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Part 1 General Principles of Head and Neck Radiotherapy
• In the single-agent group, the e ect of chemotherapy
was signi cantly higher for platinum-based compounds than with other agents; cisplatin, at a dose
of 100 mg/m2 three times throughout the course of
radiotherapy, has been a common standard regimen
used in combination with radiotherapy.
• e bene t of concurrent chemotherapy was due to
reduction of cancer-related deaths, mainly through
improvements in local-regional control, whereas
induction chemotherapy seems to have a better e ect
on distant metastasis.
• e e ect of chemotherapy on survival decreased
with increasing patient age. Plausible explanations
include that older patients more o en die from
causes other than cancer, which makes it more dif cult to detect the bene t in these patients, or that
chemotherapy increases the number of deaths from
causes other than cancer in older patients.
• Analyses of long-term follow-up data indicated that
adding platinum-based concurrent chemotherapy
to radiation increases the incidence of late morbidity such as swallowing dysfunction and so tissue
brosis or necrosis.
• A recent phase III trial showed no di erence in
overall survival, other tumor outcome endpoints, or
toxicity pro le between an accelerated regimen plus
two cycles of cisplatin and conventional fractionation with three cycles of cisplatin, suggesting that
both regimens can serve as a platform to which new
agents can be added.
• Recent randomized trials showed that adding doc-
etaxel to a cisplatin- uorouracil induction regimen
improves overall survival or larynx preservation rate,
but, counterintuitively, the bene t seems to result
from increased local-regional control rather than
from reduced distant metastasis.
• Currently, the two combined chemoradiation regimens
having the strongest evidence for routine use as nonsurgical frontline treatment of locally advanced HNSCC
are radiation plus concurrent high-dose cisplatin; and
induction docetaxel, cisplatin, and uorouracil followed
by radiation alone or combined with carboplatin.
• Postoperative adjuvant radiation with concurrent
cisplatin is recommended only for patients with histologically proven extracapsular extension, positive
surgical margins, or both.
• Postoperative radiotherapy without chemotherapy
remains the standard of care for patients with
intermediate-risk features such as perineural invasion, close margins, and positive nodes without
extracapsular extension.
Meta-analyses of Concurrent Versus Induction
Chemotherapy Regimens
Combining radiation with chemotherapy has been extensively investigated in patients with HNSCC. However, most
of the regimens that have been studied have evolved empirically by administering drugs found to have some activity
against tumors of interest in a dose and time sequence known
to be tolerated in the setting of single-modality therapy.
Meta-analyses of available data of randomized trials in head
and neck cancer undertaken a few years ago showed that in
spite of a high initial response rate, multiagent chemotherapy
given before radiation treatment (i.e., neoadjuvant therapy)
has only a small impact on local-regional control and survival rates.72 Concurrent radiation and chemotherapy, on
the other hand, has yielded survival rates up to 10% higher
than those of radiation alone.73 Unfortunately, the complication rates of combined regimens are also higher than those
of radiotherapy alone.
e Meta-analysis of Chemotherapy on Head and Neck
Cancer (MACH–NC) Collaborative Group undertook a very
extensive meta-analysis.74 In the most recent update of that
analysis, Pignon et al. were able to add 24 randomized trials
enrolling 5,744 patients between 1994 and 2000 to their previous series of 63 trials enrolling 10,741 patients between 1965
and 1993. e updated meta-analysis thus included 87trials
with 16,485 patients comparing various local-regional treatments with or without chemotherapy.75 Updated follow-up
was obtained for most of the trials, and the overall median
follow-up time was 5.6 years. Given the substantial impact
that this thorough analysis will continue to have on treatment
policy, pertinent results are summarized below.
Overall Effect of Concomitant Chemotherapy
e HR of death was 0.81 (95% CI 0.78 to 0.86, P < 0.0001)
in favor of concomitant chemotherapy with an absolute
bene t of 6.5% at 5 years. e magnitude of the bene t
was identical for trials conducted during the two periods
(1965–1993 and 1994–2000), and no signi cant heterogeneity (P = 0.27) was found in the most recent trials. Cancerrelated and non–cancer-related deaths could be distinguished
from one another in the recent trials because the cause of
death was missing in <4% of the patients without recurrence.
e bene t of chemotherapy was due to reduction of deaths
related to HNSCC (HR 0.78, 95% CI 0.73 to 0.84, P < 0.0001)
with no e ect on noncancer deaths (HR 0.96, 95% CI 0.82 to
1.12, P = 0.62). Results were similar for event-free survival,
with an HR of 0.79 (95% CI 0.76 to 0.83, P < 0.0001) and an
absolute bene t of 6.2% at 5 years (29.3% vs. 23.1%).
Subset analyses revealed no signi cant di erence in
bene t between the group of trials testing postoperative
radiotherapy (HR 0.79, 95% CI 0.68 to 0.91) and curative
radiotherapy given in either conventional fractionation
(HR 0.83, 95% CI 0.78 to 0.88) or altered fractionation (HR
0.73, 95% CI 0.65 to 0.82). No signi cant di erence was
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seen between single-agent chemotherapy (HR 0.84) and
multiagent chemotherapy (HR 0.78). In the single-agent
chemotherapy group, the e ect of chemotherapy was signi cantly higher (P =0.006) for platinum-based compounds
than for otheragents.
Consistent with the previous ndings, the e ect of
chemotherapy on survival decreased with increasing patient
age (test for trend, P = 0.003). Recent trials with more complete data showed that the cause of death, as expected, varied markedly according to age. e proportion of deaths not
related to HNSCC increased progressively with age from
15% in patients younger than 50 years to 39% in those over
70 years of age.
Overall Effect of Induction Chemotherapy
e HR of death was 0.96 (95% CI 0.90 to 1.02, P = 0.18) with
an absolute di erence of 2.4% at 5 years. e e ect did not
vary (P = 0.23) according to the type of chemotherapy: the
HRs were 0.90 (0.82 to 0.99) for cisplatin- uorouracil, 1.01
(95% CI 0.91 to 1.12) for other multiagent regimens, and
0.99 (95% CI 0.84 to 1.18) for single agents (no trial was done
with cisplatin alone). Results for event-free survival were
similar, with an HR of 0.99 (95% CI 0.93 to 1.05, P = 0.67)
and an absolute bene t of 1.3% at 5 years (27.6% vs. 26.3%).
e HRs of death were not signi cantly di erent (P = 0.68)
between trials using radiotherapy alone, surgery plus postoperative radiotherapy, or other local-regional treatment.
Effects of Concomitant and Induction Chemotherapy on
Local-Regional Relapses and Distant Metastasis
Local-regional relapse data were available for 50 concomitant and 30 induction trials. e bene t of concomitant
chemotherapy was signi cant (HR 0.74, 95% CI 0.70 to
0.79, P < 0.0001), whereas induction chemotherapy had
no e ect (HR 1.03, 95% CI 0.95 to 1.13, P = 0.43). e two
HRs were signi cantly di erent (P < 0.0001) in favor of the
concomitant group.
Distant metastasis data were available for 44 concomitant and 26 induction trials. Both concomitant and induction chemotherapy were found to have signi cant e ects,
with HRs of 0.88 (95% CI 0.77 to 1.00, P = 0.04) for con-
comitant therapy and 0.73 (95% CI 0.61 to 0.88, P = 0.001)
for induction therapy. Although the HR of induction chemotherapy was smaller than that of the concomitant regimens,
the comparison of the two HRs did not yield a signi cant
di erence (P = 0.12).
Direct Comparison of Concomitant Versus
Induction Chemotherapy
Data from six trials that used the same agents in both arms
but with di erent timing relative to radiotherapy were also
analyzed separately. ese trials enrolled 861 patients, 717 of
whom had died at a median follow-up interval of 10.9 years.
Data for event-free survival and local-regional failure were
available for ve trials, but data on distant metastasis were
missing for most of the trials. Signi cant bene t in favor
of the concomitant chemotherapy was detected for eventfree survival (HR 0.81, P = 0.01) and local-regional control
(HR 0.77, P = 0.005) but not for overall survival (HR 0.90,
P=0.15, 5-year survival rates 27.8% vs. 24.3%).
Summary of Meta-analysis
e authors of the meta-analysis concluded that adding data
from the 24 more recent trials with minimal heterogeneity did not change the magnitude of the observed survival
bene t resulting from the addition of chemotherapy that
had been reported previously, which stayed at around 4% at
5years. is bene t was rm for concomitant chemotherapy
(HR 0.81) but was not demonstrable for induction regimens.
Important observations were that concomitant chemotherapy markedly improved local-regional control, which was not
observed for induction chemotherapy. On the other hand,
induction chemotherapy had a more pronounced e ect on
distant metastases compared with concomitant regimens,
suggesting the need to use relatively high doses of chemotherapy to in uence the manifestation of distant metastases.
Cisplatin alone, cisplatin or carboplatin plus uorouracil, or other multiagent regimens including either ciplatin or
uorouracil yielded the same magnitude of bene t. In contrast, drugs given alone (except for cisplatin) had inferior
results and, therefore, should not be recommended in routine practice. Single-agent cisplatin seems to be a common
standard regimen in combination with radiotherapy. Most
of the randomized trials used high-dose cisplatin regimens,
that is, 100 mg/m
2
given three times throughout the course of
radiotherapy (cumulative dose of 300 mg/m2). Interestingly,
the only negative “cisplatin-alone” trial in this meta-analysis used a cumulative dose of 140 mg/m2 (20 mg/m2×7),
suggesting that the cumulative dose of cisplatin could be
important.
e bene t of concomitant chemotherapy seems to be
similar regardless of whether the radiotherapy was given in
conventional or altered fractionation, but the magnitude of
the bene t was less in older patients. One explanation is that
older patients more o en die from causes other than cancer,
which makes it more di cult to detect the bene t in these
patients (dilution e ect). Alternatively, chemotherapy could
increase the number of deaths from causes other than cancer
in older patients.
Long-Term Toxicity of Concurrent
Chemoradiotherapy
e meta-analysis presented above focused on tumor control
endpoints. Data on compliance and toxicity were not available for analysis. Notably, the recording and reporting of late
morbidity associated with concurrent chemoradiotherapy
have not been su ciently consistent or systematic.76 A report
of the long-term results of a French Groupe d’Oncologie
Radiotherapie Tete et Cou (GORTEC) trial revealed that the
late complication rate associated with the combination of
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Part 1 General Principles of Head and Neck Radiotherapy
radiation with concurrent carboplatin and uorouracil was
signi cantly higher than that of radiation alone.
77
Machtay et al.78 performed a case-control secondary
analysis of three previously reported RTOG trials of concurrent chemoradiotherapy for locally advanced HNSCC:
RTOG 91-11, a phase III larynx preservation trial; 97-03,
a phase II-R trial of three concurrent chemoradiotherapy
regimens; and 99-14, a trial of accelerated fractionation
plus cisplatin. Severe late toxicity was de ned as chronic
grade 3 to 4 pharyngeal/laryngeal toxicity (according to the
RTOG/European Organisation for the Research and Treatment of Cancer [EORTC] late toxicity scoring system) or the
requirement for a feeding tube ≥2 years a er registration or
potentially treatment-related death (e.g., pneumonia) within
3years.
Of a total of 479 patients from these three studies, 130
were excluded because of local-regional failure or cancer
death, 100 for severe pretreatment laryngopharynx dysfunction caused by tumor, 13 for missing data, and 6 for early
iatrogenic death. Of the 230 patients analyzed, 99 patients
had severe late toxicity and 131 control subjects did not have
severe morbidity, thus resulting in a crude late toxicity rate
of 43%. On multivariable analysis, variables found to correlate with the development of severe late toxicity were older
age (odds ratio 1.05 per year, P < 0.001), advanced T classi cation (odds ratio 3.07, P < 0.0036), larynx/hypopharynx
primary tumor site (odds ratio 4.17, P < 0.0041), and neck
dissection a er concurrent chemoradiotherapy (odds ratio
2.39, P < 0.018).
Given the retrospective nature of this work, these ndings should be considered hypothesis-generating only. e
trials included in this study were conducted over a 10-year
period (approximately 1991 to 2001), with variations in eligibility, treatment, and data collection techniques. A second
problem inherent to retrospective studies like these is that
information on some potentially important factors, such
as tumor volume, cardiopulmonary and other comorbidity,
and quantity of tobacco consumption, was not collected in
su cient detail.
Role of Altered Fractionation in Concurrent
Chemoradiotherapy
As presented above, both altered fractionation regimens and
concurrent chemoradiotherapy can improve local-regional
control, survival, or both over conventionally fractionated
radiotherapy alone. Of two trials designed to address this
comparison, results of one trial (RTOG 0129) have been
43
reported to date.
In that large phase III trial, 743 patients
were strati ed according to tumor site (larynx vs. other),
nodal classi cation (N0 vs. N1-N2b vs. N2c-N3), and
Zubrod performance status (0 vs. 1) and assigned to receive
high-dose cisplatin concurrent with either accelerated fractionation by concomitant boost or standard fractionation.
e accelerated schedule delivered 72 Gy in 42 fractions
over 6 weeks, which included twice-a-day irradiation for
12 treatment days (as previously reported60), whereas the
standard schedule consisted of 70 Gy in 35 fractions (2 Gy
per fraction) over 7 weeks. Chemotherapy consisted of intravenous cisplatin at a dose of 100 mg/m2 on days 1 and 22 in
the accelerated group or on days 1, 22, and 43 in the standard
fractionation group.
No signi cant di erences were observed between the
accelerated and standard fractionation groups with regard to
deaths within 30 days of therapy (3.3% vs. 1.9%, P = 0.26)
or overall rates of grade 3 to 4 acute toxicity (80% vs. 84%,
P = 0.21) or late toxicity events (26% vs. 21%, P = 0.18). At
the data cut-point (August 2009), 418 patients were alive.
At a median follow-up time of 4.8 years (range 0.3 to
6.5 years), no signi cant di erence in overall survival was
observed between the two groups (3-year overall survival
rate 70.3% [95% CI 65.6 to 75.1] for accelerated vs. 64.3%
[95% CI 59.3 to 69.2] for standard fractionation, P = 0.18). A
nonsigni cant reduction in the death rate of 10% (HR 0.90
[95% CI 0.72 to 1.13]) was observed in the accelerated group,
but no signi cant di erence was observed in progressionfree survival or pattern of relapse between the accelerated
and standard fractionation arms. is trial thus showed that
accelerating radiotherapy in the setting of concurrent chemoradiotherapy does not improve outcome. As there was also
no di erence in the toxicity pro le, both regimens (accelerated fraction radiation plus two cycles of cisplatin and standard fraction radiation with three cycles of cisplatin) can serve
as a platform to which new agents can be added.
Taxane-Based Induction Chemotherapy
e success of taxanes in the treatment of other solid tumors
has generated a resurgence of interest in neoadjuvant chemotherapy with taxane-containing regimens for head and neck
cancer. Results of three randomized trials addressing the
e cacy of neoadjuvant docetaxel, cisplatin, and uorouracil regimen (TPF) relative to cisplatin and uorouracil (PF)
for patients with locally advanced HNSCC were recently
reported. e EORTC trial 2497179 compared four cycles of
docetaxel (75 mg/m2 on day 1), cisplatin (75 mg/m2 on day 1),
and uorouracil (750 mg/m2/d for 5 days) to three cycles of
cisplatin (100 mg/m2 on day 1) plus uorouracil (1,000mg/m2
for 5 days), both followed by radiotherapy alone (conventional
or altered fractionations to 66 to 74 Gy), whereas the TAX
324 study80 evaluated three cycles of docetaxel (75 mg/m2
on day 1), cisplatin (100 mg/m2 on day 1), and uorouracil
(1,000 mg/m2/d for 4 days) against three cycles of cisplatin
(100 mg/m2 on day 1) plus uorouracil (1,000 mg/m2 for
5days), both followed by radiotherapy with weekly carboplatin (AUC 1.5). Table 1.2 summarizes the published results
of these trials. e EORTC trial revealed more severe leukopenia, neutropenia, and alopecia in the group given TPF but
more severe hearing loss and toxic death in the PF group.
TAX 324 showed that despite antibiotic prophylaxis, rates of
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Table 1.2
Endpoints
Response rate (%) 68 54 0.006 72 64 0.07
Median progression-free survival (mo) 11.0 8.2 0.007 36 13
3-yr survival rate (%) 37 26 – 62 48 0.002
Median overall survival (mo) 18.6 14.2 0.005 71 30 0.006
Hazard ratio 0.73 (0.56–0.94) 0.02 0.70 (0.54–0.90) 0.006
Median follow-up times were 32.5 mo in the EORTC trial79 and 42 mo in the TAX 324 study.
febrile neutropenia and neutropenia infection were higher in
the TPF group. However, patients in the TPF group had fewer
treatment delays than did those in the PF group, and rates of
grade 3 to 4 nonhematologic toxic e ects were similar in the
two groups (65% in TPF and 62% in PF). Interestingly, TAX
324 showed that the addition of docetaxel improved localregional control rates (P = 0.04), but the incidence of distant metastases in the two groups did not di er signi cantly
(P= 0.14). So, contrary to expectations, the bene t of adding
docetaxel to cisplatin and uorouracil seems to result from
improved local-regional control.
e third phase III trial, by the French cooperative
group (GORTEC), addressed the role of neoadjuvant TPF
in larynx preservation.81 Patients with previously untreated,
histologically proven stage III or IV carcinoma of the larynx or hypopharynx and meeting other eligibility criteria
were randomized to receive three cycles of TPF (75 mg/m2
of docetaxel on day 1, 75 mg/m2 of cisplatin on day 1, and
750 mg/m2/d of uorouracil for 5 days) or modi ed PF
(80 mg/m2 of cisplatin on day 1 and 800 mg/m2/d of uorouracil for 5 days), followed by conventional radiotherapy
alone (70 Gy), for those who responded to the chemotherapy. At a median follow-up time of 36 months, the 3-year
estimated larynx preservation rates were 70.3% with the TPF
regimen and 57.5% with the PF regimen (P = 0.03). Con-
sistent with the results of other larynx preservation trials,
there were no signi cant di erences between groups in rates
of overall survival or disease-free survival. It is hoped that
details of late toxicity will be reported a er longer follow-up.
Adjuvant Therapy for Locally Advanced HNSCC
Effi cacy of Neoadjuvant Docetaxel, Cisplatin, and Fluorouracil (TPF) Versus Cisplatin and Fluorouracil
(PF) Followed By Radiation Alone or Combined with Weekly Carboplatin for the Treatment of Locally
Advanced Head and Neck Squamous Cell Cancer
EORTC 24971 (N = 358) TAX 324 (N = 501)
TPF PF P Value TPF PF P Value
80
postoperative radiotherapy (60 to 66 Gy in 2-Gy fractions)
alone or combined with cisplatin (100 mg/m2 every 3 weeks
for 3 cycles). In the RTOG trial,82 radiochemotherapy signi cantly reduced the risk of local-regional recurrence
compared with radiation alone (HR 0.61, P = 0.01) but did
not improve overall survival. In contrast, the EORTC trial83
showed signi cant improvement in progression-free survival
(HR 0.75, P = 0.04) and overall survival (HR 0.70, P = 0.02) in
addition to local-regional control. Notably, both trials found
that the addition of cisplatin had no signi cant e ect on the
incidence of distant metastases. Both studies also found that
cisplatin considerably increased the rate of grade 3 or higher
adverse events (from 34% to 77% [P < 0.001] in the RTOG
trial and from 21% to 41% [P = 0.001] in the EORTC trial).
To determine which patients are most likely to bene t
from intensive postoperative radiochemotherapy, a pooled
analysis of data from both trials was performed.84 is analysis revealed that in both trials, only patients with extracapsular extension and positive surgical margins bene ted from
radiochemotherapy. is combined analysis thus contributed to re ning the criteria for the high-risk category and
the treatment algorithm. Adjuvant radiation with concurrent
cisplatin is now recommended only for patients with histologically proven extracapsular extension, positive surgical
margins, or both. For those with intermediate-risk features
(e.g., positive nodes without extracapsular extension, perineural invasion, close margins), the current standard of care
is postoperative radiotherapy without chemotherapy. E orts
are underway to test the combination of radiotherapy, with
or without chemotherapy depending on the risk features,
with molecular therapeutics for this subset of patients.
Although data from several trials addressing adjuvant
chemoradiation were included in the meta-analyses, the
results of two larger-scale trials done by the RTOG82 and
the EORTC83 are brie y summarized here because they contributed to re ning the standard of care. Both studies randomly assigned patients with high-risk surgical-pathologic
features to surgery followed by conventionally fractionated
Current Standard and Further Work in Combining
Radiation with Chemotherapy
In spite of more than 3 decade of clinical research, many
scienti c questions related to combinations of radiation and
chemotherapy are still not answered. ese include whether
neoadjuvant chemotherapy with docetaxel, cisplatin,
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Part 1 General Principles of Head and Neck Radiotherapy
and uorouracil followed by radiation with or without
carboplatin is superior to concurrent radiation-cisplatin;
whether neoadjuvant docetaxel, cisplatin, and uorouracil
can further improve the outcome of radiation with concurrent cisplatin; and whether newer cytotoxic agents are more
e ective when given concurrently with radiotherapy. Many
studies are underway to resolve some of these questions,
but results will not be available soon. Until such scienti c
questions are resolved, the two combined chemoradiation
regimens having the strongest evidence for routine use as
nonsurgical treatment of locally advanced HNSCC are radiation plus concurrent high-dose cisplatin and induction docetaxel, cisplatin, and uorouracil followed by radiation alone
or combined with carboplatin.
Combining Radiation with Agents
Targeting Signaling Pathways (Targeted
Agents)
Key Points
• Recently published ndings of a phase III trial
showed that adding the EGFR inhibitor cetuximab
to radiation signi cantly improves local-regional
control and survival rates without increasing
radiation-induced side e ects, such as mucositis and
dysphagia.
• e proof-of-principal cetuximab trial revealed that
targeting a perturbed signaling pathway in neoplasms can selectively sensitize tumors to radiation.
• Coordinated laboratory and clinical studies led the
U.S. Food and Drug Administration to approve
cetuximab in combination with radiotherapy as a
new frontline treatment for patients with locally
advanced HNSCC.
• ree regimens, all supported by level 1 evidence, are
currently available for frontline nonsurgical treatment of locally advanced HNSCC: radiation with
concurrent chemotherapy (particularly cisplatin);
radiation with concurrent cetuximab; and neoadjuvant docetaxel, cisplatin, and uorouracil followed by
radiation (with or without carboplatin).
e results of correlative biomarker analyses and preclinical
work on modulating tumor radiation response by targeting EGFR, as summarized above, provided the impetus for
launching and completing a multinational phase III study
testing the e cacy of the combination of the EGFR inhibitor cetuximab with radiation relative to radiation alone for
patients with locally advanced HNSCC.
patients from 73 centers in the United States and 14 other
countries were randomly assigned to receive high-dose radiotherapy alone (predominantly in accelerated fractionation
by concomitant boost) or the same radiotherapy regimens
plus eight doses of cetuximab (starting 1 week before and
continuing during the course of radiotherapy). As summarized in Table 1.3, this proof-of-principle, highly referenced
trial demonstrated that the addition of cetuximab resulted
in signi cant improvement in local-regional control rate
(3-year rate 47% vs. 34%, P = 0.005) and survival (median
time 29 to 49 months, 3-year rate 45% to 55%, P = 0.03)
without increasing radiation-induced side e ects, such as
mucositis and dysphagia. Consequently, the U.S. Food and
85
A total of 424
Table 1.3
Endpoints Radiotherapy Alone Radiotherapy + Cetuximab Hazard Ratios (5% CI) P Values
Local-regional control
Median duration (mo)
Rate at 2 yr (%)
Progression-free survival
Median duration (mo)
Rate at 2 yr (%)
Overall Survival
Median duration (mo)
Rate at 3 yr (%)
Distant metastasis
Rate at 1 yr (%)
Rate at 2 yr (%)
a
Cumulative incidence.
Modifi ed from Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med
2006;354:567–578.
Effi cacy of Radiotherapy with Cetuximab Versus Radiotherapy Alone for the Treatment of Locally
Advanced HNSCC
a
14.9
41
12.4
37
29.3
45
10
17
24.4
50
17.1
46
49.0
55
8
16
0.68 (0.52–0.89) 0.005
0.70 (0.54–0.90) 0.006
0.74 (0.57–0.97) 0.03
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Drug Administration approved cetuximab in combination
with radiotherapy as front-line treatment for patients with
locally advanced HNSCC in February 2006. Notably, the
antibody did induce an acneiform rash, common to EGFR
antagonists, and a few patients could not receive this
treatment because of infusion reactions.
A recent update of the results of the cetuximab trial86 yielded
a median overall survival time of 49.0 months (95% CI 32.8 to
69.5) for patients treated with cetuximab and radiotherapy versus 29.3 months (95% CI 20.6 to 41.4) in the radiotherapy-alone
group (HR 0.73, 95% CI 0.56 to 0.95, P= 0.018). e 5-year
overall survival rate was 45.6% in the cetuximab plus radiotherapy group and 36.4% in the radiotherapy-alone group. An additional nding was that overall survival was signi cantly better
among patients who experienced an acneiform rash of at least
grade 2 severity compared with patients with grade 0 or grade 1
rash (HR 0.49, 95% CI 0.34 to 0.72, P = 0.002).
Standard Nonsurgical Front-Line Therapy
for Locally Advanced HNSCC
ree regimens supported by level 1 evidence are currently available for front-line treatment of locally advanced
HNSCC. ese are concurrent chemoradiation (particularly
with three cycles of cisplatin given in 100 mg/m2 every third
week); radiation with concurrent cetuximab; and induction
docetaxel, cisplatin, and uorouracil followed by radiation
(with or without carboplatin). Unfortunately, the absence
of head-to-head comparisons among these three regimens
makes it di cult to objectively select a particular regimen for
individual patients in the absence of a contraindication for
platinum compounds. e choice at the present time is o en
based on local expertise, oncologist or patient preference,
and some cost considerations.
Several trials are ongoing to address integration of
cetuximab into the concurrent radiation-cisplatin platform,
combining docetaxel, cisplatin, and uorouracil with
radiation-cisplatin, adding cetuximab to induction docetaxel,
cisplatin, and uorouracil, and so on. e results of these
trials are expected to provide more clarity for streamlining
clinical practice.
PREVENTION OF HEAD AND
NECK CANCERS
Key Points
• Field cancerization resulting from interactions
between prolonged carcinogen exposure and individuals’ genetic pro les renders an individual who
survives an upper aerodigestive cancer susceptible to
developing a SPT in the same anatomic region.
• SPTs are the leading cause of death among patients
with early-stage head and neck cancers.
• A large multi-institutional randomized trial launched
based on the encouraging results of smaller studies
did not show a bene t for isotretinoin (cis-retinoic
acid) in reducing the rate of SPTs.
• Identi cation of key genetic changes resulting in
the development of malignant clones and markers
of multistep carcinogenesis will aid in identifying
patients at highest risk so that they can be enrolled in
future chemoprevention trials.
• Another vital component in SPT prevention e ort
is the development of novel agents with low toxicity
pro les that target key molecular pathways that are
disrupted early in the carcinogenesis.
e concept of “ eld cancerization” was rst described by
Slaughter et al.87 in 1953 and has long been validated by clinical data. is evolving notion describes di use subcellular
injury to epithelium, resulting from interactions between
prolonged carcinogen exposure and individuals’ genetic
pro les, that renders the whole anatomic eld at risk for
developing invasive cancers through the progressive stepwise accumulation of genetic alterations. It follows that an
individual who develops and survives an upper aerodigestive
cancer is at a higher risk for (susceptible to) forming a SPT
in the same anatomic region during the ensuing years. e
concepts of eld cancerization and multistep carcinogenesis
form the basis for research on cancer chemoprevention.
Results of relatively large series revealed that patients
cured of their rst head and neck cancer had a projected
lifetime risk of developing SPTs of more than 20%. e estimated annual SPT development rate ranged from 4% to 6%
for at least 8 years a er the diagnosis of the rst cancer.
fact, SPTs are the leading cause of death among patients with
early-stage head and neck cancers.90 is patient population
has served as a model for addressing the e cacy of adjuvant
chemoprevention regimens. An initial trial testing the role
of cis-retinoic acid in preventing SPTs yielded encouraging results.91 Unfortunately, a large multi-institutional randomized trial showed that isotretinoin did not signi cantly
reduce the rate of SPTs (HR 1.06, 95% CI 0.83 to 1.35) or
increase survival (HR 1.03, 95% CI 0.81 to 1.32) compared
with placebo for patients with early-stage HNSCC.
ever, this trial did show that current smokers had a higher
rate of SPTs than did those who had never smoked (HR 1.64,
95% CI 1.08 to 2.50) or had formerly smoked (HR 1.32, 95%
CI 1.01 to 1.71). e HR of death from any cause for current
smokers versus never-smokers was 2.51 (95% CI 1.54 to 4.10)
and that for current smokers versus former smokers was
1.60 (95% CI 1.23 to 2.07). Major sites of SPTs included lung
(31%), oral cavity (17%), larynx (8%), and pharynx(5%).
Identi cation of individuals at high risk of developing a
second cancer is a critical step in chemoprevention research.
88,89
92
How-
In
20
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Part 1 General Principles of Head and Neck Radiotherapy
Since leukoplakia and erythroplakia carry an increased risk
of transforming into squamous carcinomas, patients with
these lesions have been selected to test chemoprevention of
malignant transformation. e weaknesses of this model are
that the natural history of leukoplakia is rather variable, with
spontaneous improvement occurring in many cases, and
the malignant transformation rate at 8 years can vary from
18% to 36% depending on the degree of dysplasia observed
histologically.93 Consequently, large series and prolonged
follow-up studies are required to properly test the e cacy
of any given primary chemoprevention strategy. Identi cation of key genetic changes resulting in the development of
malignant clones and markers of multistep carcinogenesis
will aid in identifying patients at highest risk so that those
patients can be enrolled in chemoprevention trials, thereby
reducing the required sample size. Markers can also serve as
intermediate surrogate endpoints for assessing the e cacy of
chemoprevention regimens, thereby shortening the length of
the required follow-up.
Another vital component in the prevention of SPTs is
the development of novel agents with low toxicity pro les
that target key molecular pathways that are disrupted early
in the pathogenesis of carcinogenesis. Examples include
agents targeting the insulin-like growth factor receptor and
the PI3K–AKT–mTOR axes, which are in various stages of
preclinical and clinical development (reviewed by William
94
et al.
).
SUMMARY
It has been exciting and gratifying to participate in laboratory research and clinical trials on head and neck cancer
during the past 3 decades. Advances in technology have
improved the precision with which radiation can be conformed to irregular target volumes and thereby reduce normal tissue toxicity. Progress in molecular biology techniques
has opened new research avenues yielding new concepts or
knowledge, such as the multistep tumor progression model,
genetic susceptibility to environmental carcinogen-induced
tumorigenesis, and processes of virus-induced changes in
cellular behavior, factors, and mechanisms governing cellular and tissue radiation response. Some of the new wisdom
has already found applications in developing novel therapy
strategies that have completed or are undergoing preclinical and clinical testing. All in all, the basic and translational
research e orts have nally paid o in that the head and neck
cancer mortality rate in the United States has declined since
the inception of record-keeping. For example, the annual
death rate for men due to oral cavity and pharyngeal cancers
in the United States decreased by an average of 1.9% and 3%
between 1975–1993 and 1993–2001, respectively.
It is very likely that the pace of discovery will increase
in the coming years. For example, it is reasonable to envisage
1
that, before long, sensitive methods for detecting occult
tumor foci for screening and staging purposes will be developed and new approaches in characterizing the molecular
pro les and signatures of individual cancers will accurately
depict their virulence, predict their response to therapy,
and guide the selection of treatment. Optimism in developing rational novel therapeutic strategies aimed at speci c
molecular targets to prevent malignant transformation or
to reverse malignant phenotype is also increasing. Hopefully, the new insights and technologies gained from further
research will have an additional sizable impact in reducing
the mortality caused by head and neck cancers.
e fast pace of new discoveries and the large number
of research directions make determining what constitutes
standard therapy for a variety of patient subsets increasingly
complex. In situations where several treatment options can
yield approximately the same local-regional tumor control
rate, other determinants to be taken into account in selecting the treatment of choice include cosmetic and functional
outcome, acute and long-term morbidity (quality of life),
resource utilization (cost), physician expertise, and patient
convenience.
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