crucial
in the transformation process. E6 binds to and inactivates
the tumor suppressor protein p53, a ecting many cellular
functions including impairment of DNA repair a er damage
by other agents and suppression of the ability of cells to die
by apoptosis. E7 degrades pRb, thereby releasing transcription factors such as E2F, which in turn induces the expression of other cellular proteins. E6 and E7 can also directly
bind to several other host proteins, such as Bak and p21
thereby contributing to ampli cation of genetic instability.
e expression of E6 and E7 alone does not seem to be su cient for transforming cells, but the additional genetic alterations necessary for neoplastic conversion remain uncertain.
In reviewing data from the U.S. National Cancer Institute’s
Surveillance, Epidemiology, and End Results program registries from 1973 to 2004, Chaturvedi et al.36 noted a change
in the demographics of oral squamous cell carcinoma
(OSCC), that is, carcinomas arising from the mucosa of
the oral cavity and oropharynx, in the United States. e
incidence of HPV-related OSCC increased signi cantly from
1973 to 2004, particularly among white men and at younger
ages. In contrast, the incidence of HPV-unrelated OSCC was
stable up to 1982 and then declined signi cantly from 1983
to 2004. e age at diagnosis declined from 1973 to 2004 for
HPV-related OSCCs (0.5-year decrease per decade; P<0.001)
but increased for HPV-unrelated OSCCs (0.7-year increase
per decade; P < 0.001). Similar trends have also been reported
from other Western countries, such as Sweden
37
and Norway.
An increasingly large body of data shows that the prognosis for patients with HPV-related oropharyngeal carcinomas (OPSCCs) is consistently better than for those with
HPV-unrelated OPSCCs a er treatment with surgery,39 radiotherapy,
40,41
induction chemotherapy followed by chemoradiation,42 and concurrent radiation plus cisplatin.43 Based on
this strong evidence, several clinical trials have been undertaken or are being designed to test several potentially less toxic
regimens. However, until such trials yield conclusive results,
head and neck oncologists should not change the current
treatment policies for patients with HPV-positive OPSCCs.
BIOMARKERS
Key Points
• ree strong prognostic biomarkers have emerged
for HNSCC. e absence of circulating EBV DNA
titer, presence of HPV in cancer cells, and low tumor
EGFR expression are associated with better outcome
a er current standard therapies for patients with
nasopharyngeal cancer, oropharyngeal carcinoma,
and HNSCC not associated with EBV or HPV,
respectively.
• Patients with NPC and persistent circulating
EBV DNA a er completion of radiotherapy with
concurrent cisplatin have a high distant relapse
Cip1
,
38
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Part 1 General Principles of Head and Neck Radiotherapy
rate and are thus suitable candidates for addressing
intensi cation of systemic therapy.
• With current standard therapies, patients with
HPV-associated OPSCCs have much better localregional control and overall survival rates than those
with HPV-unrelated OPSCCs.
• HPV-associated OPSCC is now considered a distinct
cancer entity, and protocols focusing on reducing
long-term morbidity are being designed for such
patients.
• e search for biomarkers that can predict the likeli-
hood that a certain cancer subset will respond to a
given therapy (predictive marker) has not yielded
promising leads.
• High-EGFR–expressing HNSCCs are more pro -
cient in repairing radiation-induced DNA injury
and hence recur more frequently a er radiotherapy,
but whether inhibitors of EGFR can preferentially
enhance the radiation response of these tumors has
not been resolved.
• Because the cost of cancer treatment has been
increasing steeply with only modest improvements
in e cacy, the identi cation, standardization, and
validation of predictive biomarkers are crucial for
rational selection of speci c therapies for a given
subset of patients to improve outcome, reduce overall
toxicity, and contain cost.
Although mortality rates from cancer have gradually
declined in the United States over the past 10 years,
of cancer therapy has increased drastically during that time
(American Cancer Society report on Cancer Facts & Figures
2009). is increase in cost results from progressive intensi cation of therapies, such as the addition of chemotherapy
to radiation or to surgery plus radiation, the emergence of
44
the cost
expensive novel agents, and the lack of validated markers to
guide rational patient selection for available therapies. Consequently, expensive and complex combined therapy regimens have o en been prescribed to large groups of patients
that bene t only a small subset of those patients, and o en at
the cost of increased acute and long-term morbidity. erefore, identi cation and validation of biomarkers to guide
the rational selection of speci c therapy for a given subset
of patients have become critical for improving the outcome,
reducing the toxicity burden, and containing the costs of
cancer treatment.
Progress in searching for useful markers for early detection of tumor, estimation of tumor burden, prediction of
response to therapy, and monitoring disease progression
has been slow. A prototypical marker is prostate-speci c
antigen, which proved to be quite useful for prostatic cancer
screening, prognostic grouping, and monitoring of response
to therapy. Unfortunately, equivalent markers have yet to
be identi ed for most other solid tumors. However, recent
studies in head and neck carcinomas have generated some
optimism, as discussed in the sections that follow.
Prognostic and Predictive Biomarkers
e distinction between prognostic and predictive biomarkers has not been widely appreciated. erefore, until recently,
these terms have been used rather loosely and interchangeably. Figure 1.1 illustrates the concept and de nition for
di erent classes of markers. e rates and extent of separation among the curves will vary with the disease type and
stage and the e cacy of therapy, but the general principles
and the relative ranking are applicable. In panel A, marker
X represents an aggressive tumor feature, the presence of
which is associated with poorer survival rate a er both treatment (Rx) regimens 1 and 2, though Rx 2 is more e ective
than Rx 1. Marker Y (panel B), on the other hand, exempli es a predictive marker for response to Rx 2. Hence, its
presence is associated with better survival a er Rx 2 (solid
brown curve). Panel C illustrates that some markers could
Figure 1.1
ers. X and Y (A, B) represent pure prognostic
and predictive markers, respectively, whereas Z
(C) stands for a marker that predicts favorable
response to treatment (Rx) 2 in addition to
prognosis (see text for details).
Schematic illustration of prognostic and predictive biomark-
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have both prognostic and predictive values. e absence of
marker Z is associated with better prognosis (solid and dotted black curves vs. dotted purple curve). However, since this
marker also predicts response to Rx 2, its presence is associated with a better outcome a er Rx 2 (solid purple curve)
relative to Z+ a er Rx 1 (dotted purple curve) and Z- a er
Rx 2 (solid black curve).
Figure 1.1 shows that carefully designed clinical trials
incorporating patient strati cation according to biomarkers and randomizing patients to received distinct therapy
modalities are needed to yield a conclusive answer as to
whether a marker is prognostic, predictive, both, or neither.
ree potent prognostic biomarkers for HNSCC have
emerged in recent years. Two of these biomarkers are related
to virus-associated head and neck carcinomas: circulating
EBV titer for NPC and the presence of the HPV genome or
its surrogate marker, p16, for OPSCC. e third biomarker,
epidermal growth factor receptor (EGFR), seems to be more
applicable for other HNSCCs.
Circulating EBV DNA Titers in
Nasopharyngeal Carcinoma
e association between EBV and NPC was summarized
in a previous section. Lo et al.45 have developed a real-time
quantitative polymerase chain reaction assay for measuring
circulating levels of tumor-derived EBV DNA in the serum
or plasma of patients with NPC. ey found in a longitudinal follow-up of 17 patients that elevations in serum EBV
DNA titer could be detected as early as 6 months before
clinical manifestation of recurrence, whereas the titer stayed
low or undetectable in patients who remained in remission.
Asubsequent study of patients treated with radiation, with
or without chemotherapy, at the same center46 showed that
having a pretreatment EBV DNA titer exceeding 4,000 copies per mL was associated with a 2.5-fold higher risk of NPC
recurrence. More interestingly, having a high posttreatment
EBV DNA titer was found to be an even stronger marker
for poor overall outcome, that is, a 11.9-fold increase in
recurrence rate. Conversely, having a posttreatment titer of
<500 copies per mL was associated with favorable overall survival and relapse-free survival rates (Fig. 1.2) and also correlated with low relapse rate. Similar results were reported by
Lin et al.47 in a series of patients treated with weekly neoadjuvant chemotherapy (cisplatin alternating with uorouracil
for a total of 10 doses) followed by radiotherapy.
e combination of intensity-modulated radiotherapy
(IMRT), as discussed in the section “High-Precision Radiotherapy” below, with concurrent cisplatin has yielded localregional control rates of around 90% even among patients
presenting with locally advanced NPC. Consequently, distant metastasis has become the main pattern of relapse for
this neoplasm. erefore, plans are underway to select highrisk populations, consisting of those with persistent circulating EBV DNA a er receiving the combination of IMRT with
cisplatin, for testing the e cacy of combinations of novel
agents with conventional chemotherapy for eliminating
occult metastatic disease.
Human Papillomavirus and p16 in
Oropharyngeal Carcinomas
As noted earlier in this chapter, the incidence of HPVassociated OPSCC is increasing, particularly in the
Western world, and several retrospective case series have
shown that patients with HPV-positive OPSCC treated
with contemporary single or combined therapy modalities have a better prognosis than do patients with HPVnegative OPSCC. However, owing to small sample sizes,
other favorable prognostic factors associated with tumor
HPV status (e.g., earlier tumor stage, young age) cannot
be excluded as potential explanations for the observed
Figure 1.2
copies per mL. (O, numbers observed and N, numbers at risk.) (Modifi ed from Chan ATC, Lo YMD, Zee B, et al. Plasma
Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl
Cancer Inst 2002;94:1614–1619.)
Overall survival (left) and progression-free survival (right) curves of patients treated with radiation with or
without chemotherapy as a function of posttreatment EBV DNA titers analyzed using a cut off value of 500
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Part 1 General Principles of Head and Neck Radiotherapy
di erence in survival. erefore, a thorough correlative
study was undertaken to quantify the magnitude of
impact of tumor HPV status on tumor outcome in patients
enrolled in a large phase III trial of the Radiation erapy Oncology Group (RTOG 0129) treated with a combination of radiation with concurrent cisplatin.43 Patients
with locally advanced HNSCC were strati ed according to
tumor site (larynx vs. other), nodal status (N0 vs. N1-N2b
vs. N2c-N3), and Zubrod performance status (0 vs. 1) and
assigned to receive either accelerated fractionation with a
concomitant boost (72 Gy in 42 fractions over 6 weeks) or
standard fractionation (70 Gy in 35 fractions over 7 weeks)
regimens. Chemotherapy consisted of intravenous cisplatin at a dose of100 mg/m2 on days 1 and 22 in the accelerated fractionation group or on days 1, 22, and 43 in the
standard-fractionation group.
Of the 743 patients enrolled, 60% had OPSCC. Pretreatment biopsy specimens from the patients with OPSCC were
evaluated for HPV-16 DNA by using in situ hybridization,
and HPV-16–negative tumors were further assayed for
12 additional oncogenic HPV types (types 18, 31, 33, 35,
39, 45, 51, 52, 56, 58, 59, and 68). Tumor expression of the
cyclin-dependent kinase inhibitor p16, induced as a consequence of pRb inactivation by viral oncoprotein E7,
48
was
evaluated by immunohistochemical staining with a mouse
monoclonal antibody. Strong agreement between tumor
HPV status as determined by in situ hybridization and p16
expression was observed, but some discrepancies were noted
as well. Overall, 64% of OPSCCs were found to be positive
for HPV-DNA and 68% were positive for p16. Figure 1.3
shows the di erences in overall survival according to HPV
or p16 status. Because the sensitivity for detecting non–
HPV-16 types, expected to account for 5% to 10% of HPVpositive OPSCC, was not well known at the time of the study,
misclassi cation of HPV-positive tumors as HPV-negative
tumors likely explains the slightly larger reduction in risk
of death when p16 expression was used in the analysis.
A strength of the p16 assay is that it is not HPV-type speci c
and is therefore an excellent surrogate for tumor HPV status.
Analysis of patterns of failure among these groups showed
that the local-regional failure rate at 3 years was signi cantly
lower for patients with HPV-positive OPSCC (13.6% vs.
35.1%, P < 0.001) but rates for distant metastasis were not
(8.7% vs. 14.6%, P = 0.23). Also, the cumulative incidence
of second primary tumors (SPTs) was signi cantly lower for
patients with HPV-positive OPSCC (3-year rates 5.9% vs.
14.6%, P=0.02), largely because of lower rates of smokingrelated cancers in that group.
Tobacco smoking was also found to be independently
associated with overall survival and progression-free survival, both in patients with OPSCC and in the entire study
population. Risk of death, for example, increased signi cantly by 1% per each pack-year increase in tobacco use, and
magnitudes of e ect were similar for patients with HPVpositive OPSCCs (hazard ratio [HR] 1.01, 95% con dence
interval [CI] 1.00 to 1.02) and HPV-negative OPSCCs (HR
1.01, 95% CI 1.00 to 1.03).
e RTOG 0129 study also showed that HPV-associated
OPSCCs were more common among people who had never
smoked or had sporadically smoked and were also signi cantly associated with several favorable prognostic factors,
including younger age, white race, better performance status,
absence of anemia, and smaller primary tumors. In multivariate analysis, age, race, performance status, tumor classi cation, nodal classi cation, and tobacco pack-years were
also signi cant determinants of overall survival. When the
unadjusted hazard ratios (HR 0.38, 95% CI 0.26 to 0.55) were
compared with the adjusted hazard ratios for HPV (HR 0.42,
Figure 1.3
had signifi cantly better overall survival compared to patients with HPV-negative tumors (two-sided log-rank test P < 0.001)
with an absolute benefi t in overall survival of 25% (95% CI 11 to 40) at 3 years. The difference was slightly larger when
stratifi ed by p16 status. (Modifi ed from Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus (HPV) and survival of
patients with oropharynx cancer. N Engl J Med 2010;363:24–35.)
Kaplan-Meier estimates with 95% confi dence intervals for overall survival for patients with oropharyngeal
squamous cell cancer stratifi ed by HPV status (A) and by p16 status (B). Patients with HPV-positive tumors
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Figure 1.4
tion, race, smoking, HPV status, anemia, performance status, treatment assignment, sex) had the most infl uence on overall
survival and to segregate patients into groups at low, intermediate, or high risk of death. B: Kaplan-Meier estimates, with
95% CIs, for overall survival among patients with oropharyngeal cancer stratifi ed by RPA risk group. (Modifi ed from Ang
KK, Harris J, Wheeler R, et al. Human Papillomavirus (HPV) and survival of patients with oropharynx cancer. N Engl J Med
2010;363:24–35.)
95% CI 0.27 to 0.66), factors other than HPV were estimated
to account for about 9% of the di erence in overall survival
between patients with HPV-positive and HPV-negative
OPSCCs (Fig. 1.3A).
Recursive partitioning analysis indicated that tumor
HPV status was the major determinant of overall survival,
followed by tobacco smoking (≤10 vs. >10 pack-years)
and then nodal category (N0-2a vs. N2b-3) for patients
with HPV-positive OPSCCs and primary tumor category
(T2-3 vs. T4) for patients with HPV-negative OPSCCs
(Fig.1.4A). Recursive partitioning led to the classi cation of
patients with OPSCC into three risk groups: low risk (reference group, with a 3-year overall survival rate of 93%),
intermediate risk (HR 3.54, 95% CI 1.91 to 6.57; 3-year overall survival rate of 70.8%), and high risk (HR 7.16, 95% CI
3.97 to 12.93; 3-year overall survival rate of 46.2%) of death
(Fig. 1.4B). Patients with HPV-positive OPSCC were generally at low risk except for those who smoked or had N2b-3
nodes, which put them at intermediate risk. Patients with
HPV-negative OPSCC were generally at high risk, but those
having no history of tobacco use and having T2-3 tumors
were at intermediate risk. Based on these ndings, several
trials are being designed that focus speci cally on patients
with HPV-related OPSCC.
Tumor Expression of Epidermal Growth
Factor Receptor
EGFR is composed of four extracellular domains (I to IV),
including the ligand-binding regions (domains I and III),
a hydrophobic transmembrane domain, a juxtamembrane
domain, an intracellular protein tyrosine-kinase domain
containing the ATP binding pockets, and a regulatory carboxyl terminal domain. It is monomeric in the absence of
ligands. Binding of a ligand to the extracellular domains I
and III alters the spatial con guration of these domains,
A: Survival tree developed with recursive partitioning analysis using S-Tree software to identify which
prognostic factors found to be signifi cant in a proportional hazards model (age, T classifi cation, N classifi ca-
creating an extended and stabilized conformation that
promotes homodimerization and heterodimerization
49
and
activates signal transduction.
e EGFR signaling pathway has evoked considerable attention as a potential biomarker for radiation
response. EGFR is overexpressed in many neoplasms, for
example, in 80% to 100% of HNSCCs, and perturbation
of EGFR signaling is regarded as a major cause of malignant transformation and progression.
50,51
An extensive correlative biomarker analysis using tumor biopsy specimens
from patients with locally advanced HNSCC enrolled in
a phase III trial of conventionally fractionated radiation
(70 Gy in 2-Gy fractions, ve times a week) showed no correlation between EGFR expression and T or N classi cation, American Joint Committee on Cancer (AJCC) disease
stage grouping, and recursive partitioning analysis classes52
(r:−0.07 to +0.17).
As shown in Figure 1.5, EGFR overexpression,
de ned in terms of some level above the median mean
optical density or a staining index measured using an
image-analysis–based immunohistochemical assay, was
found to be a strong and independent marker for higher
local-regional relapse rate (68% vs. 50% at 5 years,
P = 0.0031) and inferior overall survival rate (20% vs. 40%,
53
P = 0.006) but not for the incidence of metastasis.
is
nding was supported by those from another recent study
using automated quantitative assessment of EGFR expression in a tissue microarray from a cohort of patients with
oropharyngeal cancer treated with radiation alone, postoperative radiation, or chemoradiation.54 e investigators
revealed a strong correlation between EGFR expression,
de ned as above median level, and worse local recurrence
rate (58% vs. 17%, P < 0.01) and worse disease-free survival
rate (19% vs. 43%, P = 0.0016).
Two European studies, also conducted using specimens
from patients with HNSCC enrolled in major radiation
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Part 1 General Principles of Head and Neck Radiotherapy
Figure 1.5
treated with radiotherapy. EGFR expression was quantifi ed by computerized quantitative image analysis; parameters
measured included mean optical density (MOD, optical densities measured over the labeled areas within the structure) and
staining index (SI, the proportion of stained area relative to the total area of the structures) as shown in Panels A and B. The
impacts of EGFR expression on overall survival and on local-regional relapse rates are shown in Panels C and D, respectively. (Modifi ed from Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and
pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002;62:7350–7356.)
fractionation trials, showed that high EGFR expression was
predictive for increased tumor response in patients treated
with accelerated radiation, which suggests that EGFR is
Infl uence of tumor expression of epidermal growth factor receptor (EGFR) on overall survival and
local-regional control rates among patients with locally advanced head and neck squamous cell cancer
methodology is essential for comparing the results of future
studies. So far, quantitative, computer-assisted methods
seem to have yielded the most consistent results.
functionally related to accelerated tumor cell repopulation
during fractionated radiation.
HR for local-regional recurrence a er conventional versus
hyperfractionated and accelerated radiation was estimated to
be 1.8 in the group with an EGFR index (i.e., the proportion
of EGFR-positive tumor cells) above the median value (2P=
0.010, 95% CI 1.14 to 2.8). ese data indicate that EGFR
inhibitors could be especially bene cial in combination with
hyperfractionated and accelerated radiation regimens.
Collectively, the available data at this time indicate that
EGFR is a robust predictor of the response of HNSCC to
radiation. It is rather surprising that pretreatment level of
tumor EGFR expression was not found to predict response
to EGFR antagonists.
57,58
used, such as the type of antibody used and the scoring systems, varied widely among centers. In addition, the number
and density of receptors required to mediate a given biologic
e ect is not known. In any event, standardization of assay
55,56
In one of these studies, the
Unfortunately, the assay methods
TREATMENT OF RELATIVELY
ADVANCED CANCERS
Re nement in surgical resection and reconstructive techniques
and advances in radiotherapy planning and delivery technology
yield good outcome for most patients with early head and neck
cancers. Unfortunately, therapy consisting of surgical resection
and preoperative or postoperative radiotherapy still achieves
rather poor results in terms of disease control, preservation of
organ function, or both in patients with locally advanced cancer. Consequently, the search continues for better treatment
approaches. is quest, along with the simplicity of clinical
evaluation and well-characterized patterns of relapse, makes
head and neck carcinomas ideal models for testing the relative
e cacy of novel therapy concepts and modalities. For example,
most of the clinical radiobiologic investigations conducted to
date have involved patients with head and neck cancers.
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Altered Fractionation
Key Points
• Head and neck cancers are good models for testing
the e cacy of new therapy concepts aiming primarily at improving local-regional disease control.
• Results of meta-analysis of large randomized trials
assessing the e ects of biologically sound fractionation schedules show that on the whole, altered
fractionation yielded a signi cant survival bene t
(3.4% increase in 5-year survival rate) relative to
conventional fractionation, with highly signi cant
reductions in cancer-related death and in local tumor
failure without increases in late treatment morbidity.
• Hyperfractionation and accelerated fractionation by
concomitant boost or six weekly fractions have been
adopted in many centers for the treatment of some
patients with intermediate-stage HNSCC or those
with locally advanced HNSCC who are not suitable
for or decline chemotherapy.
Radiobiologic concepts derived from close to three decades
of integrated laboratory and clinical investigations led to the
conception of two classes of altered fractionation schedules
for the treatment of head and neck cancers. ese altered
fractionation regimens are referred to as hyperfractionation
and accelerated fractionation schedules. Hyperfractionation
exploits the di erence in fractionation sensitivity between
tumors and normal tissues manifesting late morbidity.
Commonly used regimens are 80.5 to 81.6 Gy given in
1.15 to 1.2Gy per fractions, twice a day with a 6-hour interval,
over 7 weeks. In contrast, accelerated fractionation schedules
attempt to reduce tumor proliferation as a major cause of
radiotherapy failure. Although there are many permutations
in accelerating radiation treatment, the existing schedules
can be conceptually grouped into two categories: those with
and without reduction of the conventional total dose (66 to
70Gy). Two accelerated fractionation regimens that have been
tested in large clinical trials are a concomitant boost regimen
(designed by investigators at MD Anderson)
59,60
that delivers
54 Gy in 30 fractions over 6 weeks plus an 18-Gy boost dose
given in 1.5-Gy fractions as second daily fractions during the
last 2.5 weeks, and a regimen involving delivery of six 2-Gy
fractions per week used by Danish investigators.61 ese radiobiologically sound fractionation regimens have been extensively tested in patients with intermediate and advanced head
and neck carcinomas, mainly of the oropharynx and larynx.
Bourhis et al.62 reported a thorough meta-analysis that
included updating of individual data for 6,515 patients
enrolled in 15 phase III trials. e main primary tumor sites
were oropharynx (3,079 patients, 44%) and larynx (2,377
patients, 34%), and most patients (5,221, 74%) had stage
III-IV disease. e length of follow-up ranged from 4 to
10 years, with a median of 6 years. e treatment regimens
tested were divided into three categories: hyperfractionated
and accelerated fractionation with or without dose reduction. Table1.1 summarizes the bene t of altered fractionation versus conventional fractionation on di erent outcome
endpoints. On the whole, altered fractionation yielded a
signi cant survival bene t relative to conventional fractionation (P= 0.003), with highly signi cant reductions in
cancer-related death (P=0.0002) and in local tumor failure
Table 1.1
Endpoint Overall Benefi t P Value Hyperfractionation
Improvements at 5 yr
Overall survival
Local-regional control
Hazard ratios
Total death
Cancer death
Local relapse
Regional relapse
Local-regional relapse
Metastatic relapse
a
An 8% reduction in the risk of dying.
Modifi ed from Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet
2006;368:843–854.
Absolute Improvements at 5 Years, with Hazard Ratios and (95% Ci), of Hyperfractionated Versus
Accelerated Fractionation Schedules for Locally Advanced Head and Neck Squamous Cell Cancer
a
+3.4%
+6.4%
0.92 (0.86–0.97)
0.88 (0.83–0.94)
0.77 (0.71–0.83)
0.87 (0.79–0.97)
0.82 (0.77–0.88)
0.97 (0.82–1.15)
0.003
<0.0001
0.003
0.0002
<0.0001
0.01
<0.0001
0.75
+8.2%
+9.4%
0.78 (0.69–0.89)
0.78 (0.68–0.90)
0.75 (0.63–0.89)
0.83 (0.66–1.03)
0.76 (0.66–0.89)
1.09 (0.76–1.58)
Accelerated
Fractionation
without Dose
Reduction
+2.0%
+7.3%
0.97 (0.89–1.05)
0.91 (0.83–1.00)
0.74 (0.67–0.83)
0.90 (0.77–1.04)
0.79 (0.72–0.87)
0.93 (0.74–1.19)
Accelerated
Fractionation
with Reduced
Dose
+1.7%
+2.3%
0.94 (0.84–1.05)
0.93 (0.83–1.05)
0.83 (0.71–0.96)
0.87 (0.72–1.06)
0.90 (0.80–1.02)
0.95 (0.68–1.32)
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Part 1 General Principles of Head and Neck Radiotherapy
(P<0.0001). Moreover, the bene t was signi cantly higher in
younger than in older patients (P = 0.007 for test for trend).
Overall, the magnitude of the survival bene t was signi cantly higher in the hyperfractionation group than in the
two accelerated fractionation groups (P = 0.02). However,
the authors emphasized that the populations included in the
three groups were dissimilar, as the accelerated fractionation without dose reduction group enrolled more patients
with early-stage or laryngeal cancer. Relapses in the latter
group could be e ectively salvaged, as shown in the RTOG
larynx preservation trial,
the survival endpoint. Indeed, in the only phase III trial in
which hyperfractionation and accelerated fractionation with
concomitant boost were tested simultaneously against conventional fractionation, both regimens were found to yield a
similar magnitude of e ect.
Evidence generated from numerous randomized trials
indicates that altered fractionation is a reasonable option for the
treatment of some patients with intermediate-stage (i.e., T2N0-1
or exophytic T3N0-1) HNSCC or those with locally advanced
HNSCC who are not suitable for or decline chemotherapy.
However, the use of altered fractionation regimens has declined
in recent years owing to advances in the development of highprecision radiation treatment technology, particularly IMRT,
which combines the principles of both hyperfractionation with
accelerated fractionation as discussed below.
63,64
and thus have little impact on
60
High-Precision Radiotherapy
Key Points
• IMRT can incorporate principles of both hyperfrac-
tionation and accelerated fractionation by generating a gradient of lower dose per fraction to normal
tissues and by administering twice a day fractions
during some treatment days. is feature, coupled
with the ability to reducing the total dose to critical normal tissues, makes IMRT more popular than
altered fractionation for the treatment of HNSCC.
• Emerging data from both single-institution and mul-
ticenter trials on the use of IMRT for the treatment
of nasopharyngeal and oropharyngeal carcinomas
are strong in terms of high local-regional control and
reduction of xerostomia.
• Further developments needed to fully bene t from
IMRT include quanti cation of and adapting to
intrafraction and interfraction variation, topographic
and biologic tumor imaging to improve target
de nition, among others.
• e observation that most recurrences are situated
within the high-dose region indicates that radiation
dose escalation alone will improve outcome in only a
subset of patients.
Advances in computerized radiotherapy planning and
delivery technology open the possibility of conforming
irradiation to irregular tumor target volumes, an approach
commonly referred to as conformal radiotherapy (CRT).65
Consequently, it is feasible to reduce the radiation dose to
the crucial normal tissues surrounding the tumor without
compromising dose delivery to the intended target volume, resulting in a reduction in morbidity. Reduced toxicity would, in turn, permit escalation of the radiation dose or
combining radiotherapy with intensive chemotherapy, each
of which has the potential for improving HNSCC control.
e clinical application of precision radiotherapy, however,
requires basic expertise in anatomy, imaging, and patterns
of tumor spread.
Precision radiotherapy can be accomplished by the use
of an array of x-ray beams individually shaped to conform
to the projection of the target, which is referred to as three-
dimensional conformal radiotherapy (3-D CRT). In addition, technology is also available to modify the intensity of
the beams across the irradiation eld as an added degree of
freedom to enhance the capability of conforming dose distributions in three dimensions. is radiotherapy technique
is called intensity-modulated radiotherapy (IMRT). Proton
beams o er an even higher magnitude of normal tissue sparing, which is more desirable for the treatment of, for example,
pediatric cancers and some skull base neoplasms.
With IMRT, all target volumes are irradiated during
every radiation session, but lower doses are delivered to the
subclinical disease volume at each fraction. For example,
when 70 Gy is delivered in 35 fractions (at 2 Gy per fraction)
to the gross disease, the low-risk subclinical target volumes
receive doses ranging from 56 to 59.5 Gy, also in 35 fractions
(corresponding to 1.70 to 1.75 Gy per fraction). Normal tissues outside these volumes receive even lower total doses
given in lower-dose fractions. Hence IMRT incorporates
some degree of normal tissue sparing by lowering the dose
per fraction. Consequently, delivery of six fractions of IMRT
per week, thus 35 fractions in 6 weeks, takes advantage of
the principles of both hyperfractionation and accelerated
fractionation.
e role of 3D CRT and, particularly, IMRT in reducing morbidity and, perhaps, in improving control of SCC
through radiation dose escalation is being tested at several
centers. Results already reveal that such techniques are e ective in sparing parotid glands from receiving high radiation
doses, thereby diminishing radiation-induced permanent
xerostomia in some patients.
Single-institution studies testing the role of IMRT in
the management of NPC and oropharyngeal cancers have
yielded exciting results. For patients with NPC, IMRT was
given either alone or (for those with locally advanced disease)
in combination with chemotherapy consisting of concurrent
cisplatin and adjuvant cisplatin plus uorouracil.67 In a series
of 67 patients with a median follow-up interval of 31 months,
66
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13
the 4-year estimates of local progression-free, local-regional
progression-free, distant metastasis-free, and overall survival
rates were 98%, 97%, 66%, and 88%, respectively. e worst
acute toxicity was grade 1 to 2 in 51 patients (76%), grade 3
in 15 patients (22%), and grade 4 in 1 patient (2%). e worst
late morbidity was grade 1 in 20 patients (30%), grade 2 in
15 (22%), grade 3 in 7 patients (10%), andgrade 4 in 1 patient
(2%). Xerostomia was less pronounced a er IMRT than a er
3D CRT, and its intensity decreased with time. At 3 months
a er IMRT, 8% of patients had no dry mouth, 28% had
grade 1 xerostomia, and 64% had grade 2 xerostomia. Of the
41 patients evaluated at 2 years, 66% had no dry mouth, 32%
had grade 1 xerostomia, and 2% had grade 2 xerostomia.
ese encouraging single-institution data have inspired
the launch of several prospective trials addressing the role
of IMRT in the treatment of head and neck carcinomas.
Investigators in Hong Kong completed two phase III trials
assessing the role of IMRT in preserving parotid salivary
ow. e study reported by Kam et al.68 showed that patients
given IMRT had a lower incidence of observer-rated severe
xerostomia than did patients given 2-D radiotherapy, results
that paralleled higher fractional stimulated rates of parotid
ow and whole saliva ow rates. However, there was only
a trend toward improvement in patient-reported outcome
a er IMRT relative to 2D radiotherapy. In another study,
Pow et al.
xerostomia-related symptoms than did patients given conventional radiotherapy at 12 months a er radiotherapy and
that symptoms that were experienced improved consistently
over time. Global health scores showed continuous
improvement in quality of life a er both treatments
(P < 0.001), but a er 12months, the subscale scores for
role-physical, bodily pain, and physical function were signi cantly higher in the IMRT group, indicating overall better condition in that group.
institutional settings. Trial 0022 addressed accelerated
hypofractionated IMRT without chemotherapy for early-stage
oropharyngeal cancer.70 is study accrued 69 patients with
stage T1-2 N0-1 M0 carcinoma of the oropharynx requiring treatment of the bilateral neck from 14 institutions.
e prescribed doses were 66 Gy at 2.2 Gy per fraction to
the primary tumor and involved nodes and 54 to 60 Gy at
1.8 to 2.0 Gy per fraction to elective volumes, to be given over
6 weeks. At a median follow-up time of 2.8 years for surviving
patients, the 2-year estimated local-regional failure rate was
9%. Notably, two of four patients with major underdose deviations had local-regional failure as compared with only three
of 49 patients (6%) without such deviations (P = 0.04). Xeros-
tomia of grade 2 or higher was observed in 55% of patients
at 6 months but in 25% at 12 months and 16% at 24months.
patterns, and survival in patients with NPC treated with
IMRT (70 Gy to the tumor and involved nodes and 59.4 Gy
69
showed that patients given IMRT had fewer
e RTOG also completed two trials in multi-
e other RTOG trial, 0225, assessed toxicities, failure
to subclinical disease, given in 33 fractions) with or without
chemotherapy (concurrent cisplatin and adjuvant cisplatin uorouracil).71 e estimated 2-year local progression-free,
regional progression-free, local-regional progression-free,
and distant metastasis-free rates were 92.6%, 90.8%, 89.3%,
and 84.7%, respectively. e estimated 2-year progressionfree survival and overall survival rates were 72.7% and 80.2%,
respectively. e worst late grade 3 toxicities were esophageal,
4.7%; mucous membranes, 3.1%; and xerostomia, 3.1%. e
rate of grade 2 xerostomia at 1 year from the start of IMRT
was 13.5%; only two patients experienced grade 3 xerostomia,
and none had grade 4 xerostomia. is study thus reproduced
the excellent results reported from single-institution studies.
Despite these encouraging ndings from the use of
IMRT, it must be noted that further development is needed
to fully bene t from this sophisticated technology. Areas
needing improvement to re ne margins of coverage include
quanti cation of day-to-day anatomic variations occurring during the course of radiotherapy due to motion and
changes in tumor and normal tissue volume occurring during the course of therapy, ways of adapting the therapy to
these changes (adaptive therapy) to better spare normal
tissues, topographic and biologic tumor imaging to better
de ne target volumes, and so on.
Although the results of IMRT and particle therapy are
encouraging, the observation that most recurrences originated from the high-dose region indicates that radiation
dose escalation alone will improve outcome in only a subset of patients. Further advances in the treatment of solid
tumors would likely come through the application of new
knowledge of tumor biology, as exempli ed by translational
research addressing the role of EGFR in tumor progression
and as a target for therapeutic intervention, as discussed in a
subsequent section below.
Combining Radiation with Chemotherapy
Key Points
• e combination of radiation with chemotherapy for
the treatment of HNSCC has been extensively investigated in phase III trials since the early 1970s.
• A thorough meta-analysis of 16,485 patients in 87
trials revealed that adding concurrent chemotherapy
to radiation increased the absolute 5-year survival
rate to a greater extent than did combining non–
taxane-containing induction chemotherapy with
radiation (6.5% vs. 2.4%).
• No signi cant di erence in the magnitude of bene t
was detected between concomitant chemotherapy
trials addressing frontline and adjuvant therapy,
conventional and altered fractionation, and using
single-agent and multiagent regimens.
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