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High-Dose Intra-arterial Cisplatin Therapy Followed by Radiation Therapy for Advanced Squamous Cell Carcinoma of the Head and Neck
William R. Wilson, MD;
Robert S. Siegel, MD;
Leonidas A. Harisiadis, MD;
David O. Davis, MD;
Hoang H. Nguyen, MPH;
William O. Bank, MD
Arch Otolaryngol Head Neck Surg. 2001;127:809-812.
ABSTRACT
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Objective To assess the effectiveness of a protocol consisting of 4 cycles of
high-dose intra-arterial cisplatin infusions followed by radiation therapy
for improving chemotherapy response rates, organ preservation, and survival
in patients with advanced-stage untreated and previously treated squamous
cell carcinoma of the head and neck.
Design and Setting A prospective study of sequentially enrolled patients treated in an
academic medical center. The Kaplan-Meier method was used for survival analysis.
Patients Fifty-eight nonpregnant adults, 18 years of age or older, with measurable
untreated or recurrent advanced biopsy-proven squamous cell carcinoma of the
head and neck.
Main Outcome Measures Response rate to targeted intra-arterial cisplatin infusions, organ
preservation, and survival.
Results Fifty-eight patients (44 men and 14 women) were followed up for at least
2 years (median duration of follow-up, 27 months). Twenty-nine (67%) of the
43 previously untreated patients had a complete response to intra-arterial
cisplatin therapy. Of the untreated patients, 28 are alive and disease free
after a median follow-up time of 30 months. Five of the patients with recurrent
disease had a complete response to intra-arterial cisplatin therapy. There
were 4 survivors after a median follow-up time of 17.5 months. Of note, there
were no deaths or serious complications related to the treatment in either
group.
Conclusions High-dose intra-arterial cisplatin therapy provides a high complete
and partial response rate (91%). The combination of high-dose intra-arterial
cisplatin and radiation therapy is effective in improving survival and organ
preservation rates in patients with previously untreated, advanced squamous
cell carcinoma of the head and neck. This treatment protocol is much less
effective for recurrent disease.
INTRODUCTION
TREATMENT OF head and neck cancer has evolved considerably over the
past 20 years. Surgeons have made remarkable improvements in the ability to
resect advanced tumors and to reconstruct the resulting defects. Despite these
advances, it is acknowledged that preservation of the vital structures of
the head and neck, if accomplished without added mortality, provides the best
physiological and cosmetic results. Radiation therapy has long served as both
a primary and an adjunctive treatment method directed to this goal. Hyperfractionated
radiation techniques have increased the likelihood of locoregional tumor control
by reducing affected tumor cell recovery. Chemotherapeutic agents with demonstrated
efficacy against squamous cell carcinomas (SCCs) now appear to have improved
both survival and organ integrity when used in anticipation of or in conjunction
with radiation therapy.1-2
In 1994, our group began a study to assess the efficacy of intra-arterial
cisplatin therapy in reducing the tumor cell mass present at the primary site
prior to the initiation of radiation therapy. Our protocol, based on the method
pioneered by Robbins et al,3 used selective
intra-arterial infusions of cisplatin to achieve a high-dose intensity directed
into the tumor bed, with the simultaneous intravenous infusion of the rescuing
agent sodium thiosulfate. Our goals were to look at the survival benefits
and preservation of vital organs in patients with previously untreated and
recurrent advanced SSC of the head and neck.
PATIENTS AND METHODS
PATIENT SELECTION
This study was approved by the institutional review board of the George
Washington University Medical Center, Washington, DC. Patients gave informed
consent prior to participation in the study. All patients had biopsy-proven
advanced SCC of the head and neck (ie, tumors located between the skull base
and clavicles), and all were examined and staged by the head and neck tumor
board team consisting of head and neck surgeons, medical oncologists, radiation
oncologists, and neuroradiologists. The tumors were staged according to the
criteria set forth by the American Joint Committee on Cancer Staging. Determinations
were made by physical examination, computed tomography, or magnetic resonance
imaging.
Patients were admitted to the study whether or not their tumors had
been previously treated. Among the patients with recurrent and stage IV disease,
almost all the tumors were resectable. Computed tomographic scans of the chest,
as well as bone scans when there was a suspicion of bone involvement or metastases
to bone, were obtained in all cases. The entry criteria were biopsy-proven,
measurable, advanced SSC; nonpregnant adults 18 years of age and older with
no upper age limit; and cardiac function sufficient to withstand the fluid
loading associated with high-dose intra-arterial chemotherapy. The exclusion
criteria included a creatinine clearance of less than 60 mL/min, a Karnofsky
performance status of greater than 60%, or an Eastern Cooperative Oncology
Group performance status of less than 2. The patients were then scheduled
to begin 2 phases of treatment: the first included 4 weekly cycles of intra-arterial
cisplatin infusions, followed by the second, radiation therapy.
TREATMENT PROTOCOL
Intra-arterial Cisplatin
The first treatment phase consisted of 4 weekly cycles of intra-arterial
cisplatin infusions. The patients were admitted to the arteriography suite
and underwent intravenous line placement and urinary tract catheterization
to allow sufficient hydration to promote a brisk urinary output. Arterial
catheters were placed in the femoral artery and passed up to the region of
the tumor, and an initial arteriogram was obtained outlining the vasculature
of the tumor to serve as a guide for the planned arterial infusions. Subsequently,
25 g of sodium thiosulfate was infused intravenously and immediately followed
by the directed intra-arterial infusion of cisplatin (150 mg/m2)
to the tumor bed. Amifostine (740 mg/m2) was administered intravenously
to the patients if in the course of therapy their creatinine clearance was
reduced to less than 60 mL/min. The patients were observed overnight and discharged
the following morning. The serum creatinine levels and complete blood cell
counts were carefully monitored throughout the study.
Radiation Therapy
We used a modified version of the University of Texas M. D. Anderson
Cancer Center4 accelerated fractionation scheme
using a concomitant boost schedule so that the twice-daily fractions were
given during the last 2.5 weeks of the radiation therapy course. For the twice-daily
fractions, however, we selected the 160-rad (1.6-Gy) fraction size that was
established by Wang et al.5 Therefore, radiation
therapy to a dose of 6800 rad (68 Gy) was given in 2 phases. The first phase
consisted of 20 daily fractions of 180 rad (1.8 Gy), delivering 3600 rad (36
Gy) over a 4-week period, and continued without planned break into the second
phase, also consisting of 20 fractions delivering 3200 rad (32 Gy). In this
second phase, however, an accelerated fractionation scheme consisting of 2
daily fractions of 160 rad (1.6 Gy) given 6 hours apart was used. With this
twice-daily fractionation, 3200 rad (32 Gy) was administered within 2 weeks,
while the overall course of 6800 rad (68 Gy) was completed by 6 weeks.
Opposed lateral fields were used most often for the primary site and
the upper neck area. The lower neck area and the supraclavicular fossae were
treated with an anteroposterior field to a dose of 5140 rad (51.4 Gy). Larger
nodes that were not located within the primary site fields were boosted further
with photon and/or electron beams to a dose of 6000 rad (60 Gy). After the
first 3600 rad (36 Gy), the spinal cord was excluded from the fields, and
therapy to the posterior neck area was completed with electron beams to a
dose of 5000 to 5500 rad (50-55 Gy).
The energies selected were 6 or 4 MV for the photon beams and 6 to 12
MeV for the electron beams. All beams were shaped with custom blocks or a
multileaf collimator. Shields were reshaped, typically after a dose of 5420
rad (54.2 Gy) and again after 6480 rad (64.8 Gy), to tighten the margins around
tumors as the radiation progressed.
PATIENT MONITORING
Follow-up Methods
All patients were carefully monitored for renal function status and
changes in blood cell count. The patients were asked if any change in hearing
was noted, and if affirmed, audiograms were obtained. Also, all patients were
examined every 6 weeks by a head and neck surgeon for evidence of residual
or recurrent tumor. Magnetic resonance imaging scans were obtained after the
completion of the intra-arterial infusions, 6 weeks after completion of the
radiation therapy, and, subsequently, every 6 months to ensure that there
were no deep nonpalpable recurrences and that there had been no unfavorable
change in the residual scar at the tumor site.
Management of Residual Tumor
Magnetic resonance imaging scans were obtained after completion of both
the 4 courses of intra-arterial therapy and the radiation therapy phase. The
option of surgical intervention was open at both of these times. If the course
of chemotherapy failed to result in significant reduction of primary or metastatic
neck disease, the surgical intervention option could be exercised either before
or after the radiation therapy phase. Remaining neck nodes larger than 2 cm
were an indication for neck dissection. Since residual primary tumor is difficult
to differentiate from posttherapy scarring, a biopsy was required prior to
any major resection.
RESULTS
Between August 1994 and July 1998, a total of 58 patients were entered
in the George Washington University Medical Center protocol, treated, and
followed up for a minimum of 24 months (median duration of follow-up, 27 months).
Survival was analyzed using the Kaplan-Meier survival method. There were 44
men and 14 women (age range, 29 to 85 years; median age, 59.5 years). Forty-three
patients presented with untreated primary tumors (Table 1). The tumors were staged according to the TNM system as
follows: stage II (n = 1), stage III (n = 3), and stage IV (n = 39). Twenty-nine
of the 43 patients had a complete response (no tumor identified on physical
examination or magnetic resonance imaging scans) to the 4 courses of intra-arterial
cisplatin, 10 had a partial response, and 4 had no response, for a response
rate of 91%. Twenty-eight patients (65%) remained disease free after a median
follow-up of 30 months (Figure 1)
Only 1 surviving patient has undergone the loss of a vital organ, the larynx.
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Response to Intra-arterial Cisplatin and Survival of 43 Previously
Untreated Patients
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Figure 1. Kaplan-Meier analysis of 58 patients
with previously untreated (n = 43) and recurrent (n = 15) squamous cell carcinoma
of the head neck between August 1994 and July 2000. Most deaths in the previously
untreated group occurred within the first 20 months, although some patients
died as late as 31 months.
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Of the 15 patients that presented with recurrent disease, 4 remained
alive and disease free (27%), after a median follow-up of 17.5 months. Five
patients had a complete response to the intra-arterial therapy, 6 a partial
response, and 4 no response. Of these 15 patients with recurrent disease,
10 had undergone previous radiation therapy or radiation therapy with surgery
or chemotherapy, 4 had undergone surgery alone, and 1 had undergone chemotherapy
alone.
The cause of death of 26 (45%) of the 58 enrolled patients was evaluated.
Most patients (n = 13) died of distant disease. Seven patients died of locoregional
disease; 3 died of unrelated disease; and 3 were unavailable for follow-up
and were counted as deaths (Figure 2)
Ten patients underwent resection of a residual mass in the primary tumor bed
with neck dissection. No tumor was found in the specimens from 3 of the 10
patients. Another 24 patients had neck dissections for residual cervical adenopathy.
Only 1 patient was unable to complete the protocol.
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Figure 2. Distant metastases represented
the majority cause of death among 58 patients with squamous cell carcinoma
of the head and neck, pointing up a weakness in the study protocol that has
since been corrected by adding 2 cycles of intravenous chemotherapy.
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There were no deaths or serious complications that were attributable
to the arteriography and no grade III/IV toxic reactions that were attributable
to the chemotherapy.
COMMENT
The objective of this study was to improve organ preservation and survival
in patients with advanced untreated and/or recurrent SCC of the head and neck
by the use of intra-arterial infusions of cisplatin in high doses designed
to enhance chemotherapy response rates in the primary and cervical metastatic
tumor beds prior to the initiation of radiation therapy. The 2-year survival
rate of 65% among these patients is greater than that in historical experience.6-8 The primary cause of
death—distant spread of disease—represents a problem that could
occur for several reasons. First, the locoregional control of the disease
is effective, thereby allowing the patients to live sufficiently long for
distant metastases to affect survival. Second, the focused arterial chemotherapy
and radiation dose does not address the generalized microscopic spread of
tumor cells. As a consequence, we have changed the comprehensive program for
head and neck cancer to include 2 cycles of intravenous chemotherapy after
completion of the intra-arterial chemotherapy phase and before the radiation
therapy phase.
The results of intra-arterial chemotherapy and radiation therapy on
recurrent squamous tumors were disappointing but not entirely surprising.
Previous surgery and irradiation both have a detrimental effect on the arterial
bed of the tumor site. Also, prior chemotherapy, especially with cisplatin,
would have the tendency to select out resistant tumor cells. It is for these
reasons that we think that intra-arterial infusion of cisplatin was of little
benefit to these patients.
It is also important to note that none of the 58 patients suffered a
grade III or IV toxic reaction, and there were no treatment-related deaths
due to the neutralization of the toxic effects of cisplatin in the general
circulation by the sodium thiosulfate. The adverse effects were limited to
mild nausea, ipsilateral alopecia, mild unilateral hearing loss, and transient
reduction of creatinine clearance.9 Nevertheless,
a high response rate was achieved. Only 1 patient elected not to complete
the full 4 cycles of intra-arterial cisplatin therapy.
CONCLUSIONS
The use of a targeted intra-arterial cisplatin protocol produces a high
tumor response rate in previously untreated patients with advanced SCC of
the head and neck. The combination of high-dose, intra-arterial cisplatin
infusions and subsequent radiation therapy is effective in improving survival
and organ preservation rates in previously untreated patients. This treatment
method is of limited effectiveness for patients who have previously treated
recurrent SCC.
AUTHOR INFORMATION
Accepted for publication April 6, 2001.
Presented at the annual meeting of the American Head and Neck Society,
Fifth International Conference on Head and Neck Cancer, San Francisco, Calif,
July 30, 2000.
Corresponding author and reprints: Hoang Nguyen, MPH, Division of
Hematology and Oncology, George Washington University Medical Center, 2150
Pennsylvania Ave, NW, Suite 3-428, Washington, DC 20037 (e-mail: domhhn{at}gwumc.edu).
From the Divisions of Otolaryngology (Dr Wilson), Hematology and Oncology
(Dr Siegel and Mr Nguyen), Radiation Oncology (Dr Harisiadis), Radiology (Dr
Davis), and Interventional Neuroradiology (Dr Bank), George Washington University
Medical Center, and the Washington Hospital Center, Washington, DC.
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