Head and neck cancer occurs at an incidence of
approximately 40,000 cases per year. Its primary risk factor is the
combination of tobacco smoking and alcohol. The overwhelming majority
of cases are of squamous cell histology. The disease is characterized
by local and regional presentation. Patients who fail traditional
treatment with surgery and/or radiotherapy most frequently fail
within the head and neck region. Thus, the primary focus of
investigational head and neck cancer therapy is the delivery of more
effective local and regional care.
There are three common clinical presentations of head and neck
cancer. About one third of patients will present with early stage
disease (stage I or II). This is characterized by a small T1 or T2
lesion without clinically overt lymph node involvement or distant
metastases. These patients are treated with curative intent, usually
consisting of single-modality therapy with either surgery or
radiation. Although a small fraction of these patients can develop
recurrent disease, the majority are cured. They do, however, remain
at significant risk of developing second primary malignancies within
the upper aerodigestive tract area.
Approximately two thirds of patients present with locally or
regionally advanced disease (stage III or IV, M0). These patients
have large primaries and/or lymph node involvement. Historically,
they have been treated with surgery (if the disease was resectable)
followed by postoperative radiotherapy. Despite this aggressive
multi- modality approach, disease recurs in the majority of patients
within 2 years in the irradiated field, which underscores the
inability of this therapy to eradicate locally or regionally
The third group of patients presents with metastatic disease at the
time of initial diagnosis (stage IV, M1); however, this is observed
in less than 5% of patients at the time of initial diagnosis. Also
included in this group are patients with locoregionally recurrent
disease following previous radiotherapy or surgery. These patients
are treated with palliative intent, usually consisting of combination
chemotherapy with cisplatin and 5-fluorouracil (5-FU).
The use of chemotherapy is considered separately for the three
clinical categories described above. Many patients with stage I or II
disease are cured following surgery or radiotherapy; therefore, few
investigations involving this patient group have used the addition of chemotherapy.
For patients with stage III or IV, M0 locally or regionally advanced
disease, chemotherapy has been investigated intensively over the past
20 years. At this time, the use of induction chemotherapy (2 to 3
cycles of cisplatin and 5-FU followed by local therapy with surgery
and/or radiotherapy) has not been shown to increase survival;
however, it has allowed for larynx preservation.[1-4] When compared
with surgery and radiotherapy, patients treated with induction
chemotherapy and radiotherapy had no difference in survival, but a
large percentage of patients who survived retained a functioning
larynx. Thus, induction chemotherapy can be recommended for these
patients with the goal of organ preservation, but not the goal of
increased survival. The use of simultaneous chemoradiotherapy, on the
other hand, has been shown to result in increased locoregional
control and survival. This was confirmed by a recent meta-analysis as
well as several recent randomized trials comparing radiotherapy alone
(or surgery followed by radiotherapy) vs the use of radiotherapy with
simultaneous chemotherapy (or surgery followed by simultaneous
chemoradiotherapy).[5-10] As a result, the use of concomitant
chemoradiotherapy can now be considered a possible standard treatment
option for all patients with locoregionally advanced disease.
Finally, patients with recurrent or metastatic disease receive
chemotherapy as the primary treatment modality. The goal of treatment
is prolongation of life and palliation of symptoms. With currently
available regimens, such as cisplatin and 5-FU or cisplatin and
paclitaxel, about 30% to 40% of patients will have at least a partial
response. However, median survival rates have averaged 6 to 7 months
for the last 3 decades.[11-13] The use of newer chemotherapy agents
in this disease setting is of great interest. Current investigations
looking at paclitaxel, docetaxel, vinorelbine, and gemcitabine as
single agents or in combination are in progress.
Clinical experience with oral administration of chemotherapy in head
and neck cancer patients is limited. Nevertheless, given the anatomic
location of the disease, its risk factors, and epidemiology, it is
clear that some special considerations apply to this patient
population (Table 1). Many
patients with cancer of the oropharynx, hypopharynx, or oral cavity
will present with swallowing dysfunction. This includes initial
symptoms of dysphagia or odynophagia due to advanced primary tumor
stage. Similar symptoms can occur as a result of radiotherapy or
chemoradiotherapy while the patient is undergoing treatment. In more
severe cases, patients may aspirate with an associated risk of
developing aspiration pneumonia. Mucositis and candidal infections
frequently occur during the delivery of radiotherapy. Following
completion of radiotherapy, patients experience loss of taste, at
least temporarily. In addition, patients suffer from usually
life-long xerostomia. All of the above symptoms may interfere with a
patients ability or willingness to take oral fluids or food.
Such patients may also be less willing or able to take medications orally.
Other patients may present with gastric or jejunal feeding tubes to
circumvent their inability to swallow sufficient amounts of food. The
crushing or need to solubilize oral medications in order to
facilitate administration via feeding tube may result in variability
in the administered dose and absorption. Finally, head and neck
cancer patients may suffer from hepatic dysfunction, low serum
albumin, or malnutrition that may alter their ability to handle
medications. This latter concern is, however, not unique to orally
Table 2 describes oral
chemotherapy agents that have been studied in head and neck cancer
patients. Of these, hydroxyurea is approved by the US Food and Drug
Administration for use as a radiation sensitizer. Most other agents
have been studied either infrequently or not at all.
5-FU, Hydroxyurea, and Concomitant Radiotherapy
At the University of Chicago, we have developed a regimen consisting
of infusional 5-FU with oral hydroxyurea and concomitant radiation
therapy (FHX). This regimen was based on (1) the observed
single-agent activity of both chemotherapy agents, (2) the
possibility of a synergistic interaction between hydroxyurea and 5-FU
based on the intracellular depletion of dUMP leading to enhanced
binding of 5-FdUMP to its target enzyme, thymidylate synthase, and
(3) the possibility of radiation enhancement by both drugs. The FHX
regimen was shown to have high local and regional activity in
patients with recurrent disease.[14-16] Since that time, we have
studied this regimen in patients with stage II and III disease and
have found high locoregional control and survival rates. We have
also studied the FHX combination (preceded by induction chemotherapy)
in patients with locoregionally advanced stage III and IV
disease.[18,19] Again, highly encouraging locoregional and distant
control and overall survival rates were achieved.
Based on this encouraging activity, we wished to explore further the
possibility of administering the FHX combination as an all oral
chemotherapy (outpatient) regimen. As a first step, we initiated a
phase I study of eniluracil 20 mg administered every 12 hours ×
14 doses with escalating doses of 5-FU administered twice daily ×
10 doses and concurrent, twice-daily radiotherapy (150 cGy/fraction)
for 5 consecutive days. This 5-day chemoradiotherapy regimen was
repeated every other week until completion of radiotherapy (usually 5
cycles or 75 Gy). A final analysis of this study is currently in
progress. Early evaluation suggested that systemic myelosuppression
rather than radiation enhancement was dose-limiting. We are,
therefore, currently investigating alternative schedules of
eniluracil, 5-FU, and concomitant radiotherapy in an effort to
decrease myelosuppression while increasing the potential interaction
of 5-FU and radiotherapy.
This combination of 5-FU and eniluracil is also currently undergoing
clinical evaluation in patients with recurrent or metastatic disease
(without concurrent radiotherapy) in a phase II study conducted by
the National Cancer Institute of Canada. Patients are treated with
palliative intent. Overall response rate is the primary end point of
UFT (tegafur and uracil) has also been studied in head and neck
cancer. Tanaka et al reported on 43 previously treated patients with
recurrent head and neck cancer. The overall response rate was 38%
with a partial response rate of 19% and complete response rate of
19%. Additional trials have evaluated UFT in combination with
cisplatin or carboplatin.[22-24] In a study involving 36 previously
untreated head and neck cancer patients, Gonzalez-Baron reported an
overall response rate of 94% (22% complete response rate) for the
combination of cisplatin and tegafur. The combination of
carboplatin and tegafur resulted in an objective response rate of 62%
(33% CR) in 22 patients. Additional studies evaluating the
combination of carboplatin, tegafur, leucovorin, and cisplatin with
UFT have also been reported.
UFT as Radiation Sensitizer
UFT has also been evaluated as a radiation sensitizer. Fifty-two
patients with larynx cancer were treated with this combination.
Improved disease-free and overall survival was reported as compared
with a historical control group of 113 patients treated by the same investigators.
Intravenously administered etoposide has been shown to be minimally
active in head and neck cancer. Therefore, oral etoposide has been
studied, albeit infrequently. One group of investigators reported on
16 extensively previously treated patients who were administered oral
etoposide 100 mg/m²×5 every 3 weeks; no response activity
Additional orally administered chemotherapy agents include JM-216,
capecitabine, S-1, methotrexate, and cyclophosphamide. No information
on the use of these oral agents in head and neck cancer is available
at the present time.
Orally administered chemotherapy drugs have been shown to have
activity in head and neck cancer. At the present time, the general
use of chemotherapy in head and neck cancer is most promising when
combined with simultaneous radiotherapy. Therefore, the development
of orally administered chemotherapy regimens with simultaneous
radiotherapy is of great clinical interest. This might result in the
feasibility of administering such regimens more easily on an
outpatient basis. However, special considerations do exist, in
particular the high likelihood of increased mucocutaneous reaction
such as exacerbated mucositis and esophagitis, within the irradiated
field. These toxicities and underlying tumor-related symptoms may
render the administration of oral chemotherapy difficult. Given the
possible interactions between several orally administered drugs, in
particular platinum analogues with antimetabolites such as 5-FU, UFT,
or capecitabine, and their mutual ability to enhance the activity of
radiotherapy, the development of combination chemotherapy regimens
with or without concurrent radiotherapy is also of high clinical interest.
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