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Analysis of Risk Factors Predictive of Distant Failure After Targeted Chemoradiation for Advanced Head and Neck Cancer
Ilana Doweck, MD;
K. Thomas Robbins, MD;
Francisco Vieira, MD
Arch Otolaryngol Head Neck Surg. 2001;127:1315-1318.
ABSTRACT
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Background Distant metastasis (DM) is the most common mode of recurrence among
patients with advanced head and neck carcinoma treated with intra-arterial
cisplatin and radiotherapy (RADPLAT).
Objective To identify which patients are at greatest risk for DM and would benefit
the most from new strategies designed to treat occult metastases.
Methods Between 1993 and 1999, 250 patients with advanced head and neck cancer
were treated by RADPLAT. Excluded from the analysis were 10 patients who either
did not complete the protocol or were unavailable for follow-up and 39 patients
with persistent disease or local recurrence. The incidence and the risk factors
for DM in these patients were evaluated in a model that included the following
factors: age, T and N classification, site of tumor, histologic grade, number
(0, 1, or >1) and position (high vs low) of neck levels involved, and bilateral
nodal disease. Multiple stepwise logistic regression was used for the analysis.
Results In a univariate analysis, the following variables correlated to DM:
N classification (P = .02), site of tumor (P = .01), lower neck nodes (P
= .002), number of neck levels involved (P = .001),
and bilateral nodal disease (P = .02). In a multivariate
analysis, the most significant risk factors for DM were the number of neck
levels involved and the site of the primary tumor (P<.001).
The highest odds ratios for DM were among patients with multiple levels of
nodal involvement (3.17) and patients with hypopharyngeal carcinoma (2.8).
Conclusions Patients with more than 1 level of clinical nodal involvement and patients
with hypopharyngeal carcinoma have the highest risk of developing DM as the
initial site of failure and would benefit most from treatment strategies that
address occult distant disease.
INTRODUCTION
EFFORTS TO improve the outcomes of patients with advanced cancer of
the head and neck have led to combined therapy protocols incorporating chemotherapy.1-4 The RADPLAT
protocol involves a novel drug infusion technique for delivering cisplatin
directly into the tumor bed while minimizing the effects of the drug systemically.
Radiotherapy is administered simultaneously.
The RADPLAT protocol, widely used at the University of Tennessee Health
Science Center, Memphis, showed high rates of complete response (90.5%) at
the primary site, while the complete response rate for the regional nodes
was 70.7%.6 The subsequent use of neck dissection
(primarily the selective type) in patients with bulky nodal disease (N2 and
N3) resulted in an ultimate regional control rate of 91%.7
The 5-year survival rates for patients dying of their disease and overall
survival were 53.6% and 38.8%, respectively.6
With the improvement in the locoregional control of advanced head and
neck cancer, the incidence of distant metastasis (DM) as the primary site
of failure has increased. Since there has been no clinical evidence of disease
at other sites (local and regional) in these patients, it is surmised that
they had occult DM at the time of presentation. The arising problem of death
from DM among patients treated with RADPLAT requires further investigation
to determine which patients are at greatest risk. The development of a risk
assessment formula would be useful in identifying which patients would benefit
the most from interventions designed to treat occult DM.
PATIENTS AND METHODS
Between June 1, 1993, and March 31, 1999, 250 patients with advanced
head and neck cancer were treated with RADPLAT8
(n = 165) and a sister protocol named Pento-RADPLAT (n = 85), in which pentoxifylline
was added to reduce the chronic soft tissue toxic effects of therapy,9 at the University of Tennessee Health Science Center.
Excluded from the total group of 250 patients were 6 who did not complete
the protocol and 4 who were unavailable for follow-up. To determine the total
number of patients who were at risk of having DM as the first site of failure,
39 patients with locoregional recurrence or persistent disease were also excluded.
Therefore, any patient who ultimately developed DM was likely to have had
occult distant disease at the time of diagnosis.
All patients entered into the study underwent clinical staging of disease
at the primary, regional, and distant sites using history, physical examination,
endoscopic findings, and radiologic studies (computed tomography and/or magnetic
resonance imaging). Patients with evidence of DM at the initial diagnosis
were not candidates for either protocol. The T and N classifications of the
patients included in the study are shown in Table 1.
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Table 1. T and N Stages in 250 Patients With Advanced Head and Neck
Cancer Treated With RADPLAT and Pento-RADPLAT*
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The RADPLAT protocol, which was previously described by Robbins et al,5, 8 consists of the concurrent administration
of selective supradose intra-arterial cisplatin (150 mg/m2 weekly
for 4 weeks) with parenteral sodium thiosulfate to neutralize the systemic
effects of cisplatin and conventional external-beam irradiation (180-200 rad
[1.8-2.0 Gy] per fraction to a total dose of 6850-7400 rad [68.5-74.0 Gy]
given during 7-8 weeks). The intra-arterial cisplatin is rapidly infused through
a microcatheter placed angiographically to selectively encompass only the
dominant blood supply of the targeted tumor.
Patients were followed up every week during the treatment protocol.
Tumor response was determined during therapy by physical examination, and
restaging was performed 2 months after radiation by means of criteria based
on physical examination, repeated imaging studies, and repeated endoscopy
and biopsy. Neck dissection in patients with persistent nodal disease was
performed 2 months after treatment.
Patients were followed up every month in the first year after completing
the treatment and every 2 months thereafter. End points included site of recurrence
(local, regional, or DM), site of DM, and survival. Patients included in the
study had at least 12 months of follow-up after completing the treatment.
The following variables were evaluated in relation to DM: age (<40,
40-60, and >60 years), T classification (1-4), N classification (0-3), the
site of origin of the tumor (oral cavity, oropharynx, larynx, hypopharynx,
and other sites), histologic grade (well, moderately, and poorly differentiated),
levels of nodal involvement (high levels [I and II], low levels [III-V]),
total number of levels of nodal involvement in the neck (0, no clinical node;
1, only 1 level of nodal involvement; and >1, >1 level of nodal involvement),
and unilateral vs bilateral nodal involvement.
The incidence and the risk factors for DM in these patients were evaluated
in a model that included the previous variables (age, T and N stages, site
of tumor, histologic grade, number and position [high vs low] of neck levels
involved, and the presence of contralateral disease). Multiple stepwise logistic
regression was used for the analysis.
The statistical analysis was done with JMP 4 for Windows (SAS Institute
Inc, Cary, NC).
RESULTS
Among the 250 patients in the total group, 45 (18.0%) developed DM as
the first site of failure, whereas 39 patients (15.6%) had locoregional recurrence.
Therefore, the most common site of failure in this patient subset was DM.
The mean interval for this event to occur was 12.5 ± 9.3 months from
diagnosis of primary disease. The most common site for DM was the lung (30
patients), followed by bone (13 patients), liver (13), and brain (5). Twenty-one
patients had 2 or more sites of involvement by metastases.
Univariate analyses were performed with the Pearson correlation test
to determine which patient, tumor, and treatment factors correlated with the
development of DM (Table 2). The
following variables were correlated to DM: N classification (P = .02), primary site of disease (P = .01),
involvement of the lower neck levels (levels III-V) (P
= .002), multiple levels of neck involvement (>1 level) (P = .001), and bilateral nodal disease (P
= .02). In a multivariate analysis, the most significant risk factors for
DM were the number of neck levels involved and the site of the primary tumor
(P<.001). Figure
1 shows the percentage of patients with DM according to the site
of the primary tumor and the number of levels of nodal involvement. The odds
ratio for DM in patients with carcinoma of the hypopharynx was 2.8, in comparison
with 0.41, 0.77, and 0.72 for patients with carcinoma of the oral cavity,
oropharynx, and larynx, respectively. The odds ratio for DM in patients with
2 or more levels of nodal involvement was 3.17, in comparison with 1.59 if
only 1 level was involved and 0.12 in patients with an N0 neck classification.
As independent variables, age, histologic grade, and T classification were
not associated with a higher risk for DM. Furthermore, none of the other variables
related to neck disease (N classification, involvement of the neck at high
vs low levels, and unilateral vs bilateral neck disease) correlated independently
in the regression analysis.
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Table 2. Univariate Analysis of Correlation Between Variables Studied
and Distant Metastasis*
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Figure 1. Percentage of distant metastasis
according to site and nodal involvement.
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According to Kaplan-Meier survival plot, the overall 5-year survival
rate for patients without DM was 51.6% vs 0% for patients who developed DM
(Figure 2) (P<.001). The 5-year overall survival rate for the subset of patients
who presented with N0 neck disease was 52.4% compared with 28.3% for patients
with a single level of nodal involvement and 18.0% for patients with more
than 1 level of nodal involvement (P<.001) (Figure 3).
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Figure 2. Kaplan-Meier survival plot for
patients with and without distant metastasis (DM).
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Figure 3. Kaplan-Meier survival plot for
patients without nodal disease, with single level of nodal involvement, and
with multiple levels of involvement.
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The mean time interval for survival among the patients who developed
DM as the initial site of disease recurrence was 16.7 ± 1.6 months
from the initial diagnosis.
COMMENT
Autopsy studies have shown that the overall incidence of DM among patients
with head and neck cancer is relatively high (40%-47%).10-12
However, most patients in these analyses had uncontrolled disease at the primary
site and/or the neck. The incidence of DM among patients who remain free of
disease at the local and regional sites is lower, although still substantial.
With the improvement of locoregional control of advanced head and neck cancer
with new treatment regimens such as ours, distant failure has emerged as the
most common reason for disease recurrence. The effectiveness of the RADPLAT
protocol is based on the delivery of high-dose cisplatin combined with radiation
therapy to the local disease. It has enabled us to achieve an excellent rate
of locoregional disease control, but it does not provide systemic treatment
for patients who have subclinical metastases or micrometastases at distant
sites.6-7
The recognition of risk factors for the development of DM is important
to identify high-risk patients who may benefit from systemic treatment in
addition to the RADPLAT protocol. Because our goal was to recognize which
patients were at greatest risk for harboring micrometastases, we purposely
did not include the patients with DM who also had failure in the local and/or
regional sites, since their DM may have been related to the recurrent locoregional
disease. In other words, they may not have had distant micrometastases at
the time of initial treatment.
In the present study, the rate of DM as the first site of failure in
the absence of locoregional recurrence was 18%. Similar findings were reported
by Vikram et al.13 At autopsy, Nishijima et
al14 reported a DM rate of 20% in patients
with controlled disease above the clavicle.
Histologic criteria such as extracapsular spread and multiple positive
lymph nodes were found to be related to the increase in the incidence of DM.13, 15 In our study, the evaluation of such
pathological criteria was precluded by the limited necessity to perform surgery.
In the present study, the nodal status of the patients at the initial
diagnosis was found to have the most significant effect on the development
of DM. Of all the variables examined, the most accurate predictor of DM was
the number of neck levels with clinical evidence of disease. Patients with
more than 1 level of nodal metastases had an odds ratio of 3.17 for having
DM. Of these patients, 36.0% had DM, compared with 17.9% if only 1 level of
the neck was involved and 10.2% if the neck was negative clinically. These
findings are in agreement with those of Vikram et al,13
who reported that the incidence of DM was higher (25%) in patients who presented
with palpable cervical lymph nodes than in those who did not. Alvi and Johnson15 reported that 93% of the patients who developed DM
as the first site of failure had palpable neck disease, compared with 42%
without DM. However, the authors did not analyze the difference between single
palpable node and multilevel nodal involvement. Our study showed a significant
difference between single and multiple levels of nodal involvement. It is
likely that patients with multiple nodal involvement would benefit from systemic
treatment.
The site of the tumor was the second independent variable that influenced
the development of DM. Patients with hypopharyngeal carcinoma had the highest
incidence of DM (43.2%), with an odds ratio of 2.8. Kotwall et al10 reported a DM rate of 60% in patients with hypopharyngeal
carcinoma. However, 91% of the patients had uncontrolled tumor at the primary
site or in the neck. Nishijima et al14 reported
a DM rate of 53% in patients with hypopharyngeal carcinoma, although they
did not find any significant differences between the different sites of the
head and neck. They, like Kotwall et al,10
included patients with and without controlled disease in the analysis. Our
previously published data showed that there were no differences in the local
and regional control rates among the different sites of tumor in the head
and neck in patients who were treated with RADPLAT. Patients with pyriform
sinus cancer were found to have an 88% "above-clavicle" disease control rate.16 This further strengthens our observations that patients
with hypopharyngeal cancer have a high risk of distant subclinical disease
at the time of presentation. One can speculate that the mechanism of tumor
invasion and metastasis for cancer of the hypopharynx compared with other
sites of the head and neck may be different.
The T classification and age were not related to the development of
DM, as was also reported previously by Vikram et al13
and Alvi and Johnson.15 The data from our study
lead us to conclude that patients who present with nodal disease involving
multiple levels and/or cancer of the hypopharynx have the greatest risk of
having subclinical DM and would benefit from additional systemic treatment
designed to eradicate such micrometastases. However, to our knowledge, such
therapies currently do not exist.
AUTHOR INFORMATION
Accepted for publication July 11, 2001.
Presented in part at the Fifth International Conference on Head and
Neck Cancer, San Francisco, Calif, July 31, 2000.
Corresponding author and reprints: Ilana Doweck, MD, Department of
Otolaryngology, Head and Neck Surgery, Carmel Medical Center, 7 Michal St,
Haifa 34362, Israel (e-mail: idoweck{at}netvision.net.il).
From the Department of Otolaryngology, Head and Neck Surgery, College
of Medicine, University of Tennessee, Memphis (Drs Doweck, Robbins, and Vieira);
and Department of Otolaryngology, Head and Neck Surgery, University of Florida
College of Medicine, Gainesville (Drs Doweck and Robbins). Dr Doweck is now
with the Department of Otolaryngology, Head and Neck Surgery, Carmel Medical
Center, Haifa, Israel.
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