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Does Neck Stage Predict Local Control After Irradiation for Head and Neck Cancer?

Does Neck Stage Predict Local Control After Irradiation for Head and Neck Cancer?

ABSTRACT: The impact of neck stage (N stage) on local control after treatment for head and neck cancer is controversial. This article reviews the pertinent literature. Based on this review, the authors conclude that although N stage may be inversely related to local control, the relationship is relatively weak. Hence, current data are insufficient to justify altering treatment of the primary lesion based solely on N stage. [ONCOLOGY 10(3):381-396, 1996]

Introduction

It is important to define subsets of patients who are at high
risk for recurrence after radiotherapy for head and neck cancer
so that therapy may be modified in an attempt to improve the likelihood
of cure. Various tumor-related parameters that correlate with
the probability of local control after radiotherapy include primary
tumor stage (T stage) [1,2], tumor volume [3-5] primary tumor
site [2,6-10], tumor morphology (infiltrative vs exophytic), intrinsic
radiosensitivity [11], and potential doubling time [12-15]. In
addition, time-dose-fractionation parameters have been shown to
influence tumor control rates in patients treated with radiotherapy
[16-18]. Extent of tumor oxygenation [19,20] and hemoglobin level
during [21] or before treatment also may be important.

In 1985, Wall et al [22] first suggested that neck stage (N stage)
may be indicative of the local aggressiveness of the primary cancer,
and therefore, may be yet another factor that influences local
tumor control. Before that time, most practitioners believed that
the likelihood of control in the neck and at the primary site
were independent of each other and were related to various pathologic
and clinical factors at each site, as well as the treatment administered
to each site. The question is of obvious importance because if
a relationship between N stage and local control does exist, it
may signal a need for treatment modification (eg, altered fractionation,
concurrent chemotherapy) or, in some instances, a change in therapeutic
modality (eg, surgery instead of radiotherapy).

The notion that there might be a dependent relationship between
local control and N stage was controversial in 1985, and this
issue has not been resolved during the last 10 years. Data from
various institutions on this topic are conflicting. This paper
reviews the literature pertinent to this question.

Does N Stage Predict Local
Control After Radiotherapy Alone?

M. D. Anderson Data

Wall et al [22] reported on a series of 248 patients with squamous
cell carcinoma of the supraglottis treated with radiotherapy alone
for curative intent at the M. D. Anderson Cancer Center (Houston,
Texas) between 1960 and 1980. The authors grouped primary lesions
according to T stage (T1 and T2 vs T3 and T4) and analyzed the
influence of N stage, histologic grade, and hemoglobin levels
before and during radiotherapy on the probability of local control.
Neck stage was stratified into 10 groups according to the number,
size, and laterality of clinically positive nodes.

Patients with T1-T2 tumors had a lower local control rate in the
presence of any positive node(s), as compared with patients with
a clinically negative neck (P = .06). For patients with
T3-T4 cancers, a single positive node more than 3 cm in diameter
did not adversely influence local control, in contrast to the
presence of more advanced neck disease (P =. 03). The authors
also analyzed the data using the Cox proportional hazards test
and noted an inverse relationship between N stage and local control,
which was pronounced for T3-T4 lesions compared to T1-T2 tumors.
There was no significant relationship between local control and
histologic grade or hemoglobin levels.

Patterns of Fractionation Study

Withers et al [23] analyzed 676 patients treated in nine institutions
with external-beam radiotherapy alone for primary squamous cell
carcinoma of the tonsillar fossa between 1976 and 1985. The nine
institutions included in the patterns of fractionation study were
the Princess Margaret Hospital (Toronto, Canada), Massachusetts
General Hospital (Boston), M.D. Anderson Cancer Center (Houston),
Christie Hospital (Manchester, United Kingdom), Clatterbridge
Hospital (Liverpool, United Kingdom), University of Florida (Gainesville),
Royal Marsden Hospital (London), Mount Vernon Hospital (London),
and Portsmouth Hospital (Portsmouth, United Kingdom). A multivariate
analysis using the Cox proportional hazards model found that T
stage, N stage, total dose, and overall treatment duration significantly
(P <.05) influenced local control.

University of Florida Studies

Freeman et al [2] analyzed 607 patients treated for squamous cell
carcinoma of the oropharynx, hypopharynx, or supraglottic larynx
with continuous-course radiotherapy alone or followed by planned
neck dissection at the University of Florida between 1964 and
1988. Patients with simultaneous primary lesions were excluded.
All patients were followed for at least 2 years, and no patients
were lost to follow-up. Parameters tested in a multivariate analysis
of local control included T stage (T1, T2, T3, and T4), N stage
(N0, N1, N2A-N3A, and N2B-N3B), primary site (oropharynx, hypopharynx,
and supraglottic larynx), and fractionation scheme (once- and
twice-daily).

Parameters that significantly influenced local control were T
stage (P < .01), fractionation (P <
.01), and primary site (P = .01). Local control rates were
improved after twice-daily fractionation compared with once-daily
irradiation, and patients with hypopharyngeal primary lesions
had lower local control rates than those with cancer in the oropharynx
and supraglottic larynx. Neck stage had no apparent impact on
local control (P = .97).

A separate multivariate analysis also was performed for each mucosal
site, (oropharynx, hypopharynx, and supraglottic larynx). Once
again, N stage did not appear to significantly influence local
control in any of these subgroups.

Lee et al [7] evaluated 243 patients treated between 1964 and
1990 with external-beam irradiation alone or combined with an
interstitial implant for tonsillar cancer at the University of
Florida. Patients treated before 1989 were included in the analysis
of Freeman et al [2]. Local control rates were examined using
multivariate analysis; parameters included in the analysis were
anterior extension, T stage, anterior tonsillar pillar primary,
nasopharynx extension, fractionation schedule, palate extension,
tongue extension, mid-line extension, brachytherapy boost, and
neck stage. Anterior extension (P = .0001) and T stage
(P = .0144) significantly influenced local control, whereas
N stage had the least impact (P = .9415) on this end point.

Mendenhall et al [5] updated the University of Florida experience
with radiotherapy alone for squamous cell carcinoma of the supraglottic
larynx between 1964 and 1992. Patients treated before 1989 were
included in the analysis by Freeman et al [2]. Multivariate analysis
revealed the following effects on local control: T stage (P
= .0001), vocal cord mobility (P = .0373), N stage
(P = .0768), fractionation schedule (P = .3532),
suitability for conservation surgery (P = .3532), sex (P
= .5405), primary site (P = .6340), and pretreatment
CT scan (P = .7299). There was a trend toward decreasing
local control with increasing N stage.

French Studies

Pernot et al [8] described a series of 361 patients treated with
brachytherapy alone (18 patients) or combined with external-beam
radiotherapy (343 patients) for squamous cell carcinoma of the
tonsillar region, soft palate, and glossotonsillar sulcus at the
Centre Alexis Vautrin (Nancy, France) between 1977 and 1991. Parameters
included in a multivariate analysis of local control were T stage,
N stage, primary site, safety margin of the interstitial implant,
overall treatment time, and interval between external-beam radiotherapy
and brachytherapy.

Primary tumor stage (P = .0001), overall treatment time
(P less than .0001), and primary site (P < .0001) significantly
influenced local control. Patients completing treatment in less
than 55 days had improved local control, as did those who had
primary lesions of the tonsillar fossa, soft palate, and posterior
tonsillar pillar, when compared with those with tumors of the
anterior tonsillar pillar and glossotonsillar sulcus. Neck stage
did not significantly affect local control.

Jaulerry et al [24] analyzed 166 patients treated with external-beam
radiotherapy for squamous cell carcinoma of the base of the tongue
at the Institut Curie (Paris) between 1960 and 1980. Stage of
the primary tumor, regression of the primary tumor during radiotherapy,
N stage (N0 vs N1 vs N2-N3), and histologic grade (well-differentiated
vs moderately or poorly differentiated) were evaluated in a multivariate
analysis. Primary tumor stage and regression of the primary lesion
significantly influenced local control, whereas N stage and histologic
grade did not.

Jaulerry et al [25] also reported on 228 patients with squamous
cell carcinoma of the head and neck (oral cavity, 59 patients;
oropharynx, 65 patients; hypopharynx, 37 patients; larynx, 67
patients) treated with radiotherapy alone at the Institut Curie
between 1986 and 1990. Univariate analysis revealed that local
control was significantly influenced by primary site (P <
.009) and T stage (P< .0001) but not by N stage (P
= .26). In a multivariate analysis, local control was significantly
related to primary site (P = .002), T stage (P <
.0001), and tumor regression at a radiation dose of 55 Gy (P
= .0009).

Data from Hong Kong

Teo et al [26] evaluated 659 patients with nasopharyngeal carcinoma
treated with radiotherapy at the Prince of Wales Hospital (Hong
Kong) between 1984 and 1987. Multivariate analysis revealed that
tumor confined to the nasopharynx was associated with improved
local control, whereas cranial nerve II-VIII palsies and male
gender were related to an increased risk of local recurrence.
Extent of neck disease did not significantly influence local control.

Lee et al reported on 1,008 patients treated with radiotherapy
alone for nasopharyngeal squamous cell carcinoma between 1976
and 1985 at the Queen Elizabeth Hospital (Hong Kong) [27]. Multivariate
analysis of local control revealed the following relationships:
age (P = .33), sex (P = .60), N stage (P =
.5), total dose (P < .01), dose per fraction (P =
.21), and overall treatment time (P = .17). Neck stage
did not affect the likelihood of local failure.

Medical College of Virginia-Tufts Study

Johnson et al analyzed 76 patients treated with "concomitant
boost accelerated superfractionated irradiation" for advanced
squamous cell carcinoma of the head and neck at the Medical College
of Virginia (Richmond) and Tufts-New England Medical Center (Boston)
[28]. Tumor volume at the primary site (TV) and in the neck nodes
(NV) was estimated for each patient based on pretreatment CT.
Total tumor volume was defined as the sum of TV and NV. Univariate
analysis of local control revealed the following: total tumor
volume (P = .0001), T stage (P = .03), N stage (P
= .009), sex (P = .10), age (P = .50), and primary
site (P = .0004). Multivariate analysis demonstrated that
total tumor volume (P = .0001), primary site ( P=
.008), and sex (P = .03) significantly influenced local
control, whereas T stage, N stage, stage group, and age had no
statistically significant impact on this end point.

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