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The Role of Neck Dissection After Chemoradiotherapy for Oropharyngeal Cancer With Advanced Nodal Disease
Gary L. Clayman, DDS, MD;
Chad Jeffery Johnson II;
William Morrison, MD;
Lawrence Ginsberg, MD;
Scott M. Lippman, MD
Arch Otolaryngol Head Neck Surg. 2001;127:135-139.
ABSTRACT
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Objective To analyze and compare the effectiveness of sequential platinum-based
chemotherapy and radiotherapy with and without selective neck dissection in
patients with N2a and greater stage node-positive squamous cell carcinoma
of the oropharynx.
Design Nonrandomized controlled trial.
Setting Tertiary referral center.
Patients Sixty-six patients with squamous cell carcinoma of the oropharynx staged
N2a or greater.
Interventions Platinum-based induction chemotherapy followed by definitive radiation
therapy; and selective neck dissections 6 to 10 weeks following the completion
of radiation therapy in patients with radiographic evidence suggesting residual
neck disease.
Main Outcome Measures Locoregional recurrence and disease-free survival.
Results Of 66 patients, 24 (36%) had complete responses in the primary local
tumor (oropharynx) and regional disease (neck nodes), as assessed clinically
and radiographically. These patients had lower rates of locoregional recurrence
than did patients showing no or partial responses, but the differences were
not significant (P>.05). Of 18 patients undergoing
neck dissection, 10 (56%) had pathological evidence of residual tumor. Patients
showing a complete response of regional and neck disease had significantly
improved disease-specific and overall survival (P
= .01 for both) compared with patients showing no or partial responses of
their neck disease. Patients with no or partial responses who underwent neck
dissections had significantly improved overall survival compared with similar
patients who did not undergo neck dissections (P
= .002).
Conclusions Even in patients with bulky nodal disease, a complete response in the
neck to sequential chemotherapy and radiotherapy may indicate that neck surgery
is not necessary for good locoregional control and improved disease-free survival.
Neck dissection is recommended for patients with no or partial radiographic
responses.
INTRODUCTION
BECAUSE OF the tremendous morbidity of local and regional manifestations
of head and neck cancer, effective therapies must specifically target locoregional
control and control of distant metastases. Since Fletcher and colleagues1 first reported in 1959 that megavoltage radiation
therapy was effective in the management of squamous cell carcinoma of the
tonsil, treatment paradigms have continued to evolve. By the 1970s, standard
treatment consisted of 2-Gy fractionation with boost doses given to the primary
tumor. With this strategy, local control rates of 94%, 79%, and 58% have been
reported for T1, T2, and T3 tumors, respectively.2
Because of severe problems with late complications, total irradiation
doses higher than 67 Gy were not possible with this standard approach. This
led to the development of accelerated fractionation schemes in the 1980s,
which were designed to minimize tumor cell repopulation during radiotherapy
without increasing the late effects of radiation.3
More recently, Gwozdz and colleagues4 reported
on a concomitant boost/fractionation schedule in patients with squamous cell
carcinoma of the tonsillar fossa with regional (node-positive) disease. In
patients who received a daily boost during the final phase of treatment, this
approach achieved 5-year local control rates of 96%, 96%, and 82% in T1, T2,
and T3 tumors, respectively. Rates of 5-year regional control in patients
receiving concomitant boost fractionation with neck dissections were 92%,
76%, 89%, and 89% in N0, N1, N2, and N3 disease, respectively.
In 1998, Brizel and colleagues5 published
the results of a randomized study comparing hyperfractionated radiation therapy
with and without concurrent and adjuvant chemotherapy for locally advanced
head and neck cancer. At a median follow-up of 41 months, they found that
rates of overall survival and locoregional control were significantly improved
in the combined therapy group vs the hyperfractionation alone group. Of patients
who underwent hyperfractionated radiotherapy alone and subsequently underwent
neck dissection, 6 (38%) of 16 had residual disease in the neck, compared
with 3 (12%) of 24 who underwent combined therapy.
The inclusion of neck dissection as part of standard therapy for patients
treated with either radiation therapy alone or radiation therapy plus chemotherapy
has been controversial.6, 7, 8, 9, 10
Although it is clear that selective neck dissection is needed in node-positive
patients who fail to respond to prior therapy, it is less clear whether patients
who achieve complete or partial clinical responses in the neck will benefit
by surgical intervention.
The goals of the present study were as follows: (a) to analyze the effectiveness of sequential platinum-based chemotherapy
and radiotherapy on locoregional recurrence (LRR) and disease-free survival
in patients with N2a and greater stage node-positive oropharyngeal cancer
and (b) to determine the value of selective neck
dissection in this patient group.
PATIENTS AND METHODS
Between July 1, 1990, and April 1, 1995, 66 patients with squamous cell
carcinoma of the oropharynx with associated advanced nodal disease (N2-N3)
were treated with platinum-based induction chemotherapy followed by definitive
radiotherapy. Platinum-based chemotherapy was given at a dose of 100 mg/m2 for a median of 3 cycles (range, 1-4 cycles), and consisted of cisplatin
plus fluorouracil in 57 patients (86%), cisplatin plus paclitaxel in 6 patients
(9%), and other platinum-containing combinations in 3 patients (5%). Radiation
therapy was given in a concomitant boost fractionation schedule to a median
dose of 72 Gy (range, 68-74 Gy) in 42 fractions over 6 weeks.
Clinical response, particularly in the primary sites of the tonsil and
tongue base, may be difficult to assess radiographically with computed tomography
(CT) or magnetic resonance imaging (MRI) because of lymphoid tissue enhancement.
In those equivocal cases, clinical impression was the determining factor in
response. Complete response (CR) was defined as the
disappearance of all evidence of tumor. Partial response (PR) was defined as a decrease of 50% or more in tumor size as determined
by clinical examination, CT scan, or MRI scan.
Patients with incomplete responses in the neck following completion
of treatment or who were otherwise recommended by the Multidisciplinary Head
and Neck Oncology Program, The University of Texas M. D. Anderson Cancer Center,
Houston, underwent neck dissections 6 to 10 weeks following the completion
of definitive radiation therapy. Selective neck dissections were performed
when minimal residual disease within lymph nodes was detected. Modified radical
or radical neck dissections were performed on patients who exhibited substantial
residual adenopathy that had invaded nonlymphatic structures.
Disease control, disease-specific survival, and overall survival curves
were produced using the Kaplan-Meier product limit method. All patients were
followed up for survival until time of death or study termination. Proportions
of patients who exhibited the response variables of interest in the various
treatment groups were compared by  2 analysis. Statistical
analysis was performed using Statistica for Windows (StatSoft, Inc, Tulsa,
Okla).
RESULTS
PATIENTS
The study population included 52 men (79%) and 14 women (21%). The median
patient age was 52.5 years (range, 26-75 years). Most patients had primary
tumors in either the base of the tongue (n = 37 [56%]) or the tonsil (n =
22 [33%]), and the remaining 7 (11%) had tumors of the pharyngeal wall. The
tumor and node classifications are shown in Table 1.
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Table 1. Tumor and Node Stages*
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Of the 66 patients eligible for this study, clinical evaluations of
treatment response were available for 65 after the completion of induction
chemotherapy alone and for 59 after the completion of chemotherapy and radiotherapy.
(No data were available for 1 patient, and 6 received subtherapeutic doses
of radiotherapy.) Evaluations based on either CT or MRI scans after completion
of chemotherapy and radiotherapy were available for the primary local tumors
of 48 patients and for the regional neck disease of 50 patients. Sixteen patients
with favorable T1 and T2 primary tumor responses underwent posttherapy ultrasonographic
evaluations of the neck.
RESPONSE TO SEQUENTIAL CHEMOTHERAPY AND RADIATION THERAPY
As expected, a significant increase in clinical CRs occurred in patients
undergoing sequential chemotherapy and radiation therapy vs those undergoing
induction chemotherapy alone (76.3% vs 49.2% for the primary tumor [P = .002] and 59.3% vs 30.8% for the neck disease [P = .001]) (Table 2).
These differences were verified by the results of CT or MRI studies performed
in a selected, smaller test group of patients.
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Table 2. Response to Sequential Chemotherapy and Radiation Therapy
in Patients With Node-Positive Carcinoma of the Oropharynx*
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LRR AFTER SEQUENTIAL CHEMOTHERAPY AND RADIATION THERAPY AS RELATED
TO THERAPY RESPONSE
To determine if a CR to sequential chemotherapy and radiation therapy
was a predictor of local control, we analyzed rates of LRR as a function of
treatment response, as determined by CT or MRI after sequential treatment
with chemotherapy and radiotherapy (Table
3). The median follow-up time was 26.7 months (range, 3.0-108.5
months). Although there were no significant differences in rates of LRR in
patients with a CR compared with those with a PR (P>.10),
there was a strong trend toward decreased LRR in patients with a CR either
in the primary tumor alone or in the primary tumor and the neck together (P = .08). Of 24 patients who had CRs of the primary tumor
and the neck by clinical and radiographic analysis, 2 had local recurrences,
1 had a distant metastasis, and 0 had regional recurrences. There were no
isolated regional recurrences. None of the 29 patients who had a CT- or MRI-documented
CR in the neck subsequently experienced a recurrence in the neck.
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Table 3. Locoegional Recurrences in Patients With Node-Positive Carcinoma
of the Oropharynx by Response to Sequential Treatment With Chemotherapy and
Radiotherapy*
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LRR IN PATIENTS WHO DID AND DID NOT UNDERGO SALVAGE SURGERY AFTER COMPLETION
OF SEQUENTIAL CHEMOTHERAPY AND RADIATION THERAPY
Eighteen patients underwent neck dissections, including 14 who underwent
neck dissections only and 4 who underwent neck dissections and primary resections.
Of these 18, 10 (56%) had pathological evidence of residual tumor. The results
of a neck dissection showed microscopic residual disease in one patient with
a radiographic CR in the neck. In general, patients who required salvage surgery
after PRs of the primary tumor or neck to sequential chemotherapy and radiotherapy
had higher LRR rates than those who did not require salvage surgery, but the
differences were statistically significant only for clinical responses of
the primary tumor (P = .02). Patients who required
neck dissections and primary resections after chemotherapy and radiotherapy
had significantly (P = .01 and .001, respectively)
higher LRR rates (4 [100%] of 4) than those who did not undergo any salvage
surgery (6 [12%] of 48) or those who underwent neck dissections only (1 [7%]
of 14).
DISEASE-FREE AND OVERALL SURVIVAL AFTER SEQUENTIAL CHEMOTHERAPY AND
RADIATION THERAPY
Overall and disease-free survival of patients with N2a and greater stage
node-positive cancer of the oropharynx treated with sequential chemotherapy
and radiotherapy was 49.2% and 78.4%, respectively (Figure 1A-B). There was a significant difference in disease-free
and overall survival (P = .01 for both) in patients
showing a CR in the neck to sequential chemotherapy and radiotherapy compared
with patients showing only a PR (Figure 2A-B). There also was a significant improvement in disease-specific
survival associated with salvage neck dissection (vs no dissection) in patients
with a primary site CR but only a neck or regional PR to sequential chemotherapy
and radiation therapy (P = .02) (Figure 3).
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Figure 1. Cumulative overall (A) and disease-free
(B) survival of patients with node-positive cancer of the oropharynx after
sequential chemotherapy and radiotherapy.
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Figure 2. Cumulative overall (A) and disease-free
(B) survival of patients with a complete vs a partial response of the neck
to sequential chemotherapy plus radiotherapy. The difference in survival between
those with a complete response vs those with a partial response was significant
(P= .01) in A and B.
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Figure 3. Disease-free survival of patients
with node-positive cancer of the oropharynx with local control but partial
neck response to sequential chemotherapy and radiotherapy with and without
salvage neck dissection. The difference between those who underwent and those
who did not undergo neck dissection was significant (P= .02).
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COMMENT
Despite important advances in organ preservation and survival with platinum-based
chemotherapy and radiotherapy,11, 12
the failure to achieve locoregional control remains a major cause of treatment
failure and death in patients with locally advanced head and neck cancer.
The role of neck dissection after chemoradiotherapy for head and neck cancer
(eg, in respect to initial node stage and locoregional response13, 14)
is unclear. To address this important clinical management issue, we focused
this study on a single head and neck subsite (oropharynx), to limit disease
heterogeneity, and on advanced nodal disease (N2-N3), a clinical setting in
which the role of neck dissection after chemoradiotherapy is extremely relevant.
We found that LRR rates were consistently lower in patients with a CR
than in those with a PR to sequential chemoradiotherapy, as assessed by CT
or MRI scan. Locoregional recurrences occurred in only 2 (8%) of the 24 patients
with a CR of the primary tumor and neck disease (which were only local in
both cases) vs in 3 (38%) of the 8 patients with a PR. No patient with a CR
in the neck subsequently experienced a recurrence in the neck. A primary site
CR (with or without a CR in the neck) was associated with a trend toward fewer
LRRs (P = .08). (Treatment response after chemotherapy
alone in our study apparently did not affect the LRR rates.)
Overall, the patients with a CR in the neck (as assessed by CT, MRI,
or ultrasonography) had significantly improved rates of disease-free and overall
survival compared with the patients with no response or a PR. Of the 29 patients
with a CR in the neck, 25 did not undergo neck dissections; only 3 (10.3%)
of the 29 experienced LRR, 2 of whom did not undergo surgery. Among patients
with no response or a PR in the neck, those who underwent neck dissections
had significantly improved overall survival compared with those who did not
(P = .02). Indeed, the disease-specific survival
rate in the subgroup of patients who underwent neck dissections after no response
or a PR in the neck was not significantly different from that seen in patients
who had a CR in the neck. Patients with residual disease in primary and regional
sites following induction chemotherapy and definitive radiotherapy were never
successfully salvaged surgically.
Our findings (especially that no patient with a CR in the neck subsequently
experienced a recurrence in the neck) suggest that, even in patients with
bulky nodal disease, a CR in the neck to chemoradiotherapy may indicate that
neck surgery is not necessary to achieve local control and improved disease-free
survival. This is consistent with the conclusions reached in several previous
studies. Armstrong and colleagues9 tested a
chemoradiation protocol (similar to that used in the present study) in 80
patients with locally advanced resectable cancer of the larynx, hypopharynx,
and oropharynx. Among patients who did not undergo neck dissection, a neck
recurrence occurred in only 1 of 17 with a CR in the neck. Peters et al15 reported that the risk of neck relapse in patients
with oropharyngeal cancers treated with definitive radiotherapy alone was
unrelated to pretreatment nodal size and that patients achieving a CR in the
neck could safely avoid surgery.
In conclusion, because of the excellent local control and improved overall
survival among patients with a CR in the neck, we do not recommend neck dissection
in this group. Nevertheless, because of the potential of microscopic persistent
disease,7 patients with a CR at the 6- to 8-week
postchemoradiotherapy evaluation should have a second evaluation 2 to 3 months
later. If gross disease is found in the latter evaluation, the patient should
be considered for neck salvage surgery. We continue to recommend neck dissection
in patients with oropharyngeal cancer achieving no response or a PR to chemoradiotherapy.
AUTHOR INFORMATION
Accepted for publication July 13, 2000.
This study was supported in part by grant CA16672 from the National
Cancer Institute, Washington, DC; and grant 1-P50DE-11906-01 from the Oral
Cancer Center of Excellence, Houston, Tex. Dr Lippman is the Margaret and
Ben Love Professor in Clinical Cancer Care.
Presented at the annual meeting of the American Head and Neck Society,
Palm Desert, Calif, April 26, 1999.
From the Departments of Head and Neck Surgery (Drs Clayman, Morrison,
and Ginsberg and Mr Johnson) and Thoracic/Head and Neck Medical Oncology (Dr
Lippman), The University of Texas M. D. Anderson Cancer Center, Houston.
Corresponding author and reprints: Gary L. Clayman, DDS, MD, Department
of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center,
1515 Holcombe Blvd, Campus Box 441, Houston, TX 77030 (e-mail: gclayman{at}mdanderson.org).
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