Cancer Medicine, 5th Edition
Bast, Robert C.; Kufe, Donald W.; Pollock, Raphael E.; Weichselbaum,
Ralph R.; Holland, James F.; Frei, Emil, editors.
Publisher: Canada: BC Decker Inc;
Copyright 2000. [5th edition.]
Section 27: Neoplasms of the Head and Neck –
86. Head and Neck Cancer – Treatment (Excerpts)
Treatment
General Principles
After a histologic diagnosis has been established and tumor extent determined,
the selection of appropriate treatment for a specific cancer depends
on a complex array of variables, including tumor site, respective morbidity
of various treatments, patient performance and nutritional status, concomitant
health problems, social and logistic factors, therapy anticipated for
potential recurrences or second primaries, and patient preference. These
variables are each considered with respect to the established effectiveness
of various treatment regimens available (Table 86.3).
Several generalizations are useful in therapeutic decision making, but
variations on these themes are numerous. Surgical resection and radiation
therapy are the mainstays of treatment for most head and neck cancers.
For small primary cancers without regional metastases (stage I or II),
wide surgical excision alone or curative radiation therapy alone is
used. Functional and cosmetic results are usually better following radiotherapy.
Local tumor control rates are generally better with primary surgical
resection, but if local recurrences occur after primary radiation therapy,
they can often be successfully treated with salvage surgery, resulting
in similar overall survival rates. Surgical complication rates are generally
increased following radiation. Salvage of surgical recurrences by radiation
therapy is less effective than is surgical salvage of radiation failures.
For more extensive primary tumors or regional metastases (stage III
or IV), planned combinations of pre- or postoperative radiation and
complete surgical excision are generally used.136 For selected patients
with advanced cancers of specific sites, such as the larynx, treatment
approaches with radiation alone, with surgery held in reserve for salvage
of recurrences, have been used in attempts to preserve structure and
function. Although these organ-preserving techniques have been successful
in many patients, they were generally associated with lower overall
survival rates.137–142
The overall management goals in treating patients with head and neck
cancer are to achieve the highest cure rates at the lowest cost in terms
of functional and cosmetic morbidity. These goals include early diagnosis,
effective rehabilitation, and appropriate palliation when cancers are
incurable. The achievement of these goals requires the close interaction
and cooperation of a multidisciplinary team of practitioners representing
surgery, radiation, chemotherapy, prosthodontics, dentistry, social
services, dietetics, physical medicine, pathology, nursing, and sometimes
psychiatry.
Effective rehabilitation is an important part of the overall treatment
of head and neck cancers. Modern advances in surgical reconstruction,
microvascular free-tissue transfer, and prosthodontics have significantly
improved functional performance.143 Rehabilitation concerns must be
addressed at initial treatment planning and carefully integrated with
the various treatment modalities used. Pretreatment dental evaluations
and speech and swallowing assessments are routine. Needed dental care
and/or extractions should be planned prior to chemotherapy or radiation
to reduce dental-associated sepsis, mucositis, and osteoradionecrosis.
The overall impact of treatment and rehabilitation decisions on a patient’s
quality of life is an important issue that may require use of specialized
social or psychiatric support systems for the patient and family. Finally,
the prolonged nature of treatment for advanced disease, which may extend
over many months, requires consideration of the social and financial
effect of treatment decisions on the patient, the family, and the patient’s
employer.
Biopsies of primary tumors should not be excisional unless the biopsy
procedure is sufficient for definitive treatment and the surgeon performing
the excision is responsible for providing curative treatment. Oncologic
principles of surgical resection must not be compromised by ill-conceived
reconstructive efforts or attempts at modifying the necessary resection
in order to minimize functional or cosmetic morbidity. Head and neck
cancers are serious threats to life. Temporary preservation of function
at the cost of high morbidity and death from recurrent cancer is a poor
bargain. Positive surgical margins after tumor resection or gross residual
cancer portends inevitable treatment failure. Molecular pathologic staging
may identify other patients earlier, where additional therapy may be
essential to achieve cure.133 Appropriate management must also include
the use of precise modern techniques of conservative surgical resection
(e.g., partial laryngectomy and functional neck dissection) that, in
selected patients, have cure rates similar to those of more radical
techniques.144
Radiotherapy
General
Radiation therapy is an effective modality in treating local/regional
disease. For early (T1 and T2) lesions, it gives results comparable
to those achieved by surgery. For certain tumor sites, such as the larynx,
it is preferred over surgery in the treatment of early tumors because
it maintains organ function. When lesions are intermediate in size,
it is used adjuvantly (following surgical excision) to improve local/regional
control. Vikram and colleagues found that the rates of local/regional
tumor recurrence were markedly higher if there was a greater than 6-week
delay between surgery and postoperative radiotherapy.146 For advanced,
inoperable lesions and for lesions arising in certain sites, such as
the nasopharynx, radiation therapy may be the only modality that offers
a potential for cure. Its therapeutic effectiveness has now been enhanced
by the concomitant use of chemotherapy.
Ionizing radiation (high-energy photons, electrons, neutrons, charged
particles) interacts with matter in subtle ways.146 Tumors can vary
dramatically in their ability to repair the DNA damage inflicted by
radiation. Hyperthermia and concomitant chemotherapy are methods of
reducing this repair ability. HNSCCs are generally characterized as
moderately radioresponsive, meaning that fairly large dosages of radiation
are required to achieve high probabilities of tumor control. Fortunately,
the required dosages are within the tolerance of the various critical
structures of the head and neck.
The effectiveness of a given dose of radiation depends on the manner
in which it is given.146 Over the past 25 years, “standard”
treatment regimens have evolved to treat head and neck cancer. In the
United States, the “curative” standard treatment regimen consists
of giving 180 to 200 cGy once a day for 5 days a week to a total dose
of 6,500 to 7,400 cGy, whereas in Canada and England, giving a higher
daily dose of 220 to 250 cGy once a day for 5 days a week to a total
dose of 5,000 to 5,500 cGy is more commonly used. These schemas have
evolved empirically to allow regeneration of normal tissues during the
course of radiotherapy. Radiation kills the stem cells in the basal
layer, and several weeks later the cells in the more superficial layers
are not adequately replaced when they are lost through normal physiologic
processes. This denudes the epithelium, giving rise to a mucositis reaction
that can greatly inhibit a patient’s ability to swallow solids
and liquids. This does not occur immediately but is progressive after
several weeks of radiotherapy. Patients must be monitored closely to
ensure that this problem is minimized. If a patient becomes too debilitated,
then consideration should be given to placement of a feeding tube to
ensure adequate nutrition. A similar process occurs in the skin in the
treatment portals, giving rise to a sunburn-like desquamation. Certain
chemotherapeutic agents (5-fluorouracil, actinomycin D, doxorubicin,
methotrexate, mitomycin C, platinum agents, and the taxanes) can potentiate
these reactions. Such agents are being used more frequently as part
of increasingly more aggressive treatment of head and neck tumors.
Although mucositis can delay the delivery and increase the overall treatment
time, the major limiting factors for final dose determination are the
long-term effects of radiation on normal tissues. The late effects of
head and neck irradiation can include thickening or fibrosis of the
subcutaneous tissues or fibrosis in the temporomandibular joint (which
can cause trismus). In contrast to acute reactions, the magnitude of
the late effects is determined more by the total dose given than by
the daily fraction size. Salivary gland function and taste perception
are altered by radiation.147–149 The loss of saliva is significant
after about 1,000 cGy is given to the glands; this decreased salivary
output may persist for years. Approximately 4,000 to 5,000 cGy cause
permanent loss of salivary gland function. Taste loss is significant
after 4,000 to 4,500 cGy to the oral cavity. The degree of recovery
is dose and volume dependent but it appears that pilocarpine (Saligen®)
can be helpful in reducing side effects.150,151
The decrease in saliva and changes in its chemical composition cause
alterations in the microorganisms inhabiting the mouth, which, in turn,
can cause a marked increase in the number of caries. Aggressive dental
prophylaxis can reduce this problem, and work-up by a dentist with expertise
in these problems is mandatory before radiotherapy is initiated. The
incidence of osteoradionecrosis can be considerably reduced if the necessary
repairs and/or extractions are done pretreatment rather than waiting
until problems occur in a heavily irradiated field.152–154 A delay
of 2 to 3 weeks is required between extractions and the initiation of
radiotherapy to allow adequate healing.
Technologic Advances
Advances in radiotherapy have been tied to advances in technology. Modern
radiotherapy departments use linear accelerators rather than cobalt
60 units, producing sharper field edges and higher dose rates. Megavoltage
electron beams are used to treat the posterior neck nodes to tumoricidal
dosages without risk of spinal cord damage. Computer-controlled multi-leaf
collimators facilitate custom blocking techniques and sequential changes
in field geometry as a patient progresses through treatment. This reduces
morbidity by lowering the dose to adjacent normal tissues. CT and MRI
are used to locate tumors for radiation therapy treatment planning with
many departments having dedicated CT simulators. Figure 86.3 shows a
reconstructed CT scan with a large tumor of the maxillary, ethmoid,
and frontal sinuses outlined on anterior and lateral projections. Information
from such scans is inputted into treatment planning computers to design
individualized optimal treatment plans. Figure 86.4 shows the isodose
distribution from a treatment plan for the tumor shown in Figure 86.3.
Two levels are shown. Note how the radiation dose distribution lies
deeper in the region of the maxillary and ethmoid sinuses but is “pulled”
anteriorly at a level through the frontal sinus, thus sparing the frontal
lobe. Noncoplanar field configurations, often using vertex presentations,
are now fairly standard techniques in many radiotherapy centers. Treatment
field arrangements are verified immediately using a fluoroscopic simulator.
With such techniques, there should be many fewer marginal misses than
in the past.
Curative Radiotherapy
HNSCCs respond to radiation injury through a loss of reproductive capability,
resulting in a clonogenic cell death. This cell-killing ability is essentially
an exponential function of the radiation dosage (within the context
of a given radiation fractionation schema), and so the dosage required
for a given level of tumor control is approximately proportional to
the number of clonogenic cells in the tumor.146 Subclinical microscopic
disease requires a dosage of approximately 5,000 cGy, a 1-cm337 tumor
requires approximately 6,500 cGy, and large (T3 or T4) tumors require
dosages in the range of 7,000 to 7,500 cGy to maximize the chances of
achieving tumor control.155,156 Patients with head and neck tumors are
generally treated with shrinking-field techniques, wherein the various
regions at risk receive dosages commensurate with the tumor mass they
are thought to contain. A typical head and neck treatment regimen involves
at least three separate alterations in radiation field geometry. Dosages
greater than 7,500 cGy may be achieved using interstitial radioactive
implants, which allow the delivery of ultra-high dosages to small volumes
with the dose levels to critical normal tissues kept within safe limits.
Table 86.4 shows representative local control rates and survival data
for patients with SCCs of common head and neck sites treated with definitive
radiotherapy.156 Although the local/regional control rates are excellent
for the small lesions, there is obviously a need for improvement regarding
definitive radiation therapy for larger lesions.157
The choice between radiotherapy and surgery as definitive primary treatment
is dependent on the interplay among many factors.158 For early lesions
of the larynx and the tip of the tongue, the two modalities yield equivalent
local/regional control and survival. However, the functional result
is better with radiotherapy, and so it is the treatment of choice. For
early lesions of the lip or skin cancers of the nose or eyelid, the
ultimate cosmetic result is better with radiotherapy. For sites, such
as the nasopharynx, that are surgically unapproachable, radiotherapy
is the only tenable form of definitive treatment. For early lesions
of the tonsil and tongue (base and lateral aspect), the results are
equivalent to those of surgery, and informed patient choice should guide
the treatment decision. Radiotherapy is also given following diagnosis
of SCC metastatic to the cervical lymph nodes from an unknown primary
site. The treatment fields encompass the probable sites of tumor origin:
nasopharynx, tonsillar fossa, base of tongue, and hypopharynx. The patient
survival at 2 to 3 years ranges from 30 to 60%.159
Accelerated and Hyperfractionated Radiotherapy
An area of current clinical interest in radiotherapy is the use of nonstandard
fractionation patterns in radiotherapy in an attempt to improve the
therapeutic response ratio.160,161 Late radiation effects limit the
total amount of radiation that can be safely given in the standard treatment
schema. The slowly proliferating normal tissues are the dose-limiting
structures for these late effects. Such tissues tend to have large shoulders
on their cell survival curves, which indicates an increased ability
to repair sublethal radiation damage as compared with that of rapidly
proliferating normal tissues.146 Hence, a logical approach would be
to give smaller radiation treatment fractions so as not to exceed the
shoulder on the late-effects tissue cell survival curves and then to
go to a higher total dose. The assumption is implicit that the tumor
will behave like the rapidly proliferating normal tissues in that it
will not have a large shoulder on its radiation cell survival curve
and so a therapeutic gain will result. To avoid inordinately prolonging
the overall treatment time and allowing tumor repopulation kinetics
to become the dominant effect, multiple daily fractions must be given.146,162
A sufficient time interval (generally more than 6 hours) must be allowed
between treatments to allow for adequate repair of sublethal and potentially
lethal damage.
Hyperfractionation refers to giving multiple daily doses such that the
overall treatment time is about the same as for a course of conventionally
fractionated once-a-day radiotherapy.163 Early work using hyperfractionated
radiotherapy for head and neck cancer took place at the University of
Florida.164 Doses up to 8,011 cGy were given using 120 cGy twice daily
with an apparent benefit compared to historic controls. The Radiation
Therapy Oncology Group (RTOG) has subsequently conducted a dose-searching
study with patients being randomized to receive total doses of 6,720,
7,200, 7,680, or 8,160 cGy using 120 cGy twice daily. A preliminary
analysis for 479 patients entered onto the three lower dose arms shows
a trend toward improved local/regional control with increasing dose
(25% vs. 37% vs. 42%, p = .08) without there being any survival advantage.165
The incidence of grade 4 necrosis was 10.0% on the 6,720-cGy arm, 5.1%
on the 7,200-cGy arm, and 13.9% on the 7,680-cGy arm. Data on the 8,160-cGy
arm are not yet available. The European Organization for Research and
Treatment of Cancer (EORTC) has investigated three daily fractions of
160 cGy each for 10 days, a 3-week break in treatment, followed by a
boost to 6,720 cGy with or without misonidazole (a hypoxic cell radiosensitizer),
compared with a third arm of standard fraction radiotherapy alone in
a total of 523 patients. No significant differences in local or regional
control or survival have been reported among the three arms.166
Early mucosal reactions were more severe on the hyperfractionation arms
but late effects were equivalent. The EORTC subsequently conducted a
phase III clinical trial for patients with oropharyngeal cancer.167
This study compared twice-daily treatments of 115 cGy to a total dose
of 8,050 cGy versus a conventional fractionation schema of 200 cGy once
a day to a total dose of 7,000 cGy. Eligible patients had stage T1–2,
N0–1 tumors, with base-of-tongue primaries being excluded. A total
of 356 patients were entered between 1980 to 1987. At the 5-year end
point, local control was 59% on the hyperfractionation arm as compared
with 40% on the conventional fractionation arm (p = .02). Subset analysis
showed that the improved benefit was confined to patients with T3 tumors,
since equivalent results were noted for patients with the smaller T2
lesions. The overall survival difference at 5 years (40 vs. 31%; p =
.08) did not achieve statistical significance. Late normal-tissue toxicity
was equivalent on the two treatment arms.
Accelerated fractionation refers to giving multiple daily doses of such
a size that the overall treatment time is shortened relative to that
of conventional radiotherapy. The fraction size and the total dose given
are generally slightly less than that of conventional radiotherapy.
Wang and colleagues have developed a twice-daily schema using 160-cGy
fractions.169,170 The total daily dose is thus 320 cGy, which is too
high for the rapidly proliferating normal tissues (e.g., mucosa) to
tolerate without a planned interruption in treatment to allow for recovery
and repopulation. No randomized trial has been carried out to evaluate
it, but historic comparison suggests a possible benefit to its use.
Other accelerated fractionation schemes have been used in various pilot
studies, but no randomized trials have taken place.170–173 Another
version of accelerated fractionation that attempts to limit the normal-tissue
acute reaction is the concomitant “boost” regimen proposed
by Ang et al.175 In this approach, the accelerated portion of the radiation
therapy is delivered only during the last phase of treatment when the
proliferation rates of both tumor and normal tissues have been accelerated.
The volume of tissue that receives the twice-daily treatment is limited
to the primary target volume; there are no planned breaks in treatment.
A recent meta-analysis evaluating the clinical use of hyperfractionated
radiotherapy shows improved local control for head and neck tumor sites,175
but only the EORTC study167 described earlier had a tightly defined
set of patient entry criteria. The RTOG has just completed a randomized
trial for patients with inoperable tumors comparing three different
treatment regimens: conventionally fractionated radiotherapy to 7,000
cGy, twice-daily hyperfractionation at 120 cGy per fraction to 7,960
cGy, and the concomitant boost protocol of Ang et al.175 and Mak et
al.176 Preliminary reports indicate that there is better local/regional
control using the concomitant boost approach but that there is no early
survival advantage.
Combined Surgery and Radiotherapy
Very few well-designed randomized trials have compared surgery alone
with combined therapy in any disease site. When treatment is surgery
or radiotherapy alone, local/regional control rates for stages I and
II lesions are in the range of 75 to 90% (depending on disease site).
The local/regional control rates with single-modality therapy are much
less satisfactory in stages III and IV lesions, for which standard medical
practice employs both modalities.
Radiotherapy can be given either preoperatively or postoperatively.
The aims of preoperative radiotherapy are to sterilize microscopic disease
outside the resection field and to shrink the tumor bulk, thus making
the surgery easier to perform. Theoretically, preoperative radiotherapy
should also reduce the risk of disseminating viable tumor cells at surgery.
A dosage of 5,000 cGy over 5 to 5.5 weeks is usually given.176 No significant
problems with delayed wound healing occur at this dosage.
When radiotherapy is postoperative, the surgical resection bed has a
disrupted blood supply. Conventional wisdom says that higher dosages
of radiation are needed because of the increased likelihood of hypoxic
tumor cells, which are less radiosensitive. Generally, one delivers
5,500 to 6,000 cGy in 180- to 200-cGy fractions in a postoperative setting.
Higher dosages are used if the surgical margins are compromised or if
there is a high likelihood of the presence of macroscopic residual disease.
In particular, Peters et al. have found that at least 6,300 cGy should
be given if extracapsular nodal extension is found in the operative
specimen.178 Postoperative radiotherapy has the advantage of being given
to only those patients thought to be at a significant risk for local/regional
tumor recurrence based on a thorough review of the pathologic data.
It has the further advantage of not delaying the surgical procedure,
which for patients with operable disease is the most important treatment
modality.
Preoperative radiotherapy and postoperative radiotherapy were compared
in a randomized clinical trial by the RTOG. A total of 277 patients
with tumors of the oral cavity, oropharynx, supraglottic larynx, or
hypopharynx were entered into the study.140 Patients in the preoperative
arm received 5,000 cGy followed by surgery in 4 to 6 weeks, whereas
patients in the postoperative arm received 6,000 cGy starting 2 to 4
weeks after the surgical resection. A higher percentage of patients
in the postoperative arm completed the combined course of therapy within
protocol guidelines (74 vs. 56%). The 4-year competing-risk local/regional
tumor control was 65% in the postoperative arm versus 48% in the preoperative
arm (p = .04). For the subgroup of 194 patients who completed overall
treatment within protocol guidelines, the local/regional control rates
were 74% in the postoperative arm and 56% in the preoperative arm. There
were no significant differences between the two study arms in complication
or survival rates.
Although it is generally felt that there is little role for debulking
surgery in the treatment of head and neck cancers, there may be situations
where a gross total resection followed by high-dose radiotherapy is
preferable to treatment with radiation alone. A recent analysis by the
Head and Neck Intergroup Study IG 0034 showed that the patients who
were excluded because of positive surgical margins exhibited improved
local/regional control of tumor as compared with a matched set of patients
from the RTOG databases treated with radiotherapy alone.140,178 At 4
years, respective local/regional controls were 44 versus 24% (p = .007).
However, there was no difference in survival. This was not a randomized
trial, and no analysis was made of quality of life with either treatment.
The authors argue for testing the concept in a controlled clinical trial
rather than changing traditional resectability criteria.
Chemotherapy—General
Chemotherapeutic strategies for HNSCC are reviewed in detail under “Chemotherapy
Approaches” below. Systemic approaches to salivary gland tumors,
NPC, advanced skin cancer, esthesioneuroblastoma, and other nonsquamous
cancers are distinct from head and neck cancers at other sites and,
therefore, are discussed separately.
Natural History and Treatment by Site
Salivary Gland
Anatomy
Tumors can arise not only in the major glands but also in the small
foci of salivary gland tissue scattered throughout the upper respiratory
and digestive tracts. The most common sites of minor salivary gland
tumors are the palate, base of the tongue, and buccal mucosa.343–345
The majority of salivary gland tumors arise in the parotid glands, and
about 80% of these are benign. Tumors arising in the submandibular,
submaxillary, or minor salivary glands are much more likely to be malignant.
The largest salivary glands are the parotids, which lie anterior to
the external auditory canals. The facial nerve passes through the parotid
and divides it into superficial and deep lobes. About 80% of the parotid
gland lies in the superficial lobe and 20% lies within the deep lobe.
The internal carotid artery, the internal jugular vein, the cervical
sympathetic chain, and cranial nerves IX, X, XI, and XII are in close
proximity to the deep lobe of the parotid. The parotid’s lymphatic
drainage is to the parotid and upper jugular nodes. These nodal groups
then drain into the nodes at the angle of the mandible, the subdigastric
nodes, or the upper portion of the posterior cervical chain. Depending
on histology, these nodes may be involved. Certain histologies, such
as adenoid cystic carcinoma, tend to invade major nerve sheaths: the
facial nerve and the auricular-temporal branch of cranial nerve V. In
general, the presence of a parotid mass warrants surgical excision since
progression of even benign neoplasms may place the facial nerve at risk.
Fine-needle aspiration may, however, be used when inflammatory or infectious
etiologies are strongly considered.
The second largest glands are the submaxillary (submandibular) glands,
located in the submaxillary triangle of the neck, which lies just anterior
and inferior to the angle of the mandible. Certain tumors of the submandibular
glands may invade along nerve sheaths or perineural lymphatics to spread
to the mandible or the base of the skull. The sublingual glands are
the smallest of the major salivary glands and are located deep in the
floor of the mouth.
Histopathology
Benign lesions account for about 80% of tumors arising in the parotid
glands, 50% in the submandibular glands, and 25% in minor salivary glands.
Tumors of the sublingual glands are almost always malignant. A list
of such tumors is given in Table 86.19.
The basic histologic classification of malignant salivary tumors was
developed by Foote and Frazell (Table 86.20).347 Mucoepidermoid carcinomas
constitute about 26%, 21%, and 10%, respectively, of malignant salivary
gland tumors of the palatal, parotid, and sublingual glands.347 They
are the most common malignant tumor of the parotid.348 Well-differentiated
tumors are characterized by a slow growth rate, a low recurrence rate
after complete surgical excision (about 15%), and rare metastatic potential.
High-grade tumors are more aggressive; the local recurrence rate after
surgery alone approaches 60%.347 About 50% of patients with high-grade
mucoepidermoid carcinoma present with regional metastasis, and 30% develop
distant metastasis.349
Acinic cell carcinomas are usually well differentiated and account
for about 13% of the cancers arising in the parotid glands. Lymph node
metastasis occurs in about 15% of cases.347 Local recurrences
and distant metastases may occur many years after treatment.125,350
Adenoid cystic carcinomas (cylindromas) account for approximately 10%
of parotid gland cancers and approximately 60% of malignant neoplasms
arising in the submandibular or minor salivary glands.347,351–353
An outstanding feature of this neoplasm is its propensity to invade
major nerves and to spread along the perineural sheath. This must be
taken into account in designing treatment. Although these tumors often
follow an indolent course, as many as 40% of patients ultimately develop
regional and/or distant metastasis.354,355
Adenocarcinomas account for 10% of parotid gland cancers but they are
common tumors of the minor salivary glands. The majority of them are
high grade. About 36% of patients either present with or subsequently
develop regional lymph nodes, and therefore the draining lymphatics
need to be addressed in treatment strategies for adenocarcinomas.349
Distant metastases (bone and lungs) are common.
Carcinoma, ex pleomorphic adenoma, arises from pre-existing benign pleomorphic
adenoma. The risk of malignant transformation increases with time: 1.6%
for adenomas of less than 5 years duration and 9.4% for adenomas present
for more than 15 years.356 True malignant mixed tumors are very rare,
constituting about 2 to 5% of all malignant salivary gland tumors, and
are aggressive tumors; the neck nodes become involved in about 25% of
patients.
Primary SCC (Squamous Cell Carcinoma) of the salivary gland is rare,
accounting for less than 3% of all parotid neoplasms. However, given
the rich lymphatic network that permeates the parotids, SCCs of the
skin of the forehead, temple, or ear may metastasize to this region.
Such primary sites must be excluded before the diagnosis of primary
SCC of the parotid can be made. About 50% of patients with primary SCC
of the parotid ultimately develop positive regional nodes, and, again,
the draining lymphatics should be addressed by surgery and usually postoperative
radiation therapy.
The presentation of malignant salivary gland tumors is variable, depending
on site and histology. Facial nerve paralysis is uncommon and generally
indicates a malignant lesion. Tumors of the deep lobe of the parotid
may produce dysphagia, otalgia, or trismus. When the parapharyngeal
space is invaded, there may be cranial nerve IX, X, XI, or XII involvement.
The usual presentation of a submandibular gland tumor is painless swelling
below the mandible.
Staging
Recently, the AJCC and the UICC agreed to changes in the staging system
for salivary gland tumors to bring the two schema into agreement. T-stage
criteria are reproduced in Table 86.21, along with stage groupings.
The N- and M-stage criteria are the same as for the more common HNSCCs.
Treatment
The treatment of benign salivary gland tumors is primarily surgical.
However, there may be a role for postoperative radiation in high-risk
situations. If microscopic disease remains overlying the facial nerve
or a recurrence has developed, postoperative radiation may be effective
in preventing subsequent recurrences.357 These tumors must be followed
for extended periods because of the late recurrence and spontaneous
transformation.125
Surgery is the primary form of treatment for patients with resectable
salivary gland cancer. Early-stage (T1/T1), low-grade mucoepidermoid
cancers should be treated with local excision with free surgical margins.
Such tumors arising in the parotid are treated with parotidectomy with
preservation of the facial nerve. Early-stage, high-grade tumors of
all other histologies are treated with surgical resection plus dissection
of the regional lymph nodes. Such tumors arising in the parotid require
parotidectomy with facial nerve preservation unless the nerve is clinically
involved with disease. Patients with clinically positive neck nodes
should have a neck dissection on the involved side. For many years,
salivary gland tumors were thought to be resistant to conventional photon
irradiation, but now it is recognized that this treatment can be highly
effective when given in a postoperative setting to eradicate subclinical
disease. Postoperative radiotherapy is indicated358 when (a) the tumor
is high grade (any histology, except low-grade mucoepidermoid carcinoma
or acinic cell carcinomas) or is metastatic SCC, regardless of the surgical
margins; (b) the surgical margins are close or microscopically positive
(which often may include tumors involving the deep lobe of the parotid
gland), regardless of the grade; (c) resection has been performed for
recurrent disease, regardless of the histology or margin status; (d)
the tumor has invaded skin, bone, nerve, or extraparotid tissue; (e)
regional nodes are confirmed as positive on neck dissection; or (f)
there is gross residual or unresectable disease.
In the past, patients with T3 or T4 parotid disease required radical
parotidectomy with sacrifice of the facial nerve. Now, unless the facial
nerve is circumferentially encompassed by tumor, nerve-sparing surgery
may be used followed by radiotherapy. Dosages given to the primary
resection site are in the range of 5,500 to 6,500 cGy, depending on
the postsurgical tumor status. In the case of low-grade mucoepidermoid
carcinomas and acinic cell carcinomas, it is generally not necessary
to treat the neck nodes in the N0 neck. For other histologies, the
neck nodal drainage is generally treated to dosages in the range of
5,000 cGy. In the case of adenoid cystic carcinomas, the radiation fields
must include the courses of the adjacent cranial nerves because perineural
spread is common.
The results of treatment depend on both histology and site. In a
series from M.D. Anderson Cancer Center, 5-year survivals were 100%
for 11 patients with acinic cell carcinoma, 95% for 20 patients
with adenoid cystic carcinoma, 90% for 10 patients with low-grade mucoepidermoid
carcinoma, 82% for 20 patients with high-grade mucoepidermoid carcinoma,
70% for 30 patients with adenocarcinoma, and 59% for 16 patients with
malignant mixed tumor. In a retrospective review of 407 patients treated
at Princess Margaret Hospital, primary parotid disease was controlled
by surgery alone in 24% of cases and by surgery and radiotherapy in
74% of cases.359 In a surgical series of submandibular tumors,360 8
of 17 patients with adenoid cystic histology were free of disease after
5 years compared with only 3 of 17 with mucoepidermoid histology. Minor
salivary gland tumors arising in the paranasal sinuses often present
in an advanced stage. Goepfert and colleagues found a 2-year local control
rate of 47% (9 of 19) in patients treated with surgery alone compared
with 76% (26 of 34) in patients treated with surgery and postoperative
radiotherapy.362
For patients with large, inoperable salivary gland cancers, fast-neutron
radiotherapy is an alternative. A randomized clinical trial was
performed comparing neutron irradiation and photon irradiation in patients
with large, inoperable lesions.362 After only 32 patients had been entered,
the trial was closed early for ethical reasons. The tumor clearance
rate at the primary site was 85% for the neutron group versus 33% for
the photon group (p = .01); the clearance rate in the neck for patients
with clinically positive nodes was 86% for neutrons versus 25% for photons.
Actuarial projections showed the 2-year survival at 62% for the neutron
group, compared with 25% for the photon group (p = .10). Ten-year
data on this study continue to show improved local/regional control
on the neutron arm (56 vs. 17%, p = .009) but no difference in survival.208
This appears to be due to distant metastases, which ultimately became
of greater importance on the neutron arm owing to a reduction in deaths
attributable to local disease. A review of the published data on nonrandomized
trials shows a local control rate of 67% for 309 patients treated with
neutrons as compared with 26% for 298 patients treated with conventional
photon radiation.363 Fast neutron radiotherapy is of particular interest
in situations where the surgical alternative would entail sacrifice
of the facial nerve.
An analysis of the University of Washington experience by Buchholz et
al.365 showed no difference in either local/regional control or survival
for patients treated postoperatively with neutrons after surgery that
left behind gross residual disease versus a comparable group of patients
treated with neutron radiotherapy alone. For patients with adenoid cystic
tumors less than 4 cm in size, it was found that the local/regional
control rates with fast neutron radiotherapy were about 75% for both
major and minor salivary gland.365,366 Neutron radiotherapy also appears
to be an effective treatment for large, multiply recurrent pleomorphic
adenomas, although the follow-up period is too short to make a definitive
statement in this regard.367
Control of local/regional disease is only a part of the problem. Table
86.22 shows the incidence of distant metastasis from a series of parotid
tumors as a function of histology.368 This ranges from a low of 8% for
mucoepidermoid tumors to a high of 42% for adenoid cystic tumors.
Although early-stage, low-grade tumors have high cure rates with surgery/radiotherapy,
standard local therapy is not so successful in locally or regionally
advanced metastatic or high-grade disease. Therefore, a moderate amount
of phase II chemotherapeutic study has been conducted in search of effective
systemic therapy for these difficult cases.369
Whereas adenoid cystic carcinoma is a slow-growing neoplasm, the mucoepidermoid
subtype appears to grow faster and more closely resemble HNSCC in its
biologic and clinical behavior. The single-agent response patterns reflect
these differences. Paralleling results in HNSCC, methotrexate has yielded
a 36% response rate in mucoepidermoid cancer. In salivary gland cancers
of other histologies, however, methotrexate has produced only a 6% response
rate. In contrast to methotrexate, doxorubicin is relatively inactive
in mucoepidermoid carcinoma and HNSCC but active in other salivary gland
histologic subtypes.370 These suggestions must be interpreted with great
caution since they are based in large part on retrospective data and
very small patient numbers. Furthermore, response rates do not correlate
well with survival, with the more chemoresistant but slow-growing adenoid
cystic subtype having the longest survival.
Several single-agent studies have been conducted in salivary gland cancers.
Promising results have been achieved with cisplatin, methotrexate, doxorubicin,
and 5-fluorouracil. Tannock and Sutherland conducted a single-institution
review of results with noncisplatin single agents in adenoid cystic
cancer.372 Although achieving one of the lowest response rates (29%),
compared with other single-agent or combination trials, it also revealed
the longest median survival rate (nearly 2 years). More recently, regimens
including cisplatin have been tested. Cisplatin alone or in combination
has been evaluated in over 130 patients and has yielded response rates
in the range of 17 to 100%. Studies have evaluated single-agent cisplatin,
mainly in adenoid cystic carcinomas, and yielded conflicting results.371–382
The combination of cyclophosphamide, doxorubicin (Adriamycin), and cisplatin
is the most extensively studied regimen.372 A recent study with a dose-intensive
cisplatin-based regimen combining all four drugs active in this disease
produced high toxicity without an improvement in response or survival
over single-agent cisplatin or other combinations.378 Hormonal therapy
(based on supportive preclinical work) appears to have limited activity.383
The taxanes are the most promising new agents under study in salivary
gland tumors.
Paranasal Sinus and Nasal Cavity
Paranasal sinus and nasal cavity tumors represent 0.2% of all human
cancers. Roughly two-thirds occur in the maxillary sinus and one-third
in the ethmoid sinus. Frontal and sphenoid sinus cancers are rare—0.3%
of sinus tumors. These cancers are associated epidemiologically with
occupational exposures (woodworking, nickel refining), inhaling noxious
fumes (dioxane, nitrosamine), and tobacco (see “Epidemiology”
above). Although 80% of paranasal sinus cancers are squamous cell, a
variety of other cell types exist and are increasing in frequency relative
to SCC.125
These tumors notoriously present at a late stage; over 80% have bony
involvement at diagnosis by radiographic or clinical examination. This
fact relates to their vague and often protean symptoms: sinusitis is
the most common. The natural history is characterized by local invasion
into adjacent structures: base of the skull and orbit. Nodal and distant
metastases are staged according to standard AJCC criteria for HNSCC,
but primary tumor staging systems exist only for tumors of the maxillary
and ethmoid sinuses. Esthesioneuroblastomas have their own staging system.
The complex anatomy of the paranasal sinuses and nasal cavity and their
proximity to the orbit and skull base pose major problems in staging
and treatment planning. The maxillary sinus can be visualized as a pyramidal
chamber, which is bordered inferiorly by the alveolar ridge and palate,
medially by the nasal cavity, and laterally by the cheek. This tumor
can invade superiorly to the orbit, inferiorly into the alveolar ridge
impinging on the superior alveolar nerve, and posteriorly involving
the trunk of the maxillary branch of the trigeminal nerve and extending
into the skull base. Invasion superiorly into the orbit may frequently
compromise ocular integrity.
The ethmoid sinus is a complex of air cells between the medial walls
of the orbits. The sphenoid sinus is a deep midline structure. Lateral
wall invasion commonly results in an abducens paralysis but can also
cause facial paresthesias and numbness in the first and second divisions
of the trigeminal nerve, as well as ocular palsies. Invasion superiorly
into the cribriform plate often occurs.
The treatment of tumors of the paranasal and nasal cavity has traditionally
been linked to advances in surgical excision along with muscle preservation
or reconstitution for effective prosthesis. Early reports indicated
poor results with 5-year survivors of 20 to 40%. With the advance of
craniofacial resections and improved diagnostic imaging over the last
two decades, some improved success has been experienced in the treatment
of extensive sinus malignancies.332 Traditional surgical therapy of
paranasal/nasal sinus tumors consists of resection with free surgical
margins for low-grade lesions. High-grade malignancies frequently require
combined surgery and radiation therapy. The total maxillectomy involves
transection of the malar bone from the zygomatic process of the frontal
bone, transection of the hard palate, and separation of the maxilla
from the pterygoid plates. Reconstruction requires skin grafting and
maxillofacial prosthetic obturation.
Single-modality therapy is effective in early-stage disease. Radiation
of the cervical or retropharyngeal lymph nodes is limited to the presence
of positive nodes, advanced lesions, or perineurally invasive malignancies.
Results of pre- versus postsurgical radiation are mixed. Wang found
a 58% 3-year disease-free survival with preoperative radiation versus
a 36% 3-year disease-free survival with postoperative radiotherapy.293
However, Jesse found no difference between the two groups.336 A recent
series suggests that in patients with resectable tumors, survival rates
are better in patients treated with surgery and postoperative radiotherapy.336
Radiotherapy data are mixed, with 5-year survivals ranging from 0 to
50%.
In maxillary sinus tumors without bone invasion, surgery or radiation
is equally effective. Once bone invasion has occurred, however, combination
radiation and surgery is the suggested therapy. An exception is seen
in a study that achieved a 3-year disease-free survival of 40% and a
5-year disease-free survival of 35%, in a group of 20 patients of whom
18 had T4 lesions, using megavoltage beams, meticulous technique, and
effective doses.337,338 Additionally, the Japanese experience with chemotherapy
and radiation therapy in conjunction with necrotomy and debridement
also suggests that advances in organ preservation may be possible in
this arena.
SCC of the nasal vestibule, a distinct type of skin cancer, is related
more to tobacco use than to sunlight exposure and presents a difficult
management problem. Nasal vestibule cancers have a distinctly more aggressive
natural history with a worse prognosis than skin cancers of other sites
and, therefore, require more immediate evaluation and treatment.339
Unexpected deep extension may occur in the nasal vestibule itself, upper
lip, and other midface regions.340 Radiation is now the favored approach
for patients without regional node disease because recurrence rates
and survival data appear equivalent to those seen with surgery, the
cosmetic outcome is much better than with surgery, and the morbidity
is low.341 Furthermore, many of the radiation failures can be salvaged
surgically. In patients without clinical neck node involvement, either
surgery or radiotherapy yields 10 to 20% recurrence overall and only
a 3% recurrence rate after primary single-modality therapy of lesions
smaller than 2 cm.342 Large lesions, or those infiltrating the upper
lip, may be treated with external-beam radiation combined with radioactive
implants or paired wedged beam radiation. Regional neck node involvement
is uncommon (6%) at presentation and confers a poor prognosis with a
high (over 50%) recurrence rate despite aggressive local therapy (surgery
and radiotherapy).
Oral Cavity
Both tumor growth and treatment significantly compromise speech and
deglutition, particularly for those patients in whom cancer involves
the tongue, the floor of the mouth, or the mandible. Furthermore, the
diversity of potential sites of cancer development in the oral cavity
and variations of lymphatic drainage and rates of node metastases lend
added complexity to treatment planning.179–181 Despite the fact
that this region is readily amenable to visual examination and bimanual
palpation, more than 50% of patients are diagnosed in advanced stages.
The current T staging of oral cavity primaries is presented in Table
86.5.
SCCs of the lip are the most common oral cavity cancer. Over 90% occur
on the lower lip, usually on the exposed vermilion border, midway between
the midline and the oral commissure. Upper lip cancers most commonly
are basal cell carcinomas.182 Well-differentiated and verrucous cancers
rarely metastasize. Poorly differentiated and spindle cell varieties
tend to grow aggressively and metastasize commonly. Perineural infiltration
of large nerves is indicative of aggressive disease.
Lip
The treatment of lip cancers must consider adequate removal of tissue
to encompass the disease and yet provide the patient with a lip that
functions in speech, chewing, and oral competence and affords adequate
cosmesis.183,184 These goals are achieved equally well with either primary
radiation or surgery when the tumors are less than 2 cm in size or are
very superficial. Larger lesions are best treated with surgical resection
and reconstruction, where there is greater accuracy in evaluating the
extent of tumor and nerve or cervical lymphatic involvement.185,186
Frequently, adjacent precancerous changes are present that can be treated
with surgery (lip shaving and advancement) to prevent recurrences or
the development of second primary tumors.187 For large lesions, primary
reconstruction with local and regional flaps avoids defects that result
from tissue loss with radiotherapy, provides for future reconstructive
and treatment options, and eliminates the risk of osteoradionecrosis
of the mandible. Lesions demonstrating extensive infiltration, bone
involvement, or lymphatic metastases are increasingly managed with combined
surgery and postoperative radiation.
Radiation therapy techniques for management of lip cancers include external
irradiation, interstitial implants, and combinations of both. Either
the more traditional low dose rate or the newer, high dose rate techniques
can be used. Local tumor control rates with irradiation exceed 80%,188–190
with determinant survival at 5 years, including surgical salvage, in
excess of 95%. Similar tumor control and survival rates are reported
with primary surgical excision.191 Confirmed regional metastases decrease
the survival rates to 36 to 55%.188,192 Five-year survival rates for
patients with carcinomas of the upper lip are lower than for lower lip
lesions and range from 40 to 60%.193,194 Involvement of both lips or
the lateral commissure is uncommon. The prognosis for commissure lesions
is not as good as for cancers of other areas of the lip. Cross reported
a 5-year survival rate of 34% for patients with oral commissure carcinoma
(Table 86.6).193
Tongue
Tongue cancers account for 25% of oral cavity SCC and most commonly
arise in the oral portion or anterior two-thirds of the tongue on the
lateral edge or ventral surface. Infiltration of the underlying tongue
musculature occurs early. The intrinsic tongue muscles are loosely arranged,
interdigitating, and endowed with a rich vascular and lymphatic supply,
which may explain the early high rate of regional metastases.
Most patients present with T2 or greater lesions. Prognosis is directly
related to the degree of infiltration and the presence of regional metastases.
The biologic aggressiveness of small (less than 4 cm) tongue cancers
is noteworthy and is reflected in higher rates of occult regional metastases
than similarly staged lesions arising from other oral sites (Table 86.7).
Occult node metastases are present in 30 to 40% of early lesions.195–198
Approximately 40% of patients have clinical evidence of node metastases
at diagnosis.199 Primary echelon node drainage is to the upper deep
cervical lymphatics. Involvement of middle and lower neck nodes (levels
III and IV) is not uncommon. Bilateral nodal involvement may be present
with cancers of the tip of the tongue or those involving the midline
of the tongue. Local/regional recurrence in patients with tongue cancer
accounts for 60 to 70% of cancer deaths.200–202 Distant metastases
account for 15% of deaths and second primaries for 20 to 40%.
The management of carcinomas of the tongue has been significantly influenced
by a better appreciation of the aggressiveness of small, deeply infiltrative
lesions; the high rate of occult lymph node metastases; and an interest
in improving treatment without compromising oral function. Although
surgical excision has been the mainstay of treatment, combined surgery
and adjuvant radiation therapy to include the primary site and regional
nodes is commonly used for most advanced (stages III and IV) cancers
and is being used increasingly for small stage II cancers that exhibit
pathologic indicators of lymph node metastasis or perineural invasion.
For stage I cancers, surgical excision is effective and expeditious
with good preservation of function. For stage II lesions that are infiltrative,
hemiglossectomy achieves excellent tumor control rates and can be combined
with modified dissection of neck nodes (supraomohyoid dissections) to
provide accurate staging information and determination of the need for
adjuvant radiation. Hemiglossectomy may result in some functional morbidity
in terms of articulation and deglutition. Because of this, radiation
therapy may be used in selected cases. Nevertheless, surgery should
remain the mainstay of treatment in oral tongue malignancies. For radiation
to be as effective as surgery in controlling these cancers, interstitial
brachytherapy combined with external radiation is essential. Radiation
doses of 80 to 85 Gy are generally given via external megavoltage radiation
or in combination with brachytherapy. Interstitial treatment requires
precise placement and spacing of implants. Accurate dosimetry is enhanced
by using afterloading techniques in which the radioactive source is
inserted into previously placed hollow tubes. Tracheostomy at the time
of implant should be considered because of the potential development
of tongue edema after implantation. Occult or apparent neck disease
is usually treated using external radiation or radiation combined with
neck dissection.195 The long-term ramifications of radiation therapy
for oral cavity malignancies must also be considered, including radiation
fibrosis with impaired function of the oral structures (including the
tongue), dry mouth, and osteoradionecrosis.
Extension of cancer to the floor of the mouth or the mandible may necessitate
partial mandibulectomy or segmental mandibular resection. Modern reconstructive
techniques with vascularized composite bone and soft-tissue free flaps,
titanium metal prostheses, pedicled myocutaneous regional flaps, and
free bone grafts have improved the functional and cosmetic results of
major mandibular resections. If the neck must be surgically entered
to accomplish adequate resection of the primary tumor, a neck dissection
should be simultaneously performed. When tumors grossly involve bone,
radiation therapy is less effective in these poorly vascularized osseous
tissues and requires high doses that are associated with osteoradionecrosis.
After local failure of interstitial implants, complication rates for
salvage surgical resections are extremely high and are associated with
significant morbidity from fistulization, radionecrosis, and failure
of primary reconstructive efforts. In many cases, control fistulas and
delayed reconstruction with well-vascularized flaps are advantageous.
Although the surgical salvage of radiation failures is often successful
in early lesions, success drops to less than 50% in advanced lesions.
For more advanced primary lesions (stages III and IV), surgery and external
radiation are generally used. Radiation has been administered as either
planned preoperative or postoperative therapy, although currently we
advocate postoperative treatment in most instances. Although no prospective
controlled trials have proved the superiority of combined therapy over
surgery alone, many studies indicate improved local/regional control
rates.6,185,203–205 These improvements have generally been offset,
in part, by an increased frequency of distant metastases and second
primaries. Surgical management generally consists of partial glossectomy
and neck dissection, with the mandibular apparatus spared unless directly
involved. In instances with limited periosteal invasion, coronal and
other partial mandibular resections can be performed that spare mandibular
continuity and maximize function. Where tumors extend to the midline
or involve the tongue base, subtotal or total glossectomy may be necessary.
Modern reconstructive techniques have improved the functional results
of these aggressive resections. Provision for temporary tracheostomy
and prolonged enteral nutrition should be made. Total glossectomy or
sacrifice of both hypoglossal nerves frequently necessitates permanent
feeding gastrostomy or jejunostomy. Current experience indicates that
total glossectomy can often be accomplished without the need for laryngectomy.206
Tumor resection is more difficult after preoperative radiation therapy
unless precise tattooing of intended resection margins is accomplished
prior to therapy. Likewise, the rates of surgical complications, fistulization,
exposed bone, and radionecrosis may be increased with preoperative radiation,
although studies have been conflicting. Because of this, most centers
have adopted a policy of postoperative radiation. With postoperative
radiation, higher doses can be delivered, the extent of disease is precisely
defined, the histologic status of the lymph nodes is known, and high-risk
areas of close margins or residual cancer can be treated to a high dose.
Both ipsilateral and contralateral necks are irradiated, with the dosage
determined by the extent of disease. Postoperative radiation should
begin within 3 to 6 weeks of resection. Interstitial implants are not
used. Close surgical margins require high doses (70 Gy) because of the
difficulty in eradicating even small amounts of tumor in the tongue
after glossectomy.207 Curative radiation alone with surgical salvage
has been shown to be inferior to combined therapy in control of local/regional
disease and in the complication rate, even though survival rates are
similar with these approaches.140,208 Even with combined therapy, estimated
2-year disease-free and overall survival rates for advanced disease
are only 51 and 53%, respectively.209 The 5-year survival rates range
from 50 to 70% for stages I and II to 15 to 30% for stages III and IV
(Table 86.8).200
The management of the neck is of particular interest in patients with
tongue cancer because of the high rate of occult node metastases. For
lesions T2 or greater in size, rates of occult metastases exceed 40%
and some form of neck treatment is generally indicated. When the primary
tumor can be adequately excised via a transoral technique, unilateral
or bilateral neck dissections should be performed based on the location
of the primary disease. Radiotherapy should be used postoperatively
if pathologic indicators are recognized. When radiation alone is selected
for the treatment of primary tumors with neck node metastases, this
treatment is often combined with therapeutic neck dissection.195
Floor of Mouth
Floor-of-mouth cancers occur with a frequency similar to that for tongue
cancer. Early spread to adjacent areas (gingiva and periosteum of the
mandible) is common. The periosteum is a natural barrier to spread.
Fixation of the tongue is a sign of deep invasion. The tumor may extend
to or through the myohyoid muscle, which serves as a natural barrier
to direct spread below the hyoid bone. Lymph node metastases at presentation
are seen in approximately 40% of patients and an additional 20% have
occult lymphatic metastases.196 The occult metastatic rate increases
with the T stage of the primary: T2 tumors have a 40% and T3 tumors
a 70% occult metastasis rate.
First-echelon nodes of lymphatic drainage include the submandibular
and jugulodigastric lymph nodes (levels I and II). Submental node involvement
is unusual. Evaluation for early mandibular involvement is facilitated
by palpation since fixation to the mandible indicates periosteal involvement
and direct bone invasion is present in 50 to 60% of such tumors.
Small cancers (T1, T2) are generally treated effectively by wide resection
or radiation therapy. Little morbidity results from surgical resection
of superficial lesions. Lateral floor-of-mouth tumors can often be resected
transorally and the resection defect closed with the advancement of
adjacent mucosa, skin grafts, or secondary intention. Early cancers
involving the mandible are best treated surgically because bone involvement
compromises radiation efficacy. Surgery remains the mainstay of treatment
for early floor-of-mouth malignancies, achieving excellent functional
and curative results.
Radiation therapy for small floor-of-mouth cancers usually involves
combinations of external radiation and brachytherapy. Decision making
concerning primary therapy takes into consideration the expected functional
result, management of the neck nodes, and risk of osteoradionecrosis.
Radiotherapy for moderate-size (T2) anterior floor-of-mouth lesions
and small or deeply invasive cancers must also include treating bilateral
first-echelon lymph nodes. Rates of occult nodal metastases range from
30 to 40%.
More advanced floor-of-mouth cancers (T3, T4) are generally treated
with resection combined with postoperative radiation of the primary
and regional nodes. These resections require a transcervical approach
and are combined with neck dissection and mandibular resections as needed.
Again, mandibular continuity-sparing procedures with cortectomies can
often be employed. In these instances, we have found that the radial
free forearm (fasciocutaneous) flap offers excellent floor-of-mouth
and tongue reconstructive potential. Large surgical defects are reconstructed
with skin grafts, local flaps, myocutaneous pedicled regional flaps,
and frequently free-tissue transfers. Mandibular reconstruction for
segmental defects is performed primarily with composite free-tissue
transfers.
Doses of radiation therapy for local/regional tumor control are based
on actual tumor volume rather than T stage.210 Interstitial doses of
65 to 75 Gy are recommended for early lesions (1 to 3 cm) if brachytherapy
alone is used or external-beam radiation of 50 Gy combined with 25 to
30 Gy of interstitial radiation. Postoperative doses are given by external
radiation only at doses of 65 Gy over 6 to 7 weeks or preoperative doses
of 50 Gy over 6 weeks. No significant differences in overall survival
rates have been shown when comparing preoperative and postoperative
radiation regimens.140
Treatment results are influenced by the size of the primary tumor, presence
of lymph node metastases, degree of mandibular involvement, and adequacy
of resection. The 5-year survival rates for localized stages I and II
carcinomas of the floor of the mouth range from 60 to 80% (Table 86.9).
Cancers that cross the midline or involve the tongue or the mandible
are associated with 5-year survival rates of 50 to 60%.141 Survival
rates for more advanced lesions (stages III and IV) are less than 50%.
Lymph node metastases decrease survival rates to approximately 25%.
The major advantage of combined treatment (radiation and surgery) in
these patients is improved control of ipsilateral and contralateral
neck disease. Because rates of occult nodal disease are high in advanced
primary lesions, elective treatment of the neck with radiation or bilateral
neck dissections is indicated. Recurrence in the untreated, clinically
negative neck is the most frequent site of failure in patients treated
only with surgery.211
The debate over performing elective neck dissection versus irradiation
remains unresolved. If adequate primary tumor margins are uncertain
or if multiple histologically positive lymph node metastases are detected,
postoperative radiation to the ipsilateral and contralateral neck is
administered. The development of second primary cancers is a major cause
of morbidity and death. Fu and colleagues reported that 55 of 153 (36%)
patients developed second primaries, of whom 30 died of their second
cancer.213 Distant metastases occur in 10 to 15% of patients.212,213
Gingiva and Buccal Mucosa
Gingival cancers occur most commonly (80%) in the lower gingiva posterior
to the bicuspid teeth.213 For both sites, trismus is an ominous sign.
Clinical staging criteria are similar to those for other oral sites.
Overall, regional metastases occur in approximately 15% of gingival
cancers and are rarely associated with buccal cancers.214 Occult metastases
occur in 10 to 20% of patients. Exophytic tumors tend to be papillary
or verrucous in appearance and can be confused with benign hyperkeratosis.
Small, superficial gingival cancers can be effectively treated with
surgical resection or radiation therapy with excellent preservation
of function.215 Generally, the amount of bone resected for small lesions
is minimal and resection can be accomplished transorally. Even larger
lesions requiring partial maxillectomy or alveolectomy can be resected
without external incision. External-beam irradiation is not as effective
in local tumor control once gross bone involvement has occurred. The
intermediate (T2 or larger) lesions are best handled surgically; the
risk of osteoradionecrosis is thereby avoided. For large lesions (T3
and T4), segmental mandibulectomy or maxillectomy is required and adjuvant
radiation is frequently recommended. Elective neck dissection is not
indicated unless the en bloc resection of a large primary tumor requires
neck exposure. For patients in whom no neck dissection is performed,
elective neck irradiation should be considered. Clinically positive
neck nodes warrant neck dissection combined with resection of the primary
tumor.
Buccal carcinomas of early stage (I or II) can be treated equally well
with surgery or radiation. Radiation therapy offers the advantage of
including the draining lymphatics in the treatment fields but also risks
post-treatment fibrosis and trismus. Large primary tumors or tumors
with regional metastases are managed surgically, with the need for adjuvant
radiation determined by the adequacy of resection and risk of suspected
residual disease. Neck dissection is recommended only in cases of clinically
positive lymph nodes with buccal cancers, unless neck access is required
for surgical excision of the primary.
Overall survival rates for gingival and buccal cancers depend on tumor
size, bone involvement, and node metastases. The 5-year survival rates
for lower gingival lesions do not differ from those for the upper gingiva
and range from 78% for stage I to 15% for stage IV disease.216 Surgical
results are clearly superior to those of radiation when bone involvement
is present. Survival rates (5 year) for stages I and II buccal carcinomas
range from 65 to 75%. Determinant survival for stages III and IV disease
varies from 20 to 30%.214 For both gingival and buccal mucosal cancers,
overall survival rates have improved over recent years as surgical management
has replaced radiation therapy as the primary treatment.
Retromolar Trigone
Cancers arising in the retromolar trigone (the narrow band of mucosa
that lies behind the mandibular molar teeth and covers the ascending
ramus) are rarely confined to that gingiva but involve adjacent buccal
mucosa, anterior tonsillar pillar, the floor of the mouth, or posterior
gingiva. Thus, retromolar trigone cancers that involve the anterior
tonsillar pillar behave more like oropharyngeal cancers than like oral
cavity primaries. The risk of clinically positive and occult lymph node
metastases is higher than with other gingival cancers. The frequent
involvement of periosteum mandates partial (rim or marginal) mandibulectomy
as part of the surgical management, even for small lesions. Primary
radiation therapy is reserved for superficial lesions that cover a large
surface area, such as extension to the soft palate or buccal mucosa,
and remain mobile. Moderately advanced or deeply invasive lesions are
best treated with surgical resection (mandibulectomy and neck dissection),
followed by radiation therapy if pathologically indicated, unless the
functional or cosmetic result would be unacceptable to the patient.
Oropharynx
The clinical staging of oropharyngeal cancers depends primarily on tumor
size and is similar to the staging of oral cavity cancers (Table 86.10).
Although tumors may arise from any site in the oropharynx, most commonly
they arise from the tonsillar area and palatine arch. The most common
presenting symptom is chronic sore throat (often unilateral) and referred
otalgia. Change in voice, dysphagia, and trismus are late signs. Regional
lymphatic metastases occur frequently and are related to the depth of
tumor invasion and tumor size. Upper cervical nodes are generally first
involved, but lower nodes can become clinically involved with skipping
of the upper first-echelon nodes. Bilateral lymphatic metastases can
occur, particularly with cancers of the soft palate, tongue base, and
midline pharyngeal wall.
Tonsil
These cancers tend to be superficial, better differentiated, and of
an earlier stage than other oropharyngeal tumors. The treatment of early
tonsillar neoplasms (stages I and II) is usually radiation therapy alone.
Transoral wide local excision of small, superficial lesions may be effective
but does not address the potential of subclinical lymph node metastasis.
Deeply invasive cancers require extensive resections of the pharyngeal
wall or mandible.217,218
Radiation for early cancers offers the advantage of treating upper-echelon
lymph nodes. Treatment is usually unilateral unless extension to the
tongue base or midline soft palate is present that warrants treatment
of contralateral lymphatics. Ipsilateral treatment portals allow sparing
of the contralateral mucosa and salivary glands. Because much of the
tumor may be hidden from external-beam photons by the mandible, deeper
dose calculation with electron beam therapy is used, which can be combined
with a small interstitial implant if invasion of adjacent tongue is
present. Early cancers of the tonsillar pillar are less effectively
treated with radiation alone than are cancers confined to the tonsillar
fossa.219
Radical radiotherapy to lymph nodes controls approximately 90% of limited
nodal disease (N1) if the primary tumor is controlled, but nodal failure
increases to more than 20% if failure occurs at the primary tumor site.
Overall 5-year survival rates for patients with advanced primary tumors
or regional metastases are generally less than 25% with single-modality
therapy.219–222 Combinations of surgery and radiation therapy offer
improved rates of local and regional tumor control, which, in some studies,
has translated into improved survival.137,219,223 Similar tumor control
and survival rates have been reported for stage III (T3N0) patients
without nodal metastases who are treated with radiation alone or combined
surgery and radiation or surgery alone (Table 86.11).224,225 In general,
preoperative or postoperative radiation for advanced (stage III or IV)
cancers of the tonsillar fossa is recommended, combined with resection
to include the tonsillar fossa and regional nodes. In some instances,
advances in surgical approaches may allow for sparing of the mandible,
but composite resection of the pharynx, mandible, and neck remains a
frequent surgical approach. Postoperative rather than preoperative radiation
is currently preferred because it allows more accurate assessment of
surgical margins, local extent of disease, and degree of lymphatic involvement
and is associated with lower rates of surgical complications.
Tongue Base
Base-of-the-tongue cancer poses a more difficult therapeutic problem
than do tonsillar carcinomas. The 5-year survival rates are lower, metastases
are more common, early diagnosis is less common, and treatment morbidity
is greater. Because of the functional difficulties from wide local excision,
even of small tongue-base cancers, most early (T1, T2) tumors are treated
with definitive radiation. Three-quarters of patients are first seen
with stage III or IV disease, primarily because of the early development
of regional metastases, even with T1 or T2 tumors. Understaging of the
primary tumor is frequent because these cancers tend to be diffusely
infiltrative beyond their clinical appearance. This may account for
similarities in local tumor control rates for both “early”
and advanced lesions. The poor outcome is largely attributable to late
diagnosis.226
The staging of tongue-base carcinomas is principally dependent on primary
tumor size and the extent of regional metastases. Lymph node involvement
is present in approximately 60% of patients with small (T1, T2) primaries227
and is the major determinant of prognosis. Overall 5-year survival rates
range from 11 to 45%.228,229 The 5-year survival rates decrease from
over 60% for N0 patients to less than 30% for N1 patients.37,228,230
The results of radiation therapy alone as definitive treatment for small
primary tumors (T1, T2) are better for exophytic than for deeply invasive
tumors.227 Radiation alone is generally reserved for those patients
without clinical node metastases but can be combined with salvage neck
dissection for patients with clinically positive nodes that persist
after the completion of radiation. Local recurrence is more frequent
after radiation alone in most series,227,228,231 and salvage of local
failure with subsequent surgery is poor. In selected patients, interstitial
radiation therapy has been used to treat residual palpable disease after
external-beam radiation in anticipation of better local control. The
use of brachytherapy is associated with high rates of soft-tissue necrosis
and osteoradionecrosis, however.232,233 The results of supplemental
interstitial therapy appear to be highly dependent on the dose and technique,
with the best results reported with extensive percutaneous lateral cervical
loop implants to include treatment of the lateral oropharyngeal wall
and pharyngoepiglottic fold.234 The acute morbidity with implantation
techniques is severe and results in massive tongue edema that necessitates
tracheostomy in all patients. The use of either twice-daily, hyperfractionated
radiotherapy or concomitant chemotherapy and radiotherapy appears to
result in improved tumor control without many of the complications associated
with implants for the larger tumors.235,236
Surgical management of small primary tongue-base tumors (T1) achieves
results similar to those from radiation alone. In most cases, primary
tumors are moderately advanced and require transcervical resection via
mandibulotomy or lateral pharyngotomy approaches, combined with elective
or therapeutic neck dissection. Local tumor control rates are superior
to those with radiation alone,227,228 but regional control is poor if
clinically positive nodes are present. Elective neck dissection can
serve an important role as a staging procedure, thereby providing a
rationale for adjuvant radiation therapy. To date, no prospective randomized
trial data are available that compare surgery alone with combined surgery
with either pre- or postoperative radiation. Survival rates do not differ
substantially by stage of disease for patients with tongue-base cancers,
except for those with stage IV disease (Table 86.12).
Soft Palate and Pharyngeal Wall
These cancers are less common than other oropharyngeal neoplasms. Most
soft palate cancers occur on the anterior surface of the palate and
tend to be superficial. Regional metastases are uncommon, although lateral
extension to the tonsillar area results in an increased rate of lymph
node involvement and lesions close to the midline result in bilateral
or contralateral neck metastases in 15% of patients. Occult node metastases
are estimated to occur in 16% of patients.237 Posterior wall lesions
tend to be superficial with less tumor bulk than similarly staged lesions
elsewhere in the oropharynx. Tumor extension to the tongue base decreases
survival and increases the rate of metastases, which are often bilateral.
Advanced lesions with deep invasion have ready access to the prevertebral
space, infratemporal fossa, and skull base and can be associated with
extensive submucosal spread with clinical “skip” areas.
Radiation alone as curative treatment is preferred in most cases, even
for T3 or T4 primary tumors.238 Resection of all but the smallest soft
palate lesions is associated with significant functional disability.
The rates of occult regional metastases are difficult to determine because
elective irradiation of bilateral nodal groups is included as part of
primary treatment and must include the retropharyngeal lymphatics. Clinically
positive lymph nodes at presentation occur in 30% of patients. Small
primary tumors with positive nodes can be effectively treated with definitive
radiation to the primary tumor and neck. Neck dissections should be
initiated if disease in the neck persists for 6 weeks following the
completion of external-beam therapy. Extensive pharyngeal wall cancers
or palate cancers with extension to the tonsil and those cases with
advanced regional metastases are usually treated with combined surgical
resection and postoperative radiation. Overall 5-year survival rates
for soft palate and facial pillar cancers are 60 to 70% and range from
80 to 90% for T1 or T2 lesions to 30 to 60% for stages III and IV lesions.227
Local/regional recurrence is the most frequent cause of failure.239
Hypopharynx
The hypopharynx represents one of the most lethal sites of SCC. Lymph
node metastases are clinically evident at time of diagnosis in 70 to
80% of patients119,120,240 and are indicative of advanced disease. Bilateral
and contralateral lymph node metastases occur in 10 to 20% of cases,
particularly if tumors cross the midline of the hypopharynx. Primary
tumor extension beyond the hypopharynx is common.241,242 Hypopharyngeal
cancers are characterized by a propensity to spread submucosally to
involve the oropharynx or esophagus. Ulcerated, deep infiltration and
“skip areas” are common. This leads to difficulties in adequately
assessing the margins of the tumor and contributes to poor local tumor
control, even with the addition of adjuvant radiation.242 The majority
(over 75%) of hypopharyngeal cancers arise in the pyriform sinus, whereas
20% occur in the posterior pharyngeal wall. Postcricoid cancers are
rare (less than 5%). Posterior pharyngeal wall cancers tend to grow
superficially and only involve the prevertebral fascia in advanced lesions.
Pyriform cancers spread early to other contiguous structures, such as
the larynx, postcricoid area, thyroid gland, and thyroid and cricoid
cartilages. Most pyriform sinus cancers arise along the medial wall
followed by the lateral wall of the sinus. The postcricoid mucosa is
contiguous with the apex of the pyriform, and the tumor can spread circumferentially
to involve the entire lower hypopharynx. Because of the locale of hypopharyngeal
cancers and their growth patterns and proximity to the larynx, surgical
management generally entails partial or total pharyngectomy combined
with laryngectomy.123
The staging of hypopharyngeal cancer is based both on the subsite of
the pharynx involved and the size of the tumor, the presence of vocal
cord fixation, and the extent of lymph node metastases (Table 86.13).
Distant metastases at the time of diagnosis are rare. Staging evaluation
is critical for treatment planning and must include endoscopic evaluation
to determine precisely the tumor margins, extent of invasion of adjacent
structures, and presence of second primary tumors or “skip areas.”243
Determination of the precise site of origin and inferior extent of a
tumor can be difficult with large tumors or with those obstructing the
esophageal inlet.
Because of the necessity to remove the larynx as part of the surgical
treatment of most hypopharyngeal cancers, radiation therapy alone as
treatment has been extensively investigated.244 Retrospective analyses
have consistently demonstrated that survival rates are lower and local/regional
failure rates higher with radiation alone as compared with surgery or
surgery and radiotherapy.120,142,241,242,245,246 However, for small
(T1) cancers of the hypopharynx, and, in particular, for superficial
posterior pharyngeal wall lesions, radiation therapy alone has been
used effectively, with surgery reserved for salvage.247,248 Radiation
therapy offers the advantage of treating bilateral occult lymph node
disease, including retropharyngeal nodes, which are frequently involved
when cancer arises from the posterior pharyngeal wall.249 Small cancers
of the hypopharynx can be treated equally effectively with surgical
resection, often with sparing of the larynx for posterior wall lesions
or with supraglottic laryngectomy for superficial cancers of the medial
or lateral pyriform when the apex mucosa is tumor-free. Most patients,
however, present with advanced primary tumors (T2–T4) and positive
lymph nodes. In such patients, local control rates with radiation alone
decrease to 50% and salvage surgery is rarely successful. Thus, surgical
management has become the mainstay of treatment for most hypopharyngeal
cancers. Resections may entail partial pharyngectomy, pharyngolaryngectomy,
or total pharyngectomy combined with neck dissection.
Tumors arising in the lower laryngopharynx or postcricoid mucosa often
spread to involve the esophagus. Distal submucosal spread in the esophagus
can be extensive and require partial or total esophagectomy. Reconstruction
with transposition of the stomach (gastric pullup) or jejunal free graft
is currently recommended.250–252 Following the advent of total
laryngopharyngectomy and postoperative radiation therapy, disease recurrence
more commonly occurs in distant sites (i.e., the lung). Treatment approaches
with combined preoperative or postoperative radiation have improved
the control of lymph node disease, but survival rates have not improved
substantially over those with surgery alone because of the increased
rates of distant metastases. Postoperative radiation is currently preferred
to preoperative radiation because of its lower local recurrence rates,
fewer complications, and less difficulty in accurately assessing tumor
margins.242 The clear superiority of combined surgery and radiation
over surgery alone has not been established.124,241,242,253 Although
several studies demonstrate improved survival with combined therapy,120,245
direct comparisons with surgery alone are difficult because of differences
in patient selection factors, tumor extent, and degree of lymph node
involvement. Well-designed, randomized trials to compare surgery alone
with combined therapy have not been performed.
The presence of lymph node metastases, extracapsular lymph node involvement,
and direct extension of the primary tumor into the soft tissues of the
neck are major negative prognostic factors. Overall 5-year survival
rates range from 10 to 30% for posterior pharyngeal wall cancers,247,248,254–256
and from 20 to 40% for pyriform sinus cancers (Table 86.14).119,120,124,142,245,246
Local/regional recurrence continues to account for the greatest number
of deaths from disease.124,257
Distant metastases are rarely evident at the time of presentation. The
development of distant metastases may appear many years after primary
therapy and seems to correlate with extent of regional lymph node involvement.120,258
The rates of distant metastases range from 20 to 50%120,124 and increase
with the extent of lymph node metastatic disease. In a recent study
by the EORTC, induction chemotherapy and radiation therapy were used
for stages II and III hypopharyngeal cancers. In these randomized trials,
which compared laryngeal preservation with combination chemotherapy
and radiation therapy with surgery with postoperative radiation therapy,
survival (including surgical salvage) remained equal. Approximately
30% of patients with stage III disease can preserve their larynx.
Larynx
Because of the prominent role the larynx plays in speech communication,
swallowing, respiration, and protection of the lower airway, the treatment
of cancer of the larynx presents formidable functional consequences
in addition to the intrinsic threat to life posed by these cancers.
Unique to this particular site of head and neck cancer, quality-of-life
issues have been incorporated into treatment decision making more extensively
than for other cancer sites.259 Cancer of the larynx is generally diagnosed
at an earlier stage of development than are other head and neck sites,
primarily owing to the early manifestation of symptoms. As a result,
cure rates are generally higher than for other sites.
The three laryngeal subdivisions (see “Anatomy” above) form
the basis for classifying cancers arising at the different sites within
the larynx and have clinical importance in the embryologic development,
vascular and lymphatic anatomy and the patterns of tumor growth in the
larynx, and in the frequency of metastases. The characteristics used
in the clinical staging of primary tumors arising in each of these major
subdivisions differ (Table 86.15).
Considerable attention has been devoted to anatomic studies of the vascular
and lymphatic compartments of the larynx.260–263 These studies
have formed the basis for defining natural anatomic barriers to cancer
spread within the larynx and have contributed to the development of
precise surgical techniques for partial laryngeal resections for small
cancers.
The true vocal cords present an effective apparent boundary between
supraglottic and subglottic lymphatic spread within the larynx. This
separation breaks down with tumors involving the anterior or posterior
commissures and with deep invasive tumors that extend vertically across
the true and false vocal cords (transglottic cancers). Normally, the
internal perichondrium of the thyroid cartilage also presents an effective
barrier to cancer spread. However, cancer involvement of the anterior
commissure or transglottic extension is associated with invasion of
the thyroid cartilage in 40 to 60% of cases.264,265
Early diagnosis is critical for achieving high survival rates and larynx
preservation.266 Most cancers that are diagnosed at an early stage of
development arise in the glottic larynx. This is so because minimal
changes in the mass of the vibrating vocal cord due to tumor growth
result in changes in its vibrating characteristics evident as dysphonia
or hoarseness. Supraglottic cancers are usually more advanced than glottic
cancers at the time of diagnosis because they do not generally produce
early symptoms of hoarseness. Rather, the earliest symptoms of a supraglottic
cancer are usually sore throat, dysphagia, referred otalgia, or the
development of a neck mass representing regional metastasis. Airway
compromise may be an early symptom with subglottic cancer.
Modern clinical evaluation of laryngeal cancers includes indirect mirror-assisted
or fiberoptic laryngoscopy, direct laryngoscopy, CT, and MRI scanning
of the larynx and neck, as well as videostroboscopic analysis. These
radiologic assessments are of value in assessing direct extension to
the pre-epiglottic and paraglottic spaces of the larynx, detecting cartilage
invasion, and evaluating the soft tissues and lymph nodes of the neck.
These studies have replaced conventional tomography and contrast laryngograms.
The precise evaluation of tumor extent demands direct laryngoscopy under
anesthesia. With large obstructive tumors, this may necessitate prior
tracheostomy. In some patients with large obstructive lesions, debulking
the tumor mass at the time of direct laryngoscopy can obviate the need
for tracheostomy and thereby reduce the potential risk of tumor seeding
of the tracheostomy site. Even with precise clinical evaluation, inaccurate
estimation of tumor extent (usually underestimation) occurs in 30 to
40% of cases.267 Most often this involves failure to identify invasion
of the laryngeal cartilage framework. Nevertheless, with clinical examination
confirming normal vocal cord function and the absence of anterior commissure
involvement, there is no clear role for radiologic imaging of the larynx.
Supraglottic primary tumors account for 25 to 50% of all laryngeal cancers.268,269
A knowledge of the laryngeal compartments aids in understanding the
spread and staging of supraglottic and glottic cancers. The staging
of supraglottic cancers is based on the subsite or region of the supraglottis
involved in the cancer. Subsites include the false vocal cords, arytenoids,
lingual and laryngeal surfaces of the epiglottis, and aryepiglottic
folds. The epiglottis itself is also subdivided into the region extending
above the plane of the hyoid and that below the hyoid. Suprahyoid epiglottic
tumors tend to have a better prognosis than infrahyoid cancers with
the exception of those invading the aryepiglottic fold (marginal area)
to involve the pyriform sinus. Early cancers (T1 and T2) involve one
or more subsites but have normal vocal cord motion. Those cancers that
cause fixation of the vocal cord or involve the postcricoid region,
medial wall of the pyriform sinus, or pre-epiglottic space are staged
T3. Those that extend beyond the larynx or invade thyroid cartilage
are staged T4.
Glottic carcinomas are also staged according to the subsites involved.
Cancers limited to the true vocal cords are T1 (T1a—one vocal cord
involved, T1b—both vocal cords involved) and those with extension
to the false cord above or the subglottis below are staged T2. Vocal
cord fixations are classified T3, whereas those with cartilage involvement
or extension outside the larynx are T4.
Subglottic cancers that are limited to the subglottic region (T1) or
to the subglottis and true vocal cords (T2) are early cancers. Fixation
of the vocal cord (T3) and cartilage invasion or extension outside the
larynx (T4) are associated with a worse prognosis. The nodal classification
for staging is the same as for other HNSCC sites.
Curative radiotherapy is generally the treatment of choice for early-stage
laryngeal lesions. It is for the moderately advanced lesions that one
must consider the trade-offs between definitive radiotherapy with salvage
surgery held in reserve and a surgical approach. The patient must be
brought into the decision-making process when the various treatment
options are being formulated.
A treatment algorithm for premalignant and early glottic malignancies
is shown in Figure 86.5. Obviously, examination under anesthesia and
biopsy is the gold standard in the assessment of early lesions, with
radiographic imaging reserved for assessment of the paraglottic space
when decreased cord mobility is noted and thyroid cartilage if an infiltrative
lesion of the anterior commissure is noted. Certainly, radiation therapy
remains the management of choice in early glottic cancers. Nevertheless,
in some instances, patients may choose conservative laryngeal surgery,
including endoscopic laser excision of localized lesions or partial
laryngeal surgery; both require frozen-section analysis of margins if
the patient and tumor factors support such an approach. Additionally,
in some instances, conservative laryngeal surgical salvage may be attempted
in those 10 to 20% of cases where external-beam therapy has been unsuccessful
in stages I and II cancers.
The design of the radiation portals must be tailored to the individual
patient, but some general comments can be made. In general, supraglottic
tumors have access to a richer lymphatic drainage than do tumors of
the glottic larynx and so radiation fields tend to be larger in order
to treat the larger volume at risk for metastatic disease.270 Typically,
one treats the primary tumor volume and regions at risk for subclinical
metastatic disease to 5,000 cGy and then reduces the field size to areas
of gross disease and delivers an additional 2,000 to 2,400 cGy. The
spinal cord is shielded at 4,500 cGy and megavoltage electron beams
are used to treat the posterior cervical nodes to higher doses as required.
Because of the V shape of the anterior neck, wedge-compensating filters
are often required to ensure uniform radiation dose distributions. If
the anterior supraclavicular fossa is at risk for micrometastatic disease,
it is treated to 5,000 cGy using an anterior field suitably matched
to the upper neck fields. Early-stage (T1-2N0) glottic lesions are generally
treated with relatively small fields localized to the primary tumor.
Tumors of the subglottic larynx can spread to the upper paratracheal
nodes and to the nodes in the cervical chain, and radiation fields for
this disease must, therefore, include the upper mediastinum.271
The treatment of more advanced laryngeal cancers (T3 and T4) has historically
included surgery with or without radiation therapy. Prospective randomized
studies have shown convincingly that chemotherapy and radiation therapy
(including surgical salvage) are equally effective in the long-term
survival of patients with T3 laryngeal cancers as compared to surgery
with or without radiation therapy. It is important to note that approximately
60% of patients may preserve their larynx, and thus a significantly
better quality of life is preserved.259,272 Speech communication profiles
are clearly better in patients treated with organ-sparing approaches,
and they suffer no deterioration of swallowing function.273 However,
local control is poorer for patients with T4 lesions. Current standard
of care argues that laryngeal preservation protocols be considered in
treating such patients. A treatment algorithm for advanced glottic cancers
is shown in Figure 86.6.
Many surgical procedures for laryngeal carcinoma involve the creation
of a tracheal stoma. This area is sometimes at significant risk for
tumor recurrence, which is most likely associated with peritracheal
metastases that erode into the peristomal area. For this reason, bilateral
peritracheal dissections should be performed in T4 glottic cancers and
radiation therapy provided postoperatively if metastases to this echelon
of nodes are found pathologically. Once a stomal recurrence has developed,
the prognosis is very grave regardless of whether it is treated with
surgery or radiotherapy. Sisson and colleagues report on a series of
28 patients with stomal recurrences treated with one or more surgical
resections.275 The 5-year survival was only 17%. Schneider and colleagues
report on patients with tracheal recurrences treated with radiotherapy;
good palliation of local pain and/or bleeding was achieved, but the
2-year survival was only 6%.276 Given the poor results with salvage
therapy, it is clearly better to prevent stomal recurrence in the first
place. If risk factors for stomal recurrence are present (Table 86.16),
then the tracheal stoma should be irradiated as part of the initial
management.
Supraglottic
Important factors in selecting therapy for supraglottic cancers are
tumor location and pre-epiglottic extension. Tumors limited to the suprahyoid
epiglottis are amenable to radiation with fields that encompass neck
regions at risk for lymphatic metastases. Additionally, some proponents
of limited surgical interventions recommend endoscopic laser excision
with observation of the neck for N1 disease. An algorithm for early
supraglottic cancers is shown in Figure 86.7. Tumors involving the aryepiglottic
folds, pyriform sinuses, or infrahyoid epiglottis tend to be more aggressive,
are deeply infiltrative, and frequently involve the pre-epiglottic space.
Radiation alone is less effective than surgery, resulting in more frequent
local recurrences that require surgical salvage. Often these recurrences
are difficult to detect early enough to allow salvage by laryngeal conservation
surgery and, therefore, require salvage total laryngectomy. Persistent
postradiation edema of the supraglottic larynx is not uncommon and contributes
to difficulty in detecting recurrence, which occurs in 40 to 50%.276–278
Pre-epiglottic extension of cancer carries a poor prognosis. However,
these situations can be managed effectively with horizontal supraglottic
laryngectomy, which allows preservation of the voice. Indeed, even advanced
tumors with extension of cancer to the valleculae and tongue base can
often be treated by supraglottic laryngectomy with results equal to
those of total laryngectomy. Very superficial tumors of the suprahyoid
epiglottis can also be treated with simple epiglottectomy. Because supraglottic
laryngectomy is associated with variable degrees of postoperative aspiration,
adequate pulmonary status is a prerequisite for this surgery, as is
intact mobility of the true vocal cords.
In every patient undergoing supraglottic laryngectomy, preoperative
permission must be obtained for total laryngectomy in case the surgical
findings dictate that more extensive surgery is needed to extirpate
the cancer. Approximately 20% of patients require prolonged tracheostomy,
and this is usually related to edema secondary to postoperative radiation.
The rates of persistent swallowing difficulties are low, however, and
the need for completion laryngectomy for persistent aspiration ranges
only from 0 to 5%.279–281
The frequency of neck node metastases is high with T2 or greater tumors.
Treatment of the clinically negative neck may be accomplished with surgery
or radiation. Surgical approaches should include removal of bilateral
primary nodal groups at risk (levels II, III, IV) for occult disease.
For N0 disease, most authors advocate elective modified radical dissection
or selective dissection of nodal groups.282–284 Others argue that
neck dissection can be delayed until clinically evident metastases occur.285,286
For T1 and T2 lesions, most authors demonstrate overall cure rates of
68 to 73%283,287 with determinate 3-year survival rates of 80 to 85%268,282,288
when elective neck dissection is included. Most recurrences occur in
the neck, and this argues for prophylactic neck treatment.
Radiation is also effective for early lesions. Local control rates for
patients with supraglottic tumors treated with radiation alone range
from 68 to 94% and survival rates from 50 to 89%. The latter set of
survival figures is comparable to those for planned surgery and adjuvant
radiotherapy, which range from 46 to 90%. Although the figures are comparable
for T1 and T2 lesions, there is a trend favoring the combined approach
for larger lesions. Nonrandomized series from different institutions
are not strictly comparable since unstated patient selection factors
are generally involved. For example, the excellent local control results
by Goepfert and colleagues for T3 and T4 lesions are for a selected
set of tumors that were exophytic in nature.290 Survival rates tend
to run lower than local control rates for supraglottic tumors because
of deaths from second primaries and other intercurrent diseases. Cure
rates range from 73 to 75%290–292 and increase to 80 to 85% with
the addition of surgical salvage.293–295 Most recurrences are local
and preservation of voice is successful in 65 to 70% of patients when
salvage surgery is included.295,296
The treatment of more advanced supraglottic cancers (T3, T4) remains
controversial. Laryngeal preservation remains a focus on this population
as well, however. A patient management algorithm is shown in Figure
86.8. In cases with clinically evident regional metastases, combined
surgery and postoperative radiation are usually recommended since this
treatment approach is associated with better local control rates297
and better control rates for neck disease in both the ipsilateral and
contralateral neck.298 Approximately 50% of patients have clinically
palpable lymph nodes at the time of diagnosis and 20 to 25% have bilateral
nodal involvement. In the clinically negative neck, elective neck dissection
shows cancer metastases in 15 to 30% of patients. Failure to control
disease in the neck is a major cause of mortality in advanced supraglottic
cancers. In most reports, radiation alone for the control of supraglottic
cancers with N2 or N3 nodes is clearly inferior to combined therapy.
Therefore, in instances where T1–T3 lesions of the supraglottis
are associated with N2 or N3 disease, neck dissection should be performed
when the primaries are treated by radiation therapy. Although the issue
of optimal initial management for the patient with N0 disease has not
been settled, an individualized approach has been recommended in which
bilateral selective node dissections are performed. Postoperative radiation
is reserved for patients with proven regional metastases.280,299
Overall 5-year survival rates for supraglottic cancers range from 40
to 50% (Table 86.17).295,300 Local failures occur in approximately 10%
of patients and regional failures in 15 to 20%. Rates of distant metastases
range from 11 to 18%,270,295,301,302 with rates approaching 30% in patients
with stage IV disease.295 Second primaries (20 to 25% of failures) are
a major cause of death.295,300 Intercurrent illness accounts for up
to 20% of deaths.300,303
Glottic
The treatment of glottic cancer is greatly influenced by the secondary
goal of voice preservation. Mobility of the vocal cords is a critical
factor in selecting treatment. For small cancers (T1, T2) with mobile
vocal cords, radiation therapy alone for cure achieves excellent local
control rates (T1, 85 to 95%; T2, 65 to 75%) and overall survival rates
similar to those for surgical resection.304,305 Voice quality, although
often impaired by radiation, is generally better than that following
surgical resection.306,307 Local control rates are 10 to 15% better
with primary surgery, but local recurrences after definitive radiation
can often be salvaged by subsequent surgery, and this combined approach
results in overall survival figures comparable to those with primary
surgery. Tumor involvement of the anterior commissure or arytenoids
may be associated with higher local recurrence rates with radiation
alone, but this may historically have been related to understaging.
As with supraglottic cancers, careful clinical tumor staging is necessary
since underestimation of tumor extent is common. The “irradiate
and watch” treatment strategy is predicated on close follow-up
in order to detect recurrences when they are still salvageable by surgery.
Delay in the diagnosis of recurrent glottic cancers after radiation
is more frequent than with supraglottic cancers284 and often requires
total laryngectomy for cure. Thus, unreliable patients, or patients
who are difficult to examine, may be more suitable for primary surgical
treatment.
Survival figures in radiotherapy series are comparable to local control
figures, reflecting the effectiveness of surgical salvage and the fact
that few patients with early-stage glottic cancer die of their disease.
The 5-year survival rates for T1 lesions range from 80 to 95% with either
primary surgery or radiation (Table 86.18). Rates for T2 lesions are
generally in the range of 70 to 80%, but these rates are decreased 10
to 15% (local control rates drop 20 to 25%) when the mobility of the
vocal cords is impaired308 or transglottic spread is present.309 Lesions
with impairment due to invasion of muscle behave more like T3 cancers
and have a poorer response to radiation alone.303,310–313 Transglottic
cancers and those with subglottic extension have higher rates of regional
metastases and often require total laryngectomy for cure. In selected
patients with these more advanced lesions or impaired vocal cord mobility,
extended hemilaryngectomy, or more extensive subtotal laryngectomy with
resection of a major portion of the cricoid cartilage, can achieve excellent
cure rates.314,315 Voice quality is diminished with these extensive
procedures, and chronic aspiration or permanent tracheostomy may result.
Additionally, these procedures are technically challenging and experience
dependent. However, if proper patient selection is accomplished, these
procedures can be well tolerated. Although further study is required,
hemilaryngectomy with postoperative radiation therapy has been advocated
for some patients with close or involved surgical margins.316
Management of advanced T3 glottic cancers has historically consisted
of total laryngectomy with or without postoperative radiation therapy.
Although older series show suboptimal control rates (20–35%) and
survival rates (10–50%) for unselected sets of T3 and T4 tumors
treated with radiation alone, it is now recognized that with proper
selection radiotherapy, control rates for T3 lesions can approach 80%.317
In patients without regional metastases, local tumor control rates with
surgery alone are excellent. Significant increases in local control
with the addition of radiation therapy have not been clearly demonstrated.
However, in patients with regional metastases, overall prognosis is
poor and recurrence in the neck is a major problem when surgery is used
alone. Better regional tumor control rates are achieved with the addition
of adjuvant radiation therapy, and this justifies its use in these advanced
cases.289 Because rates of occult regional metastases approach 30% in
patients with advanced glottic (T3, T4) cancers, elective modified or
selective node dissections for staging purposes are recommended when
surgery is performed for primary disease. Demonstration of histologically
positive nodal metastases has been used as an indication for postoperative
radiation. Surgery alone is curative in 50 to 80% of patients without
nodal metastases138,291,311,318,319and decreases to less than 40% if
metastases are present.309,320,321
Considerable controversy surrounds the use of definitive radiation with
surgical salvage in patients with advanced (T3N0, T4N0) but localized
glottic cancers.138,322 A very large, long-term British study demonstrated
that salvage laryngectomy was possible in less than 50% of patients
who suffered tumor recurrence after definitive radiation.324 The radiation-alone
concept, however, presumes equal overall survivorship as compared with
primary laryngectomy, with associated low complication rates. Overall
survival rates range from 50 to 55%139,320 with larynx preservation
in 60 to 70% of these patients.309,320 High complication rates, however,
have been reported with late surgical salvage of radiation failures.320
The overall patterns are confusing and based entirely on retrospective
series. The resolution of this controversy in management will require
carefully designed prospective studies that include assessments not
only of survival but also of voice and quality-of-life issues and complication
rates.
A subset of laryngeal cancers that warrant special consideration are
those that involve both the glottic and supraglottic regions (transglottic).
These cancers are usually advanced and are associated with a high incidence
(30 to 50%) of regional metastases,309,324 extralaryngeal spread, and
vocal cord fixation. Although clinical understaging is common, occasionally
these cancers are quite superficial and amenable to conservation surgical
techniques. Most patients, however, require total laryngectomy. In a
careful review of 152 cases of transglottic carcinomas, Mittal reported
a 55% cure rate with combined therapy as compared with a 5-year survival
of 8% with radiation alone.310
Subglottic
Primary subglottic carcinomas account for less than 5% of laryngeal
cancers. Limited data may support the use of primary radiotherapy for
early-stage (T1, T2) lesions. However, these lesions are usually advanced
at diagnosis and require surgery (laryngectomy) and bilateral peritracheal
lymph node dissections since regional metastases occur in about 20%
of these patients.325 Many reported series contain glottic primaries
with subglottic extension and confuse these analyses. Surgical treatment
generally requires total laryngectomy combined with resection of adjacent
soft tissues (thyroid gland, strap muscles, peritracheal lymph nodes).
Five-year survival rates of 36% for radiation therapy and 42% for surgery205
have been reported. Also, cure rates as high as 70% have been reported
in a small number of patients treated with combined therapy.325 The
addition of adjuvant radiation offers the advantage of improved regional
control rates and treatment of peritracheal and upper mediastinal lymph
nodes. Histologically positive lymph nodes can be found in 65% of cases.
The risk of stomal recurrence increases substantially with cancers that
involve the subglottic larynx, particularly if prior tracheostomy was
necessary for impending airway obstruction.326 Early aggressive treatment
(often within 24 hours) has been recommended for patients requiring
tracheostomy for subglottic extension of laryngeal cancers.327
Patterns of failure for glottic carcinoma differ somewhat from other
laryngeal sites. Local failures are uncommon with primary surgical therapy
and account for fewer than 10% of recurrences. However, after primary
radiation therapy for local glottic primaries, recurrences account for
10 to 50% of failures.139,323 Regional nodal recurrences are seen in
15 to 30% of patients with advanced disease who are treated with surgery
alone.319 This contrasts to supraglottic cancers where regional recurrences
are a major site of failure.
It previously was thought that distant metastases from laryngeal cancers
were uncommon, accounting for less than 10% of failures. Distant spread
is approximately four times more common with supraglottic than with
glottic cancers.122 Rates of distant metastases associated with glottic
cancer have increased, however, with the use of combined therapy and
have been reported in approximately 20% of patients with advanced disease.139
Rates appear to be directly related to the extent of nodal disease,
with reported rates as high as 40 to 50% of failures attributed to distant
metastases in patients with N2 or N3 disease.
Carcinoma in Situ
A special issue relates to the treatment of CIS of the vocal cords.328,330
This disease often can be managed with vocal cord stripping, but if
enough serial sections are examined, foci of invasive carcinoma are
often found. Pane and Fletcher report on a series of 79 patients with
CIS and seven patients with leukoplakia/atypical hyperplasia who were
treated with radiotherapy.331 Patients were staged as either T1 or T2
using the same criteria as for invasive tumors. Local control rates
were the same as for invasive lesions: 89% for T1 and 74% for T2. However,
only 2 of 12 failures were on the initially involved cord, suggesting
that most were not true recurrences but rather new disease developing
in dysplastic epithelium. Furthermore, it took about 5 years for 80%
of the failures to develop, which further suggests a second process.
Most of the failures after primary radiotherapy tend to be invasive,
whereas failures after vocal cord stripping tend to be equally divided
between CIS and invasive disease.
Very superficial cancers limited to the free edge of the vocal cord
or CIS can be effectively treated by limited excision by conventional
means, or with laser excision, with excellent voice preservation.331,332
More extensive disease requires cordectomy or vertical hemilaryngectomy.333
Numerous methods have been devised for reconstructing the vocal cords
after conservation surgery, although, in fact, they are probably not
necessary if proper patient selection is pursued. Voice results, in
general, are inferior to that with radiation therapy alone for early
lesions. The patient with CIS, however, by inference has diffuse premalignant
mucosal findings and certainly should be targeted for novel prevention
strategies due to the likelihood of later developing invasive disease.
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