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---Avraham Eisbruch, M.D.
The incidence of cancer arising in the mucosa of the head
and neck (oral cavity, larynx, pharynx, nasopharynx, paranasal
sinuses, nose and salivary glands) in the United States is
50,000 new cases per year. The main risk factors are alcohol
and tobacco use. The overall cure rate of these tumors is
less than 50 percent, and the major factor contributing to
treatment failure is difficulty in controlling local and regional
(neck lymph node metastases) disease. The treatment modalities
used for head and neck cancer are surgery or radiation therapy
for early tumors, and surgery combined with adjuvant irradiation
for advanced tumors. Recent advances in radiation therapy
include efforts to improve the effectiveness of radiation
and to improve the quality of life of treated patients.
Improving the Effectiveness of Radiation
Two major developments have evolved in recent years
in the practice of radiation for head and neck tumors: 1)
changes in the number and frequency of radiation fractions,
and 2) the addition of concurrent chemotherapy to the treatment
course. Controlled, randomized studies have demonstrated significant
therapeutic advantages of treatments incorporating these developments
over standard radiation.
Changes in the fractionation scheme
The standard fractionation scheme for head and neck
tumors (and for most other tumors) in the United States is
once-daily treatment, delivering 1.8 to 2.0 Gy daily, five
days a week. Microscopic or sub-clinical disease requires
50 to 60 Gy delivered over five to six weeks while macroscopic
tumors require 70 Gy over seven weeks, or more. Doses exceeding
70 Gy are associated with a high rate of normal tissue complications.
Treatments according to this scheme do not, therefore, exceed
70 Gy, while advanced tumors may require a higher dose to
achieve complete eradication. It was found that the delivery
of two daily treatments, each delivering a relatively small
dose (1.15 to 1.25 Gy), allows for some repair of radiation-induced
damage by the normal tissue. These treatment schemes (called
hyperfractionation) allow increasing the total radiation dose
to about 80 Gy without increased rate of complications. Four
randomized studies comparing hyperfractionated to standard
radiation for advanced head and neck tumors have been conducted
and published to date. All the studies reported significantly
improved local and regional tumor control, and three of the
four reported improved survival using hyperfractionation compared
with standard radiation (1).
Combined chemotherapy and radiation
Several chemotherapy agents (bleomycin, hydroxyurea,
methotrexate, cisplatin, 5-fluorouracil) have a high activity
in squamous cell carcinoma of the head and neck. Therefore,
combining chemotherapy with radiation for advanced tumor has
been practiced for many years. Recently, a better understanding
is being gained of the optimal schedule for combined modality
treatments and their benefits compared with radiation alone.
Chemotherapy can be delivered before radiation, achieving
a high response rate (40 to 90 percent). It was anticipated
that tumor shrinkage induced by chemotherapy would enhance
the efficacy of radiation delivered subsequently. However,
randomized studies have shown no benefit of up-front chemotherapy
compared with radiation alone, while the toxicity of the combined
modality treatment has been significantly higher (2). In contrast,
trials of radiation delivered simultaneously with radiation
have shown significant improvement in local-regional tumor
and survival (2-5). A meta-analysis of 11 studies of concurrent
radiation and chemotherapy showed that combined treatment
has reduced mortality rate by 22 percent (2). It is assumed
that the reason for the advantage of simultaneous chemotherapy
over up-front chemotherapy or radiation alone stems from sensitization
of tumor cells to radiation by the simultaneous delivery of
At the University of Michigan, an ongoing study of the combination
of Gemcitabine concurrent with radiation for advanced, nonresectable
tumors is being performed. This chemotherapy drug was found
in preclinical studies to be a potent sensitizer of malignant
cells to radiation. In the clinical trial we have found a
high complete response rate of tumors, as well as significant
mucosal toxicity. Current efforts are aimed at optimizing
the schedule and doses of chemotherapy and radiation to preserve
the high response rate while reducing the severity of side
Figure 1: Left: Standard radiation relies on lateral beams that treat the targets in the neck. These beams include most of the parotid glands. Right: Multiple beams have been derived from CT-based planning, encompassing the targets and sparing major salivary glands.
Improving Quality of Life: Organ preservation studies
Advanced laryngeal cancer has traditionally been
treated with total laryngectomy, compromising patients' speech.
In recent years, trials to preserve the larynx rely on previous
findings that patients whose tumors responded well to chemotherapy
had a high rate of tumor eradication by radiation. A randomized
study conducted by the Department of Veterans Affairs Laryngeal
Cancer Study Group has demonstrated that selecting patients
for radiation if their tumor responded to chemotherapy resulted
in a high rate of larynx preservation (64 percent) and similar
survival compared with patients treated with laryngectomy
(6). More recent studies have shown that it is possible to
avoid mutilating surgery using a similar concept in other
tumor sites in the head and neck (7). At the University of
Michigan, efforts at organ preservation concentrate on delivering
a short course of chemotherapy and selecting the patients
whose tumors respond to chemotherapy. These selected patients
are treated with concurrent radiation and chemotherapy, while
patients whose tumors do not respond to chemotherapy undergo
surgery and postoperative radiation.
Reducing radiation-induced xerostomia
The standard radiation for head and neck tumors
involves administering a high radiation dose to the major
salivary glands bilaterally (Fig. 1). In most cases, this
causes a marked reduction in oral saliva output. The resulting
permanent xerostomia is the most prevalent late side effect
of irradiation for head and neck malignancies and is cited
by patients as the major cause of decreased quality of life.
The cholinergic agent pilocarpin was found to improve xerostomia
in some patients (8). An additional approach is being used
at the University of Michigan to minimize xerostomia. This
approach is based on computed-tomography-based planning and
delivery of radiation. Multiple beams encompass the targets
(tumor and sites at risk for metastases), while avoiding major
salivary glands (Fig. 1). Results from this studies show that
approximately 70 percent of parotid gland salivary flow can
be preserved, and subjective xerostomia questionnaires suggest
improved symptoms compared with similar patients receiving
standard radiation (9). In addition to sparing salivary glands,
a potential for improved irradiation of the targets was demonstrated
in these studies.
Advances in the understanding of the biology of
cancer and radiation, as well as technical advances in the
field, have been translated into clinically significant gains
in the treatment of head and neck cancer. Hyperfractionation
and simultaneous chemotherapy-radiation regimens seem to be
superior to standard radiation. Improving the quality of life
of patients with advanced tumors has been achieved by avoiding
mutilating surgery in selected patients who are likely to
respond to radiation. Advancements in the planning and delivery
of radiation are being used to reduce radiation-related xerostomia
and to improve the irradiation of tumors, suggesting that
an improvement in tumor control may be achieved.
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1. Stuscke M, Thames HD. Hyperfractionated radiotherapy
of human tumors: Overview of the randomized clinical trials.
Int J Rad Onc Biol Phys. 37:259-267, 1997.
2. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy
in the management of squamous cell carcinoma of the head and
neck: A meta-analysis of prospective and randomized trials.
J Clin Oncology. 14:838-847, 1996.
3. Merlano M, Vitale V, Rosso R, et al. Treatment of advanced
squamous cell carcinoma of the head and neck with alternating
chemotherapy and radiotherapy. N Eng J Med. 327: 1115-1121,
4. Al-Sarraf M, LeBlanc M, Giri S, et al. Chemoradiotherapy
versus radiotherapy in patients with advanced nasopharyngeal
cancer. J Clin Oncology. 16: 1310-1317, 1998.
5. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated
irradiation with or without concurrent chemotherapy for locally
advanced head and neck cancer. N Eng J Med. 338:1798-1804,
6. The Department of Veteran Affairs Laryngeal Cancer Study
Group: Induction Chemotherapy plus radiation compared with
surgery plus radiation in patients with advanced laryngeal
cancer. N Eng J Med. 324:1685-1690, 1991.
7. Lefebre JL, Chevalier D, Luboinski B, et al. Larynx preservation
in pyriform sinus cancer: phase III trial. J Natl Cancer Inst.
8. Johnson JT, Ferretti GA, Nethery WJ. Oral pilocarpine for
post-irradiation xerostomia in patients with head and neck
cancer. N Eng J Med. 329:390-395; 1993.
9. Eisbruch A, Ship JA, Martel MK, et al. Parotid gland sparing
in patients undergoing bilateral head and neck irradiation:
Techniques and early results. Int J Rad Onc Biol Phys. 36:469-480,
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