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Chemoradiation for Locally Advanced Squamous Cell Carcinoma of the Head and Neck for Organ Preservation and Palliation
Michael E. Poole, PA-C, MPH;
Scott L. Sailer, MD;
Julian G. Rosenman, MD;
Joel E. Tepper, MD;
Mark C. Weissler, MD;
William W. Shockley, MD;
Wendell G. Yarbrough, MD;
Harold C. Pillsbury III, MD;
Michael J. Schell, PhD;
Stephen A. Bernard, MD
Arch Otolaryngol Head Neck Surg. 2001;127:1446-1450.
ABSTRACT
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Objectives To measure the efficacy and toxic effects of our chemoradiotherapy regimen
by means of response and survival in patients with advanced squamous cell
carcinoma of the head and neck (HNSCC) for organ preservation in resectable
disease or palliation in unresectable disease.
Design All patients underwent evaluation by the multidisciplinary head and
neck cancer team, with pathological diagnosis and staging. All patients underwent
assessment for response to therapy using results of physical examination and
radiologic imaging. Patients were followed up at 3-month intervals for a planned
period of 5 years.
Setting Academic center.
Patients Thirty-eight previously untreated patients with newly diagnosed HNSCC
were treated from June 1, 1996, through December 31, 1998, of whom 20 had
resectable and 18 had unresectable tumors.
Intervention Patients received intravenous cisplatin, 100 mg/m2 for 1
hour on days 1 and 29; a 24-hour continuous infusion of fluorouracil, 1000
mg/m2 on days 1 through 4 and 29 through 32; and radiation therapy,
150 rad twice daily for 12 days. The patients were given a 7- to 10-day break,
and radiation therapy was restarted on day 29 for 12 additional days (total
dose, 7200 rad).
Main Outcome Measures Complete, partial, and total response rates; disease-free survival;
overall survival; and toxic effects.
Results Toxic effects of treatment were moderately severe, including grades
III to IV mucositis (89%), neutropenia (71%), and renal toxic effects (8%).
In the 18 patients in the unresectable group, complete response in the 17
primary tumors and 15 cervical nodal metastases was achieved in 12 (71%) and
9 (60%), respectively; in the 20 patients undergoing organ preservation, complete
response rates were 100% in the 23 primary tumors and 15 cervical nodal metastases.
Complete response for all 38 patients was achieved in 31 (82%). In the unresectable
group, the Kaplan-Meier relapse-free survival estimate is 56%, with follow-up
from 29 to 45 months. In the organ preservation group, 75% of patients are
alive without disease, and 8 have been followed up for 36 to 48 months. Of
the 5 patients who have died, only 2 died of disease, with recurrences at
13.0 and 16.5 months.
Conclusions Chemoradiotherapy consisting of cisplatin, fluorouracil, and twice-daily
external beam radiation is highly effective in achieving durable complete
responses in patients with resectable HNSCC undergoing organ preservation
and patients with unresectable HNSCC undergoing palliation. Toxic effects
of this regimen were moderate to severe.
INTRODUCTION
HEAD AND NECK squamous cell carcinoma (HNSCC) constitutes 5% of all
cancers in the United States, with approximately 45 000 new cases and
13 000 deaths per year. Most of these cancers originate in the oral cavity,
but the larynx is the most common specific anatomical site. Two thirds of
new cases present with advanced local disease and/or regional lymph node involvement,
and 10% to 20% present with distant metastasis. Locoregional recurrence after
therapy is noted in 60% of patients with advanced disease.1-3
Standard therapy for locally advanced HNSCC has been surgery and radiation.
However, these treatment modalities are associated with significant morbidity.
Chemotherapy has been reserved for palliation of unresectable, recurrent,
or metastatic disease. The combination of cisplatin and fluorouracil routinely
provides a response rate of approximately 85%, with a complete response (CR)
rate of 35%.3-4 In recent years,
chemotherapy has been used in the neoadjuvant or induction setting in an attempt
to increase overall survival by increasing locoregional control or by eradicating
micrometastases. Concomitant chemoradiotherapy for organ preservation has
proved to be an effective approach in achieving a high and durable CR rate
without surgical resection.5 In June 1996,
a chemoradiotherapy regimen for advanced HNSCC consisting of cisplatin, fluorouracil,
and twice-daily radiation was instituted as standard therapy for organ preservation
of resectable disease and aggressive palliation of unresectable disease. This
report presents the data from the first 38 patients treated with this aggressive
regimen. The demographic, response, and survival data for the patients with
unresectable and resectable disease have been calculated separately to allow
comparison between both groups and with similar patient populations described
elsewhere.
PATIENTS AND METHODS
Patients with locally advanced and/or metastatic, newly diagnosed, previously
untreated HNSCC underwent evaluation by specialists in otolaryngology–head
and neck surgery, radiation oncology, and medical oncology and were presented
at a multidisciplinary conference. All patients underwent panendoscopy, computed
tomographic scanning and/or magnetic resonance imaging, and dental evaluation
and were classified according to the system of the American Joint Committee
on Cancer Staging.6 All computed tomographic
and magnetic resonance imaging scans were read by a single radiologist who
is a specialist in head and neck radiology. Criteria for treatment included
being older than 18 years and having an Eastern Cooperative Oncology Group
performance status of 0 (fully active) to 2 (ambulatory and capable of all
self-care, but unable to carry out any work activities), no previous chemotherapy
or radiation therapy to the head and neck, white blood cell count of greater
than 4000 cells/µL, platelet count of greater than 100 000 cells/µL,
and serum creatinine level of less than 2.0 mg/dL (177 µmol/L).
The group with resectable disease, treated for organ preservation, consisted
mainly of patients with primary tumors in the base of the tongue or hypopharynx,
but other primary sites were also treated for patients who were considered
to be at poor surgical risk or who refused surgery as primary therapy. Tumors
were considered to be unresectable if they involved the base of the skull,
carotid artery, vertebral bone, or prevertebral musculature.
All patients were treated using an institutional regimen based on the
literature, and data were collected and analyzed after approval by the institutional
review board. Chemotherapy consisted of intravenous cisplatin, 100 mg/m2 for 1 hour on days 1 and 29, and continuous infusion of fluorouracil,
1000 mg/m2 for 24 hours on days 1 through 4 and 29 through 32.
All patients received prehydration using intravenous dextrose 5% and 0.45%
isotonic sodium chloride, 250 mL/h for 4 hours, with intravenous mannitol,
12.5 g, given before cisplatin therapy. Posthydration was provided during
daily fluorouracil administration as a 2-L continuous infusion of dextrose
5% and 0.45% isotonic sodium chloride. Antiemetics consisted of 2 mg of oral
granisetron hydrochloride and 20 mg of intravenous dexamethasone sodium phosphate
given before cisplatin therapy on day 1, then 10 mg of intravenous prochlorperazine
maleate every 6 hours. Intravenous lorazepam, 1 mg every 8 hours, was given
as needed for nausea and/or vomiting. Gastrostomy tubes were recommended for
all patients with oral cavity, oropharyngeal, hypopharyngeal, and laryngeal
primary tumors to provide adequate hydration and nutrition.
Radiation therapy was administered using a 6-MeV linear accelerator.
All patients received 150 rad per fraction twice a day on days 1 through 12,
with a minimum of 6 hours between fractions. After a dose of 3000 to 3600
rad, the patients received a 10-day treatment break, and radiation therapy
was then restarted concomitantly with chemotherapy on day 29, to an average
total dose of 7200 rad. Total treatment time for all patients was 6 to 7 weeks.
All patients underwent assessment for response to therapy. Kaplan-Meier
curves were used to plot the relapse-free survival and overall survival for
the resectable (organ preservation) and unresectable (palliation) groups from
the end of therapy. In the relapse-free survival estimates, patients who were
lost to follow-up and those who died without disease are censored at that
point and are denoted by symbols on the graphs, but are not included in the
survival calculations. Treatment of patients not rendered disease-free was
considered to have failed at time 0. In the overall survival estimates, deaths
due to all causes are included in the calculations, and those who died without
disease are denoted by a symbol at that point. Patients who were lost to follow-up
are denoted by a symbol at that point, but are not included in the overall
survival calculations.
RESULTS
From June 1, 1996, until December 31, 1998, 38 patients with 40 primary
tumors were treated with chemoradiotherapy. Eighteen patients with unresectable
disease received palliative therapy (unresectable group), and 20 patients
with resectable disease received organ preservation therapy (organ preservation
group). The male-female ratio was 3.2:1.0; white-black race ratio,1.1:1.0.
Mean age was 55.5 years (range, 30-76 years). The patient and tumor characteristics
for each group are shown in Table 1.
The sex ratio was essentially equal in each group, but the racial composition
was reversed between the 2 groups, with 12 black and 6 white patients in the
unresectable group and 6 black and 14 white patients in the organ preservation
group. In the unresectable group, 10 (56%) of the 18 patients presented with
T4 primary tumors. Three patients in the organ preservation group had synchronous
primary tumors, with 11 (48%) of 23 primary tumors staged as T3. Of the 38
patients, 30 (79%) presented with nodal disease. In the unresectable group,
11 (61%) of 18 had N3 disease (>6 cm in greatest dimension). All patients
in the unresectable group and 14 (70%) of 20 in the organ preservation group
had stage IV disease.
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Table 1. Patient and Tumor Characteristics*
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Seven (18%) of the 38 patients were not able to complete the full course
of therapy and required an alteration in the treatment. In 4 (11%) of 38 patients,
the second course of chemotherapy was omitted because of various toxic effects,
including severe mucositis, moderate renal toxic effects, and decreased performance
status, but the radiation therapy was completed in all 4 patients. In 3 (8%)
of 38 patients, carboplatin (area under the curve, 5) was substituted for
cisplatin on day 29 owing to mild renal toxic effects. The response rates
for each group were calculated based on an intent-to-treat basis and are shown
in Table 2. Two patients were
lost to follow-up, and one of these received only 1 week of therapy. Findings
in these 2 patients were considered nonevaluable, and were included in the
denominators of the response rates but not in the survival calculations.
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Table 2. Response to Therapy*
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Response data are presented in Table
2. In the unresectable group, the CR rates of the primary tumors
and the cervical nodal metastases were 71% and 60%, respectively. In the organ
preservation group, the CR rates were 100% for the primary tumors and the
nodal metastases. When both groups were combined, the CR rate was 35 (88%)
of 40 for the primary tumors and 24 (80%) of 30 for the cervical nodal metastases.
The total CR rate for all 38 patients was 31 (82%). Among patients who achieved
a CR, neck dissections were performed at approximately 8 weeks after completion
of therapy for 2 patients in the unresectable group with N3 disease and in
5 patients in the organ preservation group with N2c to N3 disease. Results
of pathological examination of all of these dissection specimens were negative
for metastatic disease. Based on these results, it was decided that neck dissections
would be performed only in the organ preservation group patients with a node
measuring 3 cm or greater at diagnosis and who had residual neck disease at
the end of therapy.
The Kaplan-Meier estimates of relapse-free survival and overall survival
data for both groups are displayed in Figure
1, Figure 2, Figure 3, and Figure 4 and Table 3.
As of September 30, 2000, 8 of 18 patients in the unresectable group have
died with disease at 1, 4, 6, 7, 8, 10, 14, and 19 months since the completion
of therapy, for a relapse-free survival estimate of 56%. One patient died
without disease at 13 months and 2 patients were lost to follow-up at 5.0
and 7.5 months. Six patients (33%) were alive without disease and have been
observed for 29 to 45 months. In the organ preservation group, 2 of 20 patients
have died with disease at 19 and 33 months, for a relapse-free survival estimate
of 90%. Three patients have died without disease of recurrent vaginal cancer,
ischemic heart disease, and lung cancer at 8.5, 27, and 37 months, respectively.
Fifteen patients (75%) were alive without disease, with 8 of these having
been observed for 36 to 48 months.
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Figure 1. Kaplan-Meier estimates of relapse-free
survival for patients in the organ preservation group from the end of therapy
for patients achieving a complete response. Circles indicate patients who
died without disease and were censored at the time of death. Study groups
are described in the "Patients and Methods" section.
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Figure 2. Kaplan-Meier estimates of relapse-free
survival for patients in the unresectable group from the end of therapy for
patients achieving a complete response. Circles indicate patients who died
without disease and were censored at the time of death; triangles, patients
who were lost to follow-up. Study groups are described in the "Patients and
Methods" section.
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Figure 3. Kaplan-Meier estimates of overall
survival for patients in the organ preservation group from the end of therapy.
Deaths due to all causes were included in the analysis. Circles indicate patients
who died without disease and were censored at the time of death. Study groups
are described in the "Patients and Methods" section.
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Figure 4. Kaplan-Meier estimates of overall
survival for patients in the unresectable group from the end of therapy for
all patients. Deaths due to all causes were included in the analysis. Circles
indicate patients who died without disease and were censored at the time of
death; triangles, patients who were lost to follow-up. Study groups are described
in the "Patients and Methods" section.
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Table 3. Survival Status*
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Toxic effects were graded according to the National Cancer Institute's
Common Toxicity Criteria, and the combined data of both groups are shown in Table 4. Grades III to IV neutropenia occurred
in 27 (71%) of 38 patients, with 15 (39%) requiring hospital admission for
fever and treatment with intravenous antibiotics. Thirty-four patients (89%)
experienced grades III to IV mucositis, and 22 (58%) had gastrostomy tubes
placed before treatment for nutrition and hydration. The average weight loss
during therapy was 6.8 kg. Nausea and vomiting were mild to moderate in most
patients, with only 1 patient experiencing intractable nausea. Four patients
who did not present with dysphagia continued to experience severe dysphagia
after therapy. Grades I to II renal toxic effects were seen in 8 (21%) of
38 patients, and grades III to IV effects in 3 patients (8%). There was 1
case of sepsis requiring admission to the intensive care unit and discontinuation
of therapy, and 1 case of pulmonary aspergillosis, which was successfully
treated.
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Table 4. Maximum Acute Toxic Effects During Therapy (N = 38)*
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COMMENT
This chemoradiotherapy regimen was associated with significant toxic
effects requiring aggressive supportive care, but it also provides a high
response rate, even in patients with bulky, unresectable disease. Adelstein7 published a review of randomized trials of chemoradiotherapy
for HNSCC in May 1998, which concluded that chemoradiotherapy improves overall
survival and locoregional control through radiosensitization and offers the
advantages of decreased duration of treatment and a lower rate of distant
metastases. A previous study by Adelstein et al8
compared multiagent chemotherapy and radiation therapy with radiation therapy
alone. One hundred patients with advanced, resectable disease were randomized
to chemoradiotherapy with fluorouracil and cisplatin or to radiation therapy
alone. Seventy-six percent of the patients receiving chemoradiotherapy achieved
a CR, compared with 50% of the patients who received radiation therapy only.
Relapse-free survival at 36 months was 67% and 52%, respectively, and the
distant metastasis rates were 10% and 21%, respectively. In that study,8 overall survival was not significantly different for
the 2 groups, but additional follow-up was required for accurate assessment
due to the number of patients with recurrent disease remaining alive at the
time of publication. In April 1998, Wendt et al9
published a prospective, randomized, multicenter study to evaluate chemoradiotherapy
compared with radiation therapy alone as primary therapy for unresectable
disease. In the 270 patients with evaluable results, 130 received chemoradiotherapy
consisting of cisplatin, fluorouracil, and leucovorin calcium, and the remaining
140 received radiation therapy alone. The Kaplan-Meier estimates for 3-year
locoregional control were 35% and 17%, respectively, and the estimates for
overall survival were 49% and 24%, respectively.9
Brizel et al10 described 122 patients
treated in a randomized study in June 1998. Their study used chemoradiotherapy
consisting of cisplatin, 12 mg/m2 per day for 5 days, and fluorouracil,
600 mg/m2 per day for 5 days during weeks 1 and 6, with 2 additional
adjuvant courses. This regimen was compared with radiation therapy alone (125
rad twice daily) as primary therapy in patients with locally advanced disease,
which was unresectable in 53%. Eighty-eight percent of the patients receiving
chemoradiotherapy achieved a CR, compared with 73% in the radiation therapy
group. The patients who received chemoradiotherapy also had improved locoregional
control (70% vs 44%), relapse-free survival (61% vs 41%), and overall survival
(55% vs 34%) at 3 years compared with the patients who received radiation
therapy alone. Fifty (89%) of 56 patients in the chemoradiotherapy group in
the study by Brizel et al10 had T3 and T4 primary
tumors, compared with 24 (63%) of our 38 patients; however, only 7 (13%) of
56 patients in the chemoradiotherapy group in the study by Brizel et al presented
with N3 neck disease, compared with 11 (30%) of our patients.
In our unresectable group, 11 (61%) of 18 patients presented with N3
neck disease. Seven (64%) of these 11 patients achieved a CR in the neck,
and most of these responses have been durable, with no recurrences in 5 patients
after 29 to 48 months of follow-up. One patient died at 16.5 months without
disease; 1 patient had a local recurrence at 9.5 months, and another patient
had a distal recurrence at 1 month without cervical node recurrence after
36 months.
The study by Brizel et al10 used a lower
total dose of cisplatin (60 mg/m2) and fluorouracil (3000 mg/m2) for 2 courses and a lower twice-daily fraction of radiation (125
rad) than our regimen. Their percentage of patients with mucositis was similar,
but the percentage of patients requiring admission for fever and neutropenia
was significantly higher in our report (39% vs 14%). It may be appropriate
to consider modifying the therapy by using lower doses of chemotherapy and
radiation therapy (per fraction) for patients with resectable tumors undergoing
organ preservation to decrease the toxic effects, reserving our current regimen
for patients with bulky, unresectable tumors for aggressive palliation.
CONCLUSIONS
Chemoradiotherapy consisting of cisplatin, fluorouracil, and twice-daily
radiation is extremely effective therapy for locally advanced HNSCC in organ
preservation and palliation. Its efficacy is most notable in the high rate
of durable CRs in patients with advanced resectable disease. This intensive
regimen increases the risk for significant toxic effects, especially fever,
neutropenia, and mucositis; therefore, aggressive supportive care is essential.
We will continue to follow up these patients for survival and long-term toxic
effects.
AUTHOR INFORMATION
Accepted for publication July 25, 2001.
Preliminary data presented in poster form at American Society of Clinical
Oncology conference, Los Angeles, Calif, May 18, 1998.
Corresponding author and reprints: Michael E. Poole, PA-C, MPH, Division
of Hematology/Oncology, 3009 Old Clinic Bldg, CB 7305, University of North
Carolina School of Medicine, Chapel Hill, NC 25799-7305 (e-mail: poolem{at}med.unc.edu).
From the Division of Hematology/Oncology, Department of Medicine (Mr
Poole and Dr Bernard), and the Departments of Radiation Oncology (Drs Sailer,
Rosenman, and Tepper) and Otolaryngology–Head and Neck Surgery (Drs
Weissler, Shockley, Yarbrough, and Pillsbury), University of North Carolina
School of Medicine, and the University of North Carolina Lineberger Comprehensive
Cancer Center (Dr Schell), Chapel Hill.
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