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Bone or Cartilage Invasion by Advanced Head and Neck Cancer
Intra-arterial Supradose Cisplatin Chemotherapy and Concomitant Radiotherapy for Organ Preservation
Sandeep Samant, MD;
K. Thomas Robbins, MD;
Parvesh Kumar, MD;
Jennie Z. Ma, PhD;
Francisco Vieira, MD;
Catherine Hanchett, BA
Arch Otolaryngol Head Neck Surg. 2001;127:1451-1456.
ABSTRACT
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Background Invasion of bony or cartilaginous structures by advanced upper aerodigestive
tract cancer has been considered an indication for surgery on the basis of
historic experience of poor responsiveness to radiation therapy. At University
of Tennessee–Memphis, patients with advanced head and neck cancer have
been treated on a protocol of concomitant intra-arterial (targeted) cisplatin
and conventional radiation therapy.
Objective To compare the efficacy, in terms of disease control and survival, of
this protocol in patients with T4 squamous cell cancers and invasion of bony
or cartilaginous structures (group 1; n = 45) vs those with T4 disease but
no bone or cartilage involvement (group 2; n = 90).
Design Subset analysis of protocol database and retrospective chart review.
Methods Treatment consisted of 4 weekly intra-arterial infusions of cisplatin
(150 mg/m2 per week), with simultaneous systemic neutralization
by intravenous sodium thiosulfate (9 mg/m2), and concurrent radiation
therapy at 180 rad (1.8 Gy) or 200 rad (2 Gy) per fraction to a planned total
of 6600 to 7400 rad (66-74 Gy) to the primary site or overt nodal disease.
Presence of bone or cartilage invasion was established by review of tumor
diagrams of clinical findings and computed tomography or magnetic resonance
imaging reports.
Results Of 135 patients who had T4 disease and a minimum follow-up of 9 months
(median, 40 months), 45 had clinical or radiologic evidence of bone (n = 29:
mandible, 12; maxilla, 9; sphenoid, 3; hyoid, 6) and/or cartilage (n = 18:
thyroid, 16; cricoid, 4) invasion (some patients had involvement of more than
1 site). The rate of complete response in group 1 (66.7%) was not significantly
different from that in group 2 (71.1%) ( 2 test, P = .79). The 2-year overall actuarial survival for group 1 (46.3%;
95% confidence interval, 30.3%-62.3%) was not significantly different (generalized
Wilcoxon test, P = .36) from that of group 2 (36.9%;
95% confidence interval, 25.5%-48.4%). A marked trend was noted for higher
response rates in cases of cartilage invasion (81.2%) than in those with bone
invasion (58.6%) (P = .15).
Conclusion Equivalent efficacy of treatment in the 2 groups suggests that targeted
chemoradiation can be a definitive therapeutic option in patients with advanced
head and neck cancer invading bony or cartilaginous structures.
INTRODUCTION
SURGERY continues to be the mainstay of treatment for advanced cancers
of the head and neck. The combination of chemotherapy and radiation, however,
is increasingly recognized as a viable alternative to radical surgery for
selected patients. The decision of choosing between these 2 alternatives remains
highly subjective, based frequently on intuition and personal impressions.
There is a general lack of information in the literature specifically addressing
clinical prediction of responsiveness to chemoradiation. One such example
of subjectivity, in our opinion, is the frequently cited argument that presence
of bone or cartilage invasion by cancer is a contraindication for organ-preservation
approaches. We wanted to examine whether this presenting characteristic of
the tumor is truly a clinical predictor of poor responsiveness to chemoradiation
therapy.
At the University of Tennessee Health Sciences Center, Memphis, patients
with advanced head and neck cancer are treated with concomitant high-dose
intra-arterial cisplatin chemotherapy and radiation.1
Both operable and inoperable cancers are treated with this regimen, and surgical
salvage is performed 8 weeks later in patients with operable residual disease.
We do not consider invasion of bone or cartilage a contraindication to this
approach. In this report, we compare the oncologic results of a group of patients
presenting with T4 squamous cell cancers of the head and neck with clinically
and/or radiologically documented bone or cartilage invasion with those of
another group with T4 squamous cancers without any evidence of bone or cartilage
invasion.
PATIENTS AND METHODS
Between August 1, 1993, and December 31, 1998, 293 patients with advanced
squamous cell cancers of the head and neck region received treatment on our
protocol of intra-arterial cisplatin with concomitant radiation. Among these,
135 patients presented with a T4 primary cancer.2
These patients form the basis of this study. A review of clinical charts,
computed tomography and magnetic resonance imaging reports, and information
in the protocol databases was carried out to select patients whose tumor invaded
bony or cartilaginous structures at the primary site. Forty-five such patients
were identified (group 1), leaving 90 patients who had advanced (T4) disease
at the primary site that did not involve bone or cartilage (group 2).
All patients were treated with concomitant intra-arterial cisplatin
along with conventional radiation therapy. Chemotherapy, delivered on days
1, 8, 15, and 22 of radiation therapy, consisted of cisplatin, 150 mg/m2, infused directly into the main arterial supply of the location of
primary tumor via superselective catheterization. The infusion was given during
a period of 3 to 5 minutes and was preceded by prehydration with 1 L of 5%
dextrose with 0.5N isotonic sodium chloride solution containing 20 mEq of
potassium chloride and 2 g of magnesium sulfate administered during the preceding
2 hours. Sodium thiosulfate (9 g/m2 in 200 mL of distilled water)
was given by intravenous push during 15 to 20 minutes, concurrently with intra-arterial
cisplatin. This was followed by a continuous intravenous infusion of sodium
thiosulfate, 12 g/m2, during 6 hours (the 12 g/m2 is
dissolved in 1 L of distilled water and infused at 167 mL/h). Posttreatment
hydration was achieved with 1 L of 5% dextrose with 0.5N isotonic sodium chloride
solution containing 20 mEq of potassium chloride and 2 g of magnesium sulfate
during the next 6 hours.
Radiation treatment to the primary tumor and upper part of the neck
was given at 200 rad (2 Gy) per fraction, once a day, 5 days a week to a total
dose of 6600 to 7400 rad (66-74 Gy) (35 fractions during 7 weeks). Radiation
was delivered with a linear accelerator using a combination of photons and
electrons. Fields were reduced to exclude the spinal cord at 4000 rad (40
Gy).
All patients were reassessed 8 weeks after completion of radiotherapy
with imaging studies (computed tomography or magnetic resonance imaging) followed
by an examination with multiple biopsies with the patient under anesthesia.
Residual cancer at the primary site or the node was treated with an appropriate
surgical resection and/or neck dissection. Complete response was defined as
absence of any histologic evidence of residual tumor; any residual tumor in
the biopsy specimen or surgically resected specimen resulted in a classification
of partial response. In instances where restaging biopsy was not performed
because of poor general medical status, patient noncompliance, or detection
of a distant metastasis, responses were graded as clinical complete response
or clinical partial response on the basis of the findings of clinical examination
alone. Reduction in tumor size of less than 50% was classified as no response;
patients not available for any assessment (clinical or radiologic) were included
in the unevaluable category. For the purpose of response, actuarial disease
control, and survival calculations, patients in the unevaluable category were
not removed from analysis. For instance, in calculating disease control above
the clavicles, all patients in this category were assumed to have a "failure"
at the time of restaging (ie, at 3 months).
Response rates between groups 1 and 2, and between patients with bone
invasion and those with cartilage invasion, were compared with the 2 test of proportions. Overall survival was computed with the Kaplan-Meier
method. Survival was compared between groups with the generalized Wilcoxon
test.
RESULTS
PATIENT CHARACTERISTICS AND TREATMENT DELIVERY
Table 1 shows the age, sex,
site, and nodal-stage distribution in the 2 groups. Both groups evenly represented
site and nodal involvement except for a somewhat higher proportion of patients
in group 2 with oropharyngeal cancers.
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Table 1. Patient Characteristics in Groups 1 and 2
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Among patients with bone and/or cartilage invasion (group 1), there
were 27 patients with bone invasion, 16 patients with cartilage invasion,
and 2 patients with invasion of both bone and cartilage (hyoid and thyroid
in one and hyoid and cricoid in the other). The 2 patients with bone and cartilage
invasion were included in the category of bone invasion for all response and
survival calculations in this article. Structures involved were the mandible
(n = 12), maxilla (n = 9), hyoid (n = 6), and sphenoid (n = 3) bones, and
thyroid (n = 16) and cricoid (n = 4) cartilages.
Thirty-one (69%) of 45 patients with bone or cartilage invasion received
all 4 cisplatin infusions. Nine patients received 3 infusions, 2 patients
received 2 infusions, and 3 patients received a single cisplatin infusion
because of advanced age, toxic effects, or poor compliance. Thirty-eight patients
(84%) received a radiation dose of 6500 rad (65 Gy) or more. Two patients
received 5000 and 5400 rad (50 and 54 Gy), respectively, and 5 received less
than 5000 rad (50 Gy).
TREATMENT RESPONSE
Fourteen patients in the bone invasion category had a complete histologic
response (Figure 1), which was determined
with a biopsy in 13 patients and on surgical resection in 1 patient. Three
additional patients had a clinical complete response (no biopsy was performed).
In the cartilage invasion category (Figure
2), 12 patients were proved by biopsy to have a complete histologic
response; one other patient had a clinical complete response. None of these
patients underwent surgery to the primary site. Nine patients (of the 45 in
group 1) had a neck dissection at the time of restaging.
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Figure 1. Disease control in patients with
T4 squamous cancers invading bony structures. CR indicates histologic complete
response; CCR, clinical complete response; PR, histologic partial response;
CPR, clinical partial response; NR, no response; UE, unevaluable; DM, distant
metastases; and LR, local recurrence.
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Figure 2. Disease control in patients with
T4 squamous cancers invading cartilaginous structures. CR indicates histologic
complete response; CCR, clinical complete response; UE, unevaluable; DM, distant
metastases; and LR, local recurrence.
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Table 2 lists the reponses
achieved after chemoradiation in groups 1 and 2. While 26 patients achieved
a histologically proved complete response, 4 additional patients were deemed
to have a complete response on the basis of clinical and radiologic findings.
Combining the 2 categories, a complete response rate of 66.7% (30/45) was
achieved. In comparison, the complete response rate for group 2 (no bone or
cartilage invasion group) was 71.1% (64/90). This difference was not statistically
significant (2 test, P = .79).
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Table 2. Response to Targeted Chemoradiation in Groups 1 and 2
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Table 3 lists the responses
obtained when patients in group 1 were separated by presence of bone or cartilage
invasion. Two patients who had both bone and cartilage invasion were included
in the category of bone invasion for this analysis. The difference in response
rates approaches significance (2 test, P = .15), with cartilage invasion showing a higher response rate (81.2%)
than bone invasion (58.6%).
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Table 3. Bone vs Cartilage Invasion: Response to Targeted Chemoradiation
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Table 4 shows the response
rates as analyzed for individual bony or cartilaginous structures involved.
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Table 4. Response Rates According to Individual Structures Involved*
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TOXIC EFFECTS
Acute toxic effects observed in our protocol have been described earlier.1 For this study, we reviewed the acute toxic effects
that occurred in the group with bone and cartilage invasion (group 1). Three
patients died during treatment, 1 of neutropenic sepsis and 2 of causes related
to general debility and electrolyte loss. In addition, a grade 3 hematologic
toxic reaction developed in 4 patients and a grade 3 mucosal toxic reaction
in 13 patients. One patient developed a cerebrovascular event.
There were no instances of delayed radiation-induced toxic effects that
were severe enough to warrant hyperbaric oxygen treatment or surgery. Long-term
laryngeal function and tracheostomy and feeding tube requirements were not
evaluated for this study but have been reported elsewhere.1, 3-4
LONG-TERM DISEASE CONTROL AND SURVIVAL
Follow-up ranged from 9 to 76 months, with a median of 40 months.
Figure 1 depicts the patterns
of failure observed in the subset of patients presenting with invasion of
bony structures. Among those with histologic complete response (n = 14) at
the primary site, only 1 patient underwent surgical resection of the primary
site at the time of restaging. No tumor was found in the specimen (resection
of floor of mouth and segmental mandibulectomy) in this patient. The defect
was repaired with a fibula free flap. Despite an excellent postoperative recovery,
the patient died 6 weeks later of a myocardial infarction. No conclusions
about long-term disease control are therefore possible in this patient. No
recurrence developed at the site of primary cancer in any of the other 13
patients in this category, although 4 developed distant metastasis and 1 a
nodal recurrence in the opposite side of the neck. Among the 3 patients with
clinical complete response, 1 had local failure; in the other 2, disease remained
controlled in the primary site and neck but appeared later as distant metastasis.
Among the partial responders (histologic, 3; clinical, 2), 4 had unresectable
residual disease and 1 was treated with salvage surgery. This last patient
had local recurrence a year later, at which time no salvage surgery could
be performed due to the unresectable nature of the disease. One patient with
no response was switched to intravenous palliative chemotherapy for progression
of disease. In 6 patients response was unevaluable for various reasons (poor
medical status, detection of distant metastasis, and death before restaging).
Figure 2 shows the failure
pattern of 16 patients with cartilage invasion. There were 13 complete responders
(histologic, 12; clinical, 1), only 1 of whom had local failure. This was
a patient with a supraglottic cancer who developed extensive recurrence in
the oropharynx and nasopharynx. Three patients had unevaluable results because
they died before restaging.
The 2-year overall actuarial survival for group 1 (46.3%; 95% confidence
interval, 30.3%-62.3%) was not significantly different (generalized Wilcoxon
test, P = .36) from that of group 2 (36.9%; 95% confidence
interval, 25.5%-48.4%). Figure 3
depicts the overall survival of patients in groups 1 and 2. Figure 4 shows the overall survival for the categories of bone invasion
and cartilage invasion. While there is a trend toward better survival in those
with cartilage invasion, this was not found to be statistically significant
(generalized Wilcoxon test, P = .36).
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Figure 3. Overall survival in groups 1 and
2.
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Figure 4. Overall survival for bone invasion
vs cartilage invasion.
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The 2-year actuarial disease control above the clavicles (absence of
disease at the primary site or in the neck) for group 1 (64.3%; 95% confidence
interval, 50.2%-78.3%) was also not different statistically (generalized Wilcoxon
test, P = .55) from that in group 2 (68.3%; 95% confidence
interval, 58.5%-78.0%). Figure 5 shows the actuarial control of disease above the clavicles in groups 1 and
2. The sharp drop at 3 months reflects the patients who had incomplete response
(histologic partial response, clinical partial response, and no response categories)
who could not be cleared of their disease surgically, as well as the patients
in the unevaluable category.
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Figure 5. Disease control above clavicles
in groups 1 and 2.
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COMMENT
Selecting between surgical and nonsurgical treatment for a given patient
depends on several factors: performance status and comorbidities, which determine
the patient's ability to tolerate chemotherapy; family and social history,
which predicts the patient's ability to complete intensive protocol-based
treatment; and the morphologic, radiologic, and pathologic characteristics
of the tumor, which influence the physician's judgment regarding the likelihood
of success with nonsurgical therapy. In this last category, invasion of bony
and cartilaginous structures by cancer has often been cited as reason to treat
the patient surgically.
There are 2 principal reasons why cancers invading bone and cartilage
are considered unsuitable for treatment with radiation therapy. First, these
cancers are considered less likely to respond to radiation.5-13
This impression is based on the observation of relatively poor results obtained
when patients with T4 cancers of the oral cavity and larynx are treated with
radiation as the primary modality. An extensive review of the literature by
Parsons et al11 showed that only 50% of T4
cancers of the larynx are controlled locally with radical radiotherapy. Similarly,
in a series of oral cavity cancers treated with radiotherapy at Christie Hospital
in Manchester, England, control at the primary site was found to be inversely
related to increasing T stage, node positivity, and bone involvement at presentation.12 Studies reporting the results of curative radiation
for advanced (T4) soft palate and tonsillar cancers show that less than 50%
of these cancers are expected to respond completely.5-7,13
The second reason for preferring surgical treatment for advanced cancers
of the head and neck that invade bony and cartilaginous structures is a concern
for a higher incidence of radiation-induced complications in these patients.
In Parsons and coworkers' series of T4 laryngeal carcinomas, complications
were graded as mild (soft tissue necrosis or bone exposure lasting 3 months
or less), moderate (permanent tracheostomy or gastrostomy but retained laryngeal
speech), or severe (total laryngectomy).11
Five percent, 7%, and 5% of their patients developed mild, moderate, and severe
complications, respectively. Osteoradionecrosis of the mandible has been noted
to occur in 5% to 10% of individuals treated with radiation for oral cavity
cancers.12, 14
As stated previously, involvement of bone or cartilage is not considered
a contraindication for chemoradiation at our institution. As a result, many
patients with this characteristic have been treated with our protocol of intra-arterial
chemotherapy and radiation. In particular, these are patients who would otherwise
require a total laryngectomy or a resection of a large portion of their tongue
if treated surgically.1, 4 In addition,
a few patients with paranasal sinus and nasopharyngeal cancers invading the
bones of the skull base are also included in this series. While group 1 contains
T4 cancers invading bony and cartilaginous structures, group 2 consists of
individuals with advanced tumors displaying extensive mucosal or soft tissue
extension of disease resulting in their categorization as T4 cancers. Given
the fact that both resectable and unresectable cancers are included in this
study, we believe that a complete response rate of 66.7% represents a substantial
improvement over the historical response rates observed with radiation therapy
alone. Furthermore, a complete response rate of 71.1% obtained in group 2
is not statistically significantly different from that obtained in group 1.
Hence, with our protocol, presence of bone or cartilage invasion does not
adversely affect the likelihood of disease control.
A marked trend of improved responsiveness to our protocol was noted
with cancers invading cartilage compared with those invading bone (81.2% vs
58.6%). This has important implications on the treatment of patients with
cancers of the larynx and hypopharynx. Our results with these cancers have
been discussed in detail in other reports.1, 4
Of the 17 patients displaying complete response (among 29 with bone invasion),
only 1 developed a local recurrence (Figure
1). Similarly, only 1 patient, among 13 complete responders in the
cartilage invasion category, developed a local recurrence (Figure 2). Hence, despite the presence of bone and cartilage invasion
at presentation, disease remained controlled in the long run in most complete
responders.
There were 5 partial responders in the bone invasion category (Figure 1). Only 1 of these cases was amenable
to surgical salvage. This patient had local failure a year later, and the
extent of disease precluded surgical salvage. There were no partial responders
in the cartilage invasion category (Figure
2). Since only 1 patient in the category of bone and cartilage invasion
underwent surgery at the primary site, it is not possible to comment adequately
about wound complication rates in this group of patients.
Despite the impressive control of disease above the clavicle, which
remained stable over time (Figure 5),
survival remained modest (46.3% in group 1 and 36.9% in group 2). In large
measure, this is a reflection of a significantly high incidence of distant
metastases on follow-up. However, this is not entirely surprising given the
advanced nature of the cancers in this study population. The lack of any difference
in the 2-year overall survival between the 2 groups again suggests that presence
of bone or cartilage invasion does not affect the curability of these cancers
with our treatment protocol.
The objective of this study was limited to describing the oncologic
results. Assessment of long-term function, morbidity, and quality of life
would on its own have constituted a detailed investigation that was outside
the scope of this article. While such studies are currently ongoing at our
institution, we have previously undertaken some limited analyses of functional
outcome. In a group of 47 patients with advanced head and neck cancer available
for follow-up at 18 months, 13% were found to be dependent on tube feeding.3 In another evaluation, 5 of 15 patients with advanced
pyriform sinus cancer surviving at 12 months were still dependent on tube
feedings.4 Additional information on the long-term
adverse effects of radiation, such as the development of osteoradionecrosis
of the mandible in patients with oral cavity or oropharyngeal cancers, could
be gathered by prospective assessment of pain scores and with radiologic imaging.
Although such information is obviously not available in this study, there
were no instances of any patients requiring hyperbaric oxygen or surgery for
osteoradionecrosis. It is possible that longer follow-up and larger numbers
of surviving patients with continued use of this approach may result in some
patients developing this complication.
Because of the retrospective nature of this analysis, the magnitude
of bone or cartilage invasion could not be accurately ascertained. It may
be intuitively assumed that presence of massive destruction of bony or cartilaginous
framework, such as in the mandible or the larynx, would diminish the likelihood
of retained function and increase the chance of long-term adverse effects.
Patients with such findings are usually treated surgically at our institution.
While this study cannot clarify exactly how much bony or cartilaginous destruction
may be safely treated with an organ-preserving regimen, it does establish
the oncologic efficacy of targeted chemoradiation in certain selected patients
with this finding.
Whether targeted chemoradiation can be as efficacious as surgery for
patients with bone or cartilage invasion could only be truly determined if
such patients were to be randomly assigned between these 2 treatments. However,
the ethical difficulty of conducting such a trial leaves us with only the
option of judging this regimen on its own in a phase 2 trial format. This
communication argues that targeted chemoradiation could be a viable treatment
alternative in patients with bone and cartilage invasion if the oncologic
results are not inferior to those obtained with similarly staged cancers where
such invasion is absent. In other words, if it is appropriate to treat advanced
cancers not invading bone or cartilage with the organ-preservation approach,
then it is also appropriate to treat cancers that invade these structures
in a similar fashion.
In conclusion, several factors must be considered in selecting the appropriate
line of therapy for advanced head and neck cancers. Concerns for long-term
adverse complications of radiation must be balanced against the prospect of
organ preservation. For the same stage of disease (T4), the results obtained
with and without bone or cartilage invasion were comparable in this study.
Hence, with our protocol of concomitant high-dose intra-arterial cisplatin
and radiation therapy, presence of bone or cartilage invasion by the primary
cancer does not constitute an absolute contraindication to adopting an organ-preservation
approach.
AUTHOR INFORMATION
Accepted for publication August 1, 2001.
This study was supported in part by a grant from Baptist Memorial Healthcare
Foundation, Memphis, Tenn, and grant RO1-CA67789 from the National Cancer
Institute, Bethesda, Md.
Presented at the Fifth International Conference on Head and Neck Cancer,
San Francisco, Calif, July 30, 2000.
Corresponding author and reprints: Sandeep Samant, MD, Department
of Otolaryngology, University of Tennessee Health Sciences Center, 956 Court
Ave, Suite B-222, Memphis, TN 38163 (e-mail: ssamant{at}utmem.edu).
From the Departments of Otolaryngology–Head and Neck Surgery
(Drs Samant and Vieira) and Preventive Medicine (Dr Ma), University of Tennessee
Health Sciences Center, Memphis; Department of Otolaryngology–Head and
Neck Surgery, University of Florida, Gainesville (Dr Robbins and Ms Hanchett);
and Department of Radiation Oncology, University of Medicine and Dentistry
of New Jersey/Robert Wood Johnson Medical School/Cancer Institute of New Jersey,
New Brunswick (Dr Kumar).
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