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Changing Patterns of Failure of Head and Neck Cancer
Charu Taneja, MD;
Heidi Allen, CTR;
R. James Koness, MD;
Kathy Radie-Keane, MD;
Harold J. Wanebo, MD
Arch Otolaryngol Head Neck Surg. 2002;128:324-327.
ABSTRACT
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Background With the increased use of neoadjuvant therapy for advanced stage squamous
cell carcinoma of the head and neck, we have observed an apparent change in
the pattern of failure from predominantly locoregional sites to distant metastases.
We reviewed the patterns of failure in cancers of the oral cavity, oropharynx,
and larynx at our institution during the last decade.
Objective To determine whether there has been a significant change in the patterns
of recurrence from the historical locoregional failure to distant sites, and
whether this change is associated with the increased use of multimodality
therapy.
Methods We reviewed cancer registry data on patients with squamous cell carcinoma
of the head and neck diagnosed between January 1, 1988, and December 31, 1999.
Sites included the oral cavity and oropharynx (including the tongue, floor
of mouth, retromolar trigone, gingiva, tonsil, and lip) and larynx.
Results Among 432 patients with squamous cell carcinoma of the head and neck,
280 (65%) had oral cavity and oropharyngeal cancers, and 152 (35%) had laryngeal
cancers. Overall, 19% developed locoregional recurrence, and 8% developed
distant failure. Although locoregional failure for oral cavity and oropharyngeal
squamous cell carcinoma decreased from 26% to 16% from 1988-1993 to 1994-1999,
distant failure increased significantly from 3% to 8%. During these periods,
multimodality therapy was used in 62% of oral cavity and oropharyngeal cancers,
and this rate remained essentially unchanged. For laryngeal cancer, locoregional
and distant failure remained stable at 18% and 9%, respectively. In these
laryngeal cancers, the use of multimodality therapy decreased from 60% to
46%, but this difference was not statistically significant (P = .43).
Conclusions Although locoregional control in oral cavity and oropharyngeal cancers
has improved significantly with the use of multimodality therapy, the incidence
of distant failure has doubled. In laryngeal squamous cell carcinoma, the
patterns of failure have not changed significantly.
INTRODUCTION
HEAD AND NECK squamous cell carcinomas (HNSCCs) are a diverse group
of cancers and are frequently aggressive in their biological behavior. They
account for 2% to 3% of all cancers in the United States and for 1% to 2%
of all cancer deaths. Most patients with this malignancy have advanced disease
at presentation, with regional disease in 43% and distant metastases in 10%.1 Initial therapy for these cancers has traditionally
involved surgery, radiotherapy, or a combination of both. However, the use
of radical surgery or radiotherapy has been associated with significant long-term
morbidity, such as dysphagia and loss or alteration of voice. In addition,
recurrent disease develops in 27% to 50% of these patients. The use of multimodality
therapy has gained favor in recent years in an attempt to increase organ preservation,
improve local control, and decrease the incidence of second primary tumors.
We have recently observed a marked decrease in locoregional failure
in patients receiving multimodality neoadjuvant therapy.2
Unfortunately, this appears to be associated with an increase in distant failure.
This prompted us to review our experience with HNSCC at a single institution.
The objective of this study was to analyze the patterns of failure for patients
with HNSCC and to correlate this with overall survival and the use of multimodality
treatment in locally advanced HNSCC.
PATIENTS AND METHODS
The setting of the study was Roger Williams Medical Center, Providence,
RI, which is an academic institution affiliated with Boston University School
of Medicine, Boston, Mass. The patient cohort was obtained from the cancer
registry at Roger Williams Medical Center for January 1, 1988, to December
31, 1999. All patients with oral cavity and oropharyngeal cancers (including
the tongue, floor of mouth, retromolar trigone, gingiva, tonsil, and lip)
and laryngeal squamous cell carcinoma were included. Patients with metastatic
disease at presentation were excluded from the study. All patients underwent
panendoscopy (including upper gastrointestinal endoscopy, bronchoscopy with
washings, and microlaryngoscopy), computed tomographic scans of the head and
neck, and chest x-rays for staging. Patients were staged using the classification
of the American Joint Committee on Cancer. The treatment given was surgery,
radiation, chemotherapy, or any combination of these, as deemed appropriate
for the stage by the treating physician.
To examine the change in the patterns of failure over time, we arbitrarily
divided the patients into those diagnosed between 1988 and 1993 and 1994 and
1999. We recorded the site of failure, ie, locoregional vs distant, for oral
cavity and oropharyngeal cancers and laryngeal cancers. As factors affecting
the recurrence of disease, we also recorded the stage at presentation and
treatment given. Differences between groups were tested using commercially
available statistical software (GraphPad Instat; GraphPad Software, Inc, San
Diego, Calif). A 2-sided P<.05 was considered
significant.
RESULTS
During these periods, 432 patients with oral cavity, oropharyngeal,
and laryngeal cancers were treated at Roger Williams Medical Center. The median
age of the patients was 63 years (range, 17-98 years). Sixty-two percent were
older than 60, and 75% were males. Overall, 55% of oral cavity and oropharyngeal
and 48% of laryngeal cancers were stage III and IV disease at presentation
(Table 1). Among the 432 patients,
12% had well differentiated, 39% had moderately differentiated, and 31% had
poorly differentiated HNSCCs. The grade of the cancer was unknown in 18% of
patients.
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Table 1. Patient Demographics*
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Overall, 280 patients (65%) had oral cavity and oropharyngeal cancers,
and 152 (35%) had laryngeal cancers (Figure
1). On reviewing the first site of failure, locoregional recurrence
occurred as the first event in 19% and as distant metastases in 8% of patients.
From 1988-1993 to 1994-1999, the locoregional failure for oral cavity and
oropharyngeal cancers improved from 26% to 16%, but the distant failure rate
more than doubled from 3% to 8% (P<.04). In contrast,
there was no difference in the patterns of failure for laryngeal squamous
cell carcinoma, with the locoregional and distant failure rates remaining
constant at 18% and 9%, respectively (Table
2).
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Figure 1. Primary site cancers of the oral
cavity, oropharynx, and larynx. A, 1988 to 1993. B, 1994 to 1999.
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Table 2. Sites of Failure for Oral Cavity and Oropharynx and Larynx
Cancers During 1988 to 1993 and 1994 to 1999*
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With this in mind, we looked for a possible explanation for this change
in locoregional and distant failure patterns. There was no significant change
in the percentage of patients with locally advanced (stage III and IV) disease
during the 2 periods. For oral cavity and oropharyngeal cancers, the percentage
of patients with stage III and IV disease was 50% from 1988 to 1993 and 58%
from 1994 to 1999. Likewise, for laryngeal cancers, 44% of patients had stage
III and IV disease from 1988 to 1993 and 51% from 1994 to 1999. However, these
differences were not statistically different (Figure 2).
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Figure 2. American Joint Committee on Cancer
stage of 280 oral cavity and oropharyngeal cancers and 152 laryngeal cancers
from 1988 to 1993 and from 1994 to 1999.
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Patients were treated with either surgery or radiotherapy alone (single-modality
therapy) or with a combination of surgery, radiotherapy, and chemotherapy
(multimodality therapy). For oral cavity and oropharyngeal cancers, there
was no change in the use of multimodality therapy over time (62% had multimodality
treatment). However, although the percentage of laryngeal cancers treated
with multimodality treatment decreased from 60% to 46%, this was not statistically
significant (P = .43) (Figure 3). The increase in distant failure and improved locoregional
control of oral cavity and oropharyngeal cancers did not affect overall survival
(Figure 4).
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Figure 3. Treatment given (multimodality
therapy with a combination of surgery, radiation, and chemotherapy or single-modality
therapy with surgery or radiation) for oral cavity and oropharyngeal cancers
and laryngeal cancers from 1988 to 1993 and from 1994 to 1999.
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Figure 4. There was no change in overall
survival for oral cavity, oropharyngeal, and laryngeal cancers from 1988 to
1993 and from 1994 to 1999.
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COMMENT
Patients with advanced HNSCCs have a dismal long-term survival, not
only because of metastatic disease but also because of locoregional failure.
Although locoregional control has been improved through the use of chemoradiation
in locally advanced resectable disease, it remains the most frequent site
of failure.
The population in this study was reflective of other studies, in that
most patients with HNSCC are older men.1 Compared
with other studies, there was a higher incidence of patients with stage III
and IV disease in this series. In a recent series by Haddadin et al3 of 226 patients with tongue cancer, the mean age was
64, and 27% had T3 and T4 lesions.
The use of radical ablative procedures is associated with a high morbidity,
and the goal of combination surgery and radiation has been to achieve local
control and increase organ preservation. The addition of chemotherapy to this
armamentarium further increases response rates, decreases incidence and time
to distant failure, and carries the theoretical advantage of decreasing the
incidence of second primary tumors.1, 4
The Head and Neck Contracts Program5 randomized
462 patients to surgery and postoperative radiation with or without chemotherapy
and demonstrated that, although the locoregional control rate and overall
survival were not different, chemotherapy decreased the incidence of distant
failure and increased the time to distant failure as the first event. The
maximum benefit for chemotherapy was observed in patients with N2 disease.
Similarly, the Intergroup-Study 0034 found no difference in overall survival
or locoregional control with chemotherapy, but the incidence of distant metastases
as any component of failure was lower.6
In our study, as locoregional control improved in oral cavity and oropharyngeal
cancers, the incidence of distant failure as the first event increased significantly
(P = .04). This pattern was not seen in patients
with laryngeal cancer. Although there was no significant change in the percentage
of patients presenting with locally advanced disease during the 2 periods,
we noted that the use of multimodality therapy appears to be stable for oral
cavity and oropharyngeal cancers. The use of new regimens of induction chemotherapy
with concomitant chemoradiation, with increased response rates,7-8
may explain the improved local control seen in these patients. In contrast,
for laryngeal cancers, the use of multimodality therapy appears to have decreased,
again explaining stable patterns of failure.
As with other studies,9-10
we did not note any effect of improved locoregional control on overall survival.
In our series, the median survival for stage III and IV disease was 17 months
in patients with oral cavity and oropharyngeal cancers and 27 months for laryngeal
cancers. The overall survival for all patients with HNSCC in our study was
55% at 3 years and 42% at 5 years. The reported cure rate for T3 and T4, N2
and N3 cancers ranges from 10% to 65%, as opposed to 52% to 100% for patients
with T1 and T2, N0 and N1 disease.11 The Veterans
Affairs larynx preservation study found that the addition of chemotherapy
to radiotherapy or surgery improved organ preservation rates without affecting
overall survival.9 Similarly, in a European
Organization for Research and Treatment of Cancer trial, despite a trend toward
improved survival with chemotherapy (44 months) vs surgery and radiation alone
(25 months) and decreased distant metastases, the overall 3-year survival
was not significantly different (57% and 43%, respectively).10
A single randomized trial from Europe demonstrated an overall survival benefit
with neoadjuvant therapy, despite no change in event-free survival.12
The local control rate for stage III and IV cancers of the oral cavity,
oropharynx, and larynx with radiation therapy alone varies from 32% to 87%
at 3 years' follow-up.13 In a retrospective
analysis of 257 patients with squamous cell carcinoma of the upper aerodigestive
tract, 70% had T3 and T4, node-positive disease. These patients were treated
with surgery and postoperative radiotherapy, with a 23% local failure rate
and a 60% 3-year survival.14 Another recent
series of 223 patients with HNSCC from The University of Chicago (Chicago,
Ill) demonstrated a 50% 3- to 5-year overall survival, with a locoregional
failure rate of 10% to 15%.15 The distant failure
rate in this study was 20%, with 10% to 15% of patients with N1 and N2b disease
and 26% to 31% of patients with N2c and N3 disease developing distant metastases.
For patients with American Joint Committee on Cancer stage IV disease classification,
the locoregional failure was 30%, distant failure was 11%, and 5-year survival
was 51%.16 In a multicenter randomized trial
of surgery with standard radiation in 226 patients with oropharyngeal squamous
cell carcinoma, the addition of chemotherapy improved survival in patients
with stage III and IV disease from 31% to 51% and resulted in a 66% local
control rate.17 These data are in concordance
with our experience, in which approximately 50% of patients had stage III
and IV disease and the local control was 80%, distant failure was 8%, and
3-year overall survival was 55%.
The experience of the Brown University Oncology Group, Providence, with
concurrent chemoradiation (neoadjuvant therapy in stage III and IV disease)
also demonstrated a marked reduction in locoregional failure, but at the price
of increased failure at distant sites. In 2 series of multi-institutional
protocols using paclitaxel, carboplatin, and radiation, the local and regional
failure rates were 3% and 6%, respectively, but the distant failure rate was
22%.2, 8 Of 20 recurrences in 63
evaluable patients, 10% were local, 20% were regional, and 70% were distant
failures. This represents a major departure from previous data on patients
with high-stage HNSCC.
In conclusion, for all patients with HNSCC treated during 11 years at
our medical center, there has been an improvement in locoregional control
of oral cavity and oropharyngeal cancers, but this was offset by a significant
increase in distant failure. There was no change in the pattern of failure
for laryngeal cancers, probably reflecting the decreased use of multimodality
therapy in recent years. Despite the improved local control for oral cavity
and oropharyngeal squamous cell carcinoma, there was no effect on overall
survival. Further work is needed to improve the incidence of distant failure,
as this appears to be the major cause of mortality in these patients.
AUTHOR INFORMATION
Accepted for publication October 2, 2001.
This study was presented at the annual meeting of the American Head
and Neck Society, Palm Desert, Calif, May 15, 2001.
Corresponding author: Harold J. Wanebo, MD, Department of Surgery,
Roger Williams Medical Center, 825 Chalkstone Ave, Providence, RI 02908 (e-mail: haroldjwanebo{at}juno.com).
From the Departments of Surgical Oncology (Drs Taneja, Koness, and
Wanebo, and Ms Allen) and Radiation Oncology (Dr Radie-Keane), Roger Williams
Hospital Tumor Registry (Ms Allen), Roger Williams Medical Center, Providence,
RI.
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