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The Role of Intratumoral Therapy With Cisplatin/Epinephrine Injectable Gel in the Management of Advanced Squamous Cell Carcinoma of the Head and Neck
Barry L. Wenig, MD, MPH;
Jochen A. Werner, MD;
Dan J. Castro, MD;
Kasi S. Sridhar, MD;
Harinder S. Garewal, MD, PhD;
Wolfgang Kehrl, MD;
Anna Pluzanska, MD;
Olaf Arndt, MD;
Peter D. Costantino, MD;
Glenn M. Mills, MD;
Frank R. Dunphy II, MD;
Elaine K. Orenberg, PhD;
Richard D. Leavitt, MD
Arch Otolaryngol Head Neck Surg. 2002;128:880-885.
ABSTRACT
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Objective To determine the safety and efficacy of targeted antitumor therapy with
cisplatin/epinephrine injectable gel in patients with advanced squamous cell
carcinoma of the head and neck.
Design Two prospective, double-blind, placebo-controlled phase III trials of
identical design. Crossover from blinded to open-label phase was permitted
for patients with disease progression.
Setting Tertiary referral centers in North America and Europe.
Patients One hundred seventy-nine intensively pretreated patients with recurrent
or refractory squamous cell carcinoma of the head and neck.
Intervention Cisplatin/epinephrine injectable or placebo gel was administered by
direct intratumoral injection; up to 6 weekly treatments. Dose was 0.25 mL
of active or placebo gel per cubic centimeter of tumor up to 10 mL total.
Patient benefit after local tumor control of the most symptomatic tumor was
assessed by patients and physicians using the Treatment Goals Questionnaire.
Main Outcome Measures Local tumor response and patient benefit attributable to improvements
in tumor-related symptoms.
Results Combined results for the 178 patients with evaluable data in the 2 trials
confirmed objective tumor responses in 35 (29%) of 119 patients, including
23 (19%) complete responses achieved with cisplatin/epinephrine gel, vs 1
(2%) of 59 for placebo (P<.001). Tumor response
and patient benefit were significantly correlated (P = .006): 47% (17/36) of patients with target tumor responses achieved a rigorously
defined benefit based on a prospectively selected treatment goal vs 15% (22/142)
of nonresponders.
Conclusion Cisplatin/epinephrine injectable gel reduces tumor burden, ameliorates
tumor symptoms, and provides a new therapeutic option for treating patients
with squamous cell carcinoma of the head and neck.
INTRODUCTION
HEAD AND NECK squamous cell carcinoma (HNSCC) is diagnosed in about
40 000 Americans per year and more than 600 000 persons worldwide.1-5
Most (70%) patients with HNSCC present with locally or regionally advanced
disease, nodal metastases, invasion of local structures, and/or distant metastases.
Despite aggressive standard therapy, approximately 60% of patients have recurrences.6
Recurrent local tumors can be symptomatic, impair function, and curtail
normal activity. In addition, the physical effects of treatment (ie, morbidity
associated with surgery, radiotherapy, or chemotherapy) further lower quality
of life in patients with advanced HNSCC.7
Therapeutic options for advanced HNSCC are limited. These patients generally
have undergone extensive surgery, have received near-maximum tolerated doses
of radiation, and are often poor candidates for aggressive combination therapy.7 Therefore, for more effective local and regional control
of HNSCC and to minimize systemic exposure and toxicity, locally injectable
therapies have been investigated.8
Introduced 3 decades ago, cisplatin given intravenously has proved to
be a potent cytotoxic agent for the treatment of HNSCC.1, 8
Cisplatin plus fluorouracil is one standard regimen for recurrent or metastatic
HNSCC, with an overall response rate of 30%, a complete response rate of 5%,
and a median survival of 4 to 6 months.7 However,
treatment is often poorly tolerated. Nausea and vomiting can be severe and
require the use of potent antiemetics.9 Myelotoxicity
is common. Nephrotoxicity, neurotoxicity, and ototoxicity limit its prolonged
use.10
To improve the efficacy of cisplatin chemotherapy, a novel drug system
has been developed that achieves high, sustained, tumoral cisplatin concentrations
with minimal systemic exposure.11 This drug
system, cisplatin/epinephrine injectable gel, is designed for direct intratumoral
injection and has been used to treat human malignant tumors of various histologic
types.12-16
Herein, we present the combined results of 2 placebo-controlled phase III
trials of identical design conducted to compare the efficacy of cisplatin/epinephrine
gel with a placebo gel (without active drug) for local tumor control and symptom
relief in advanced HNSCC.
PATIENTS AND METHODS
Between June 15, 1995, and March 22, 2000, 179 adult patients with recurrent
or metastatic histologically confirmed HNSCC were enrolled in 2 identical,
multicenter, prospective, randomized, double-blind, placebo-controlled trials
(one in North America and one in Europe). The primary end point was objective
response of the designated target tumor, ie, the most symptomatic or threatening
tumor. Secondary end point was the patient benefit attributable to improvement
in tumor symptoms resulting from local treatment of the target tumor (other
tumors could also be treated). Palliation of tumor symptoms rather than survival
was chosen as an end point because cisplatin/epinephrine is a local therapy
and was not expected to extend survival in this patient population. Individual
tumors had to be at least 0.5 cm3 and 20 cm3 or less
in size and measurable and accessible for direct intratumoral injection. Eligibility
criteria included the following: at least 1 previous course of therapy (surgery,
radiotherapy, or chemotherapy) for HNSCC, Karnofsky Performance Status score
of 40 or more and life expectancy of 6 months or more, and adequate hematologic
and renal function (granulocyte count >1000/mm3, platelet count
>75 000/mm3, and serum creatinine level <1.5 times the
upper limit of the institution's normal value for the patient's sex). Patients
with the following were excluded: a history of cardiac arrhythmias, New York
Heart Association class III or IV cardiac disease, or known hypersensitivity
to active agents, bovine collagen, or sulfites; patients who had been treated
within 28 days with another HNSCC therapy were also excluded. Tumors that
posed an immediate risk of hemorrhage, embolization, or uncontrolled local
infection at the treatment site were excluded, as were fibrotic lesions. Tumors
that directly involved or threatened to invade the carotid artery were excluded
by an amendment after initial experience revealed a risk of cardiovascular
events in these patients. Before the first treatment, each patient signed
an informed consent approved by the institutional review board at each study
center.
The investigational agent was cisplatin/epinephrine gel (IntraDose Injectable
Gel; Matrix Pharmaceutical Inc, Fremont, Calif). This viscous, aqueous, biocompatible-biodegradable
gel contains cisplatin (4 mg/mL) and the vasoconstrictor epinephrine (0.1
mg/mL); purified bovine collagen forms the basis of the gel matrix. In the
placebo gel, 0.9% sodium chloride was substituted for the cisplatin and epinephrine.
This gel formulation provides site-specific cisplatin at high intratumoral
drug concentrations for extended periods (1-3 days). Because active agents
(cisplatin and epinephrine) slowly disperse from the gel, the incidence of
toxicities typical of intravenously administered cisplatin is low.11
Patients were randomized 2:1 to receive cisplatin/epinephrine gel or
placebo gel, respectively, and were stratified by volume of their primary
target tumors (stratum 1, tumors 0.5 to <5 cm3; stratum 2, tumors
5 to  20 cm3). The trials consisted of a blinded treatment phase
with up to 6 weekly treatments in an 8-week period followed by 4 weekly evaluations
and monthly evaluations thereafter. If after 3 treatments tumors did not respond
or continued to progress, patients were permitted to roll over into the open-label
phase and be treated with the active drug. However, the study blind was not
broken until 6 months after the last treatment of the last patient enrolled.
At the discretion of the physicians, tumors could undergo a second course
of therapy of up to 6 weekly treatments in an 8-week period.
The dose was 0.25 mL/cm3 tumor, and tumor masses were measured
at each study visit, most often by direct physical examination (ultrasonography,
computed tomography, and magnetic resonance imaging were also used). Volume
was calculated as (length x width x height) x 0.5.
The test agents were administered in an outpatient setting or brief
hospital stay. The physician injected the agent directly into the tumor by
means of a 22- to 30-gauge needle under direct visual, computed tomographic,
or ultrasound guidance, being careful to avoid major blood vessels. Injection
technique depended on the shape and size of tumors; the gel could be injected
through several entry points or through one entry point by changing the angle
of the needle. The technique was to lay down tracks of gel 1 cm apart to ensure
complete exposure of tumor tissue to high concentrations of cisplatin.
The primary end point in this study was objective response of the target
tumor. Response was based on change in baseline tumor volume sustained for
at least 28 days: complete response (CR) was defined
as 100% reduction of tumor volume; partial response
(PR) as 50% or greater reduction; stable disease
as less than 50% reduction or less than 25% increase; and progressive disease as 25% or greater increase.
The second end point was patient benefit, which was assessed with the
validated Treatment Goals Questionnaire and Patient Benefit Algorithm developed
to evaluate the benefit of treating local disease in patients with HNSCC.17-18 The Treatment Goals Questionnaire
was validated by means of a cohort of patients with head and neck cancer and
clinicians experienced in treating these patients. From the questionnaire,
patients and physicians prospectively selected a treatment goal associated
with the target (most symptomatic or threatening) tumor. Patients selected
1 of 8 "palliative" goals (wound care; pain control; ability to see, to hear,
or to smell; physical appearance; obstructive symptoms; or mobility). Progress
was graded on a 4-point scale; achievement was defined
as 1-point or greater improvement sustained for at least 28 days. Physicians
selected 1 palliative goal or 1 of 3 "preventive" goals (prevention of invasion,
obstruction, or subcutaneous tumor from breaking through the skin); these
goals were either achieved, ie, the event was prevented for at least 28 days,
or not achieved, ie, the event occurred.
The independent assessments of the patients and physicians were incorporated
into an algorithm such that patient benefit was attained if either (1) both
agreed the goal was achieved or (2) one said the goal was achieved and the
other said there was no change. Patients were scored "no benefit" if either
the patient or the physician said that the patient's status declined.
Additional end points included time to response (from first treatment
to onset of response) and duration of response (time from onset to objective
evidence of progression).
Safety evaluations included conditions at the site of treated tumors,
results of physical documentation of local tissue examinations and laboratory
evaluations, vital signs, and adverse medical events.
RESULTS
PATIENTS
A total of 179 patients were enrolled. One patient whose tumor was penetrated
by the needle but had no drug injected because of pain and who received no
other treatments was excluded from the efficacy analysis (n = 178) but was
included in the safety analysis (n = 179). The cisplatin/epinephrine gel group
(119 patients) and the placebo gel group (59 patients) were well balanced
for prognostic characteristics (Table 1), including age, sex, Karnofsky Performance Status score, duration
of disease, and exposure to previous anticancer therapy.
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Table 1. Patient Baseline Characteristics
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Entry criteria stated that patients must have been previously treated
with at least 1 course of therapy. In fact, patients enrolled had undergone
multiple courses of therapy: 89% of patients had been treated with multiple
modalities including surgery, systemic chemotherapy, and radiotherapy, and
89% of the target tumors were in a previously irradiated field. Thirty-four
percent (60/178) of patients had undergone systemic chemotherapy after recurrence,
and 27% (48/178) of patients had had previous platinum-containing therapy.
These were intensively pretreated patients with long-standing disease who
had few, if any, treatment options.
RESPONSE OF TARGET TUMORS
As shown in Table 2, the
response rate for the target tumor (CR + PR sustained  28 days) was 29%
(35/119) for patients in the cisplatin/epinephrine gel group and 2% (1/59)
for patients in the placebo gel group, a statistically significant difference
(P<.001). Most target tumor responses were CRs
(19% CRs and 10% PRs). Smaller tumors tended to have higher response rates
than larger tumors: CR + PR for stratum 1 was 37% (23/62) and for stratum
2 was 21% (12/57). Twenty-four percent (29/119) of patients in both strata
maintained stable disease.
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Table 2. Response of Target Tumors* During the Blinded Phase
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Tumor response generally occurred within 2 to 3 weeks of the first treatment
(median time to onset of response was 21 days). The median cumulative dose
of cisplatin administered was 20 mg (range, 0.8-184 mg), and for epinephrine,
0.5 mg (range, 0.02-4.6 mg). The median duration of response was 78 days (range,
30-554+ days). At last evaluation, only 2 of the responding tumors had begun
to progress. Many of the patients with responses were not able to extend their
participation in the study beyond a few months because of systemic disease
progression, general physical debilitation, or death.
The response rates for patients who rolled over to the open-label phase
were similar to those for patients treated with active drug during the blinded
phase: 27% (11/41). Note that, between the time of the first placebo gel treatment
in the blinded phase and the first cisplatin/epinephrine gel treatment in
the open-label phase, median tumor size had doubled from 5.7 cm3
to 10.8 cm3. Similar response rates were also attained in patients
who had undergone previous systemic cisplatin or carboplatin treatments (29%
[14/48]) and in patients who were "platinum naive" (30% [21/71]).
In addition to the target tumors, which by definition had to be symptomatic
or threatening, other tumors were treated. During the blinded period, a total
of 227 tumors were treated with cisplatin/epinephrine gel (including 119 target
tumors) and 80 with placebo gel (including 59 target tumors); response rates
(CR + PR) were 30% (68/227) and 1% (1/80), respectively.
Of the potential prognostic factors analyzed in this study, only a high
baseline Karnofsky Performance Status score (P =
.02), smaller tumors (P = .03), and oral and facial
tumors (P = .03) were associated with higher tumor
response rates.
PATIENT BENEFIT AND ASSOCIATION WITH TUMOR RESPONSE
Patient benefit was evaluated by means of a validated instrument (Treatment
Goals Questionnaire) that was based on independent assessments by patients
and physicians of the patients' progress toward prospectively selected treatment
goals.18 The goals most frequently selected
by the patients were improved pain control, improved wound care, relief of
obstructive symptoms, and improved physical appearance. These goals were also
frequently chosen by the physicians. Patients treated with cisplatin/epinephrine
gel attained a significant benefit compared with patients treated with placebo
gel: 27% vs 12%, respectively (P = .05). Finally,
objective tumor response was associated with patient benefit as measured by
the Treatment Goals Questionnaire (Figure
1): 47% (17/36) of patients whose target tumors responded to treatment
attained a benefit vs 15% (22/142) of patients without tumor responses (P = .006).
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Association of objective tumor response with patient benefit as measured
by the Treatment Goals Questionnaire.
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Additional benefits that were coincidentally documented on the case
report forms but not included in the formal patient benefit assessment included
improved swallowing, speech, or psychological state; ability to sleep on treatment
side; and less drainage. Such unexpected benefits were noted by 25 patients
(21%) treated with cisplatin/epinephrine gel and 4 patients (7%) treated with
placebo.
SAFETY
Pain during injection was the most common adverse effect of the treatment
procedure: 24% (29/119) of patients treated with cisplatin/epinephrine gel
reported immediate (within 15-20 minutes) injection-related pain, as did 17%
(10/60) of patients in the placebo group. Pain was severe in 2 patients, requiring
hospitalization for intravenous morphine; 1 discontinued therapy. Elevated
blood pressure and tachycardia were also observed in less than 5% (8/179)
of patients treated with active or placebo gel. One episode of hypertension,
associated with pain, responded to intravenous morphine.
Local cytotoxic effects at the treatment site (inflammation, bleeding,
erosion, ulceration, necrosis, and eschar) were evaluated at each study visit
and were observed in 87.4% (104/119) of target tumors treated with active
drug vs 62.7% (37/59) of tumors treated with placebo. Injection therapy results
in initial erythema, which is followed in several days by local necrosis and
eschar formation. As tumor necrosis proceeds, the diseased tissues are replaced
by normal healing and reepithelialization. No specific wound care is required;
however, the necrotic tissue and eschar can be topically managed with saline
or peroxide wet-to-dry dressings as necessary. In the cisplatin/epinephrine
gel–treated patients, adverse effects typically peaked at approximately
2 weeks after the first treatment and resolved during the next 3 to 12 weeks.
Wound infection (5.9% [7/119] vs 1.7% [1/59] for placebo) and fistula formation
(3.3% [4/119] vs 0% for placebo) were reported. One facial abscess requiring
intravenous antibiotics was considered severe. Two pharyngocutaneous fistulas
required gastrostomy tubes, with 1 patient withdrawing from the study. Bleeding
occurred at the injection site in 2 patients and responded to local management.
Four patients discontinued the study as a result of blindness, facial pallor,
allergic reaction, and anemia requiring transfusion.
There were rare reports of the toxic effects usually observed with systemically
administered cisplatin—neurotoxicity, hematologic toxicity, and ototoxicity.
Early in the course of the North American study, 4 cases of treatment-related
cerebrovascular events occurred (3 in the cisplatin/epinephrine gel group
and 1 in the placebo group) either during or shortly after treatment; no additional
treatment-related events occurred after protocols were modified to exclude
tumors directly invading or in proximity to the carotid artery. Two patients
developed dehydration requiring intravenous fluids. During the blinded phase,
the incidence rates of treatment-related systemic adverse events occurring
in more than 3% of patients in the cisplatin/epinephrine gel group were as
follows: vomiting, 7 patients (6%); nausea, 7 (6%); pain, 6 (5%); and headache,
5 (4%).
COMMENT
In these 2 randomized, double-blind, placebo-controlled phase III trials,
cisplatin/epinephrine gel was shown to be effective in producing clinically
meaningful response and palliative benefit in a group of patients with advanced
HNSCC who had few, if any, remaining therapeutic options. Moreover, the strong
association between response and patient benefit clearly demonstrated the
advantage of treatment over placebo.
In this study population of intensively pretreated patients with HNSCC,
the tumor response rate (CR + PR) in the cisplatin/epinephrine gel treatment
group was 29% (35/119). In contrast, only 1 patient in the placebo group had
a response. Complete responses were nearly twice as frequent as partial responses;
this is in contrast to systemic chemotherapy, where a PR is observed 5 times
more frequently than a CR.6, 9, 19-20
Patients enrolled in these trials were in advanced stages of their disease,
and in this context, the rapid onset of response (median of 21 days) and response
duration (median, 78 days; range, 30-554+ days) were clinically meaningful.
Many patients continued in local remission at the time of study withdrawal
or start of confounding therapy. Indeed, responses lasted long enough to impact
patient well-being as reflected in the achievement of patient benefit.
We found several prognostic factors associated with high tumor response
rates: smaller tumors; oral and facial lesions; and high Karnofsky Performance
Status scores. As with systemic chemotherapy, patients who are markedly symptomatic
and less than fully ambulatory have a significantly lower response to therapy
and have a shorter expected survival.21 Most
important, previous systemic cisplatin or chemotherapy was not a prognostic
factor, suggesting that this novel formulation of cisplatin/epinephrine injectable
gel is able to intensify dose and exposure time to tumor and thereby overcome
resistance frequently observed with systemic cisplatin therapy.
The main goal of treatment in advanced HNSCC is control of local symptoms
or prevention of symptomatic deterioration.22
In this trial, the benefits derived from local treatment were measured with
a new quality-of-life instrument, the Treatment Goals Questionnaire, for evaluating
individualized patient- and physician-selected treatment goals associated
with symptomatic tumors.17-18
Independent physician and patient assessments of progress toward their selected
goals are combined to produce the dichotomous outcome, "patient benefit" or
"no patient benefit." Such an index provides information not captured in global
quality-of-life assessments. Subjects treated with cisplatin/epinephrine gel
achieved a higher rate of patient benefit as measured by the validated Treatment
Goals Questionnaire than those treated with placebo gel (P = .05). Furthermore, patient benefit was positively associated with
target tumor response (P = .01), suggesting that
treatment of these symptomatic or threatening tumors has an impact on quality
of life that is meaningful to both the patient and the physician. Patients
with tumor response were 3 times more likely than nonresponders to benefit
from treatment.
The adverse event profile of cisplatin/epinephrine gel differed greatly
from that of systemically administered cisplatin. As expected, localization
of cisplatin in the gel formulation contributed to fewer systemic adverse
effects than intravenous administration of cisplatin. However, predictable
local tissue effects, including erosion, ulceration, and necrosis, did occur
as a result of the cytotoxic activity of the drug. An unexpected severe adverse
event occurred in these studies with cisplatin/epinephrine gel: cerebrovascular
events (3 in the active drug group and 1 in the placebo group). All events
occurred in larger tumors (10-20 cm3) that were known to impinge
on the carotid artery and were most likely caused by vasospasm or inflammation
as a result of direct irritation or trauma to the artery or tumor. After the
protocols were modified to exclude tumors directly invading or in immediate
proximity to the carotid artery, no additional cerebrovascular events related
to treatment occurred.
It is of interest to compare the results obtained with this site-specific
form of cisplatin with results of standard systemic cisplatin treatment. In
a randomized phase III study comparing systemically administered cisplatin
and fluorouracil as single agents and in combination for first-line therapy
in chemotherapy-naive patients with advanced HNSCC, a CR of 5% and PR of 20%
were reported in the combination cisplatin and fluorouracil group, with significant
toxicities and no increase in survival.9 In
the group treated with cisplatin alone, response rates were only 14%, and
for fluorouracil alone, only 13%. In contrast, the trials reported herein
were conducted in a patient population in whom multiple prior therapies, including
systemic cisplatin, had failed. In this group, treatment with cisplatin/epinephrine
gel resulted in a response rate of 29% with few systemic toxicities. These
rates are not direct comparisons, however, because all measurable and assessable
disease was evaluated in the study with systemic drugs, whereas individual
tumor response was the focus of this study.
In this difficult setting of patients with recurrent or metastatic HNSCC,
treatment with intratumoral cisplatin/epinephrine gel has shown a strong association
of tumor response with clinical benefit. A relationship between response and
benefit has not been previously demonstrated for systemic chemotherapy in
patients with HNSCC. Intratumoral cisplatin/epinephrine gel may find a role
in the current treatment regimen for patients with HNSCC who cannot be treated
by surgery or radiotherapy alone or as an alternative to systemic chemotherapy.
In this study, we found cisplatin/epinephrine gel useful for patients with
advanced disease who had unresectable tumors smaller than 20 cm3.
Cisplatin/epinephrine gel produces fewer systemic adverse effects than traditional
systemic chemotherapy. Local adverse events are generally amenable to treatment
and conservative wound management. Appropriate anesthesia administered during
and after the injection procedure should be part of a comprehensive pain management
program for each patient.
CONCLUSIONS
In these phase III trials, intratumoral cisplatin/epinephrine gel was
used as a single agent in recurrent or metastatic HNSCC. Avenues that warrant
future investigation include the possible use of cisplatin/epinephrine gel
in combination with other therapies (radiotherapy, surgery, and systemic chemotherapy)
to preserve organ function and enhance clinical response. Preclinical investigations
to support future clinical trials have included a report on the use of cisplatin/epinephrine
gel to prevent local tumor growth after margin-positive resection23 and a report on radiosensitization by intratumoral
cisplatin/epinephrine gel in combination with radiotherapy.24
Studies are in progress combining cisplatin/epinephrine injectable gel with
systemic chemotherapy in the hope of attaining superior tumor control and
preventing relapse at the sites of bulky disease.
AUTHOR INFORMATION
Accepted for publication January 9, 2002.
This study was presented at the annual meeting of the American Head
and Neck Society, Palm Desert, Calif, May 14, 2001.
This study was supported by a clinical grant from Matrix Pharmaceutical
Inc, Fremont, Calif.
We thank Morgan Stewart, PhD, and Ann Olmsted, PhD, for data analysis,
and Nushin Namazi, BS, and Caren Rickhoff, BA, for assistance in preparation
of the manuscript. We also acknowledge the numerous investigators in the Clinical
Trials Group who contributed patients to the study.
Corresponding author and reprints: Barry L. Wenig, MD, MPH, Department
of Otolaryngology–Head and Neck Surgery, Northwestern University Medical
School, Evanston Northwestern Healthcare, 1000 Central St, Suite 610, Evanston,
IL 60201 (e-mail: b-wenig{at}nwu.edu).
From the Department of Otolaryngology–Head and Neck Surgery,
Northwestern University Medical School, Evanston, Ill (Dr Wenig); Department
of Otolaryngology–Head and Neck Surgery, University of Marburg, Marburg,
Germany (Dr Werner); Division of Head and Neck Surgery, UCLA School of Medicine,
Los Angeles, Calif (Dr Castro); Department of Medicine, University of Miami
School of Medicine, Miami, Fla (Dr Sridhar); Department of Internal Medicine,
Hematology and Oncology, University of Arizona, Tucson (Dr Garewal); Ear,
Nose, and Throat Department, University Hospital Eppendorf, Hamburg, Germany
(Dr Kehrl); Department of Oncology and Chemotherapy Clinic, Medical University,  ód ,
Poland (Dr Pluzanska); Department of Otolaryngology, Head and Neck Surgery,
University of Regensburg, Regensburg, Germany (Dr Arndt); Department of Otolaryngology
and Neurosurgery, The Mount Sinai School of Medicine, New York, NY (Dr Costantino);
Department of Medicine, Hematology/Oncology Section, Louisiana State University
Medical Center, Shreveport (Dr Mills); Division of Bone Marrow Transplantation,
Medical Oncology and Hematology, Department of Internal Medicine, St Louis
University Health Sciences Center, St Louis, Mo (Dr Dunphy); and Matrix Pharmaceutical
Inc, Fremont, Calif (Drs Orenberg and Leavitt). Dr Costantino is now with
St Luke's–Roosevelt Medical Center, Columbia University College of Physicians
and Surgeons, New York, NY, and Dr Dunphy is now with the Oncology Division,
Department of Medicine, Duke University, Durham, NC.
Dr Sridhar is deceased.
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