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Michigan Oncology Journal Fall 98

Advances in Radiation Treatment for Head and Neck Cancer

---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 drugs.

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 effects.

Standard radiation relies on lateral beams that treat the targets in the neck
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, 1992.
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, 1998.
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. 88:890-895, 1996.
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, 1996.


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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.