Seminars in Surgical Oncology 7:38-46 (1991)

Advances in Radiation Therapy for Head and Neck Cancer LEONARD M. TOONKEL, MD From the Department of Radiation Oncology, Mt. Sinai Medical Center, and Department of Radiology, University of Miami, School of Medicine, Miami

Radiation therapy either as a single modality or as part of multimodality plans remains an integral part of curative treatment for cancers of the head and neck. This paper traces the modernization of radiation therapy regarding tumors of the head and neck using examples of sites of malignancy where radiation therapy is the sole modality or where radiation therapy can be combined with surgery and chemotherapy for optimal results. As local-regional control rates have improved with the use of combined radiation therapy and surgery and aggressive hyperfractionation schemes for advanced primary tumors, distant metastases and second primary neoplasms are now accounting for a larger proportion of treatment failures. Until such time as more effective systemic therapy and cancer control mechanisms are developed to address these problems, radiation therapy will continue to play a major role in the overall management of patients with cancers of the head and neck. KEYWORDS:radiation therapy, single modality, combined modality, locoregional control, hyperthermia

Following Roentgen’s discovery of X-rays in 1896 and the observed adverse effects of these rays upon human tissues, X-ray treatment of cancer was conceived, and tumors of the head and neck were among the first to be treated. As early as February of 1896, Voight had reported that a case of pharyngeal cancer had been irradiated, resulting in relief of pain [ 11. During the first decade of the twentieth century, dermatologists and otolaryngologists were already using Xray therapy for the treatment of cancers of the oral cavity and facial skin with encouraging results. In 1902, Dobson treated a patient with advanced laryngeal carcinoma claiming that the patient’s lymph nodes had all but disappeared and that the primary tumor had decreased greatly in size, allowing the patient to talk once again. With continued treatments, however, necrosis of the skin ensued and the patients died of hemorrhage [2]. The superficial nature of early X-ray-producing equipment resulted in a proportionately greater effect on skin and superficial tissues, limiting the number of exposures that a patient could receive. More extensive tumors or deep-seated lesions would show an apparent good re0 1991 Wiley-Liss, Inc.

sponse, but would ultimately recur. Prior to World War I , physicians were becoming disillusioned with X-ray therapy as a curative modality. The earliest attempt to circumvent the limitations of superficial treatment was the initial development of interstitial and intracavitary therapy as radium sources became available. In the United States, surgeons such as Abbe and Janeway were among the early pioneers of interstitial treatment with radium needles and radon seeds [3]. Following the war, radiobiologic experiments in Paris, and early clinical experience, begun by Regaud and Coutard and later Baclesse, led to the prolongation of treatment courses in an effort to further reduce acute and later normal tissue reactions [4]. The first beneficial effect of elective neck irradiation was reported by Widman in 1933. He reported that 17% of 52 patients with lip cancers treated electively developed neck metastases, while 51% of 72 patients who were not irradiated failed in the neck [ 5 ] . Address reprint requests to Leonard M. Toonkel, M.D., Department of Radiation Oncology, Mt. Sinai Comprehensive Cancer Center, 4300 Alton Road, Miami Beach, FL 33140.

Advances in Radiotherapy

Despite early success with orthovoltage radiation therapy in the treatment of nasopharyngeal and oropharyngeal lesions, by the 1940s the delayed effects of radiation therapy became apparent and early enthusiasts began turning to increasingly radical surgery. The necessity to deliver higher doses of radiation therapy to adequate tissues depths led to the development of megavoltage sources. While 2 MeV Van de Graff generators were in use in the 1940s, it was not until the technological advances of nuclear physics following World War 11, and the development and production of cobalt 60, that supervoltage radiation therapy became a practical modality of treatment. The first such units were developed in the United States and Canada in 1951 [6], and by 1973 over 1,100 cobalt 60 units were in use throughout the world [71. The modernization of radiation therapy for treatment of head and neck cancers occurred from the early 1950s through the latter years of the 1970s. Dr. Gilbert Fletcher and his associates at the M.D. Anderson Hospital Cancer Center (M.D.A.C.C.) developed clinical guidelines for modern radiotherapy, based upon a triplicate evolution of radiation therapy during this era. This included advancements in physics and biomedical engineering, allowing the development of higher energy sources of radiation, including high energy linear accelerator units and betatrons. Fundamental radiobiologic observations, including the dependence upon molecular oxygen for cell killing and the exponential shape of survival curves for irradiated cells were established in the latter 1950s. A changing philosophy of cancer management to the “team approach” combining surgical and radiotherapeutic expertise, along with these advances in physics and radiobiologic observations, led Dr. Fletcher to propose what are now considered tenets of modem radiotherapy practice. First, the volume of cancer was more important than the histology in determining the dose of radiation required. Larger tumors containing higher proportions of hypoxic cells would require higher doses. Second, the dose did not have to be homogeneous through the entire area of concern, but should reflect the varying concentrations of tumor cells present. This included the delivery of lower doses to a large area surrounding a tumor mass, for control of ‘‘subclinical disease” (disease statistically assumed to be present but not clinically detected). Third, radiotherapy could be used as an adjunct, either prior to or following surgery, for the control of subclinical disease. Fourth, large bulky tumors should be resected, if possible. Fifth, since the dose-response curve for tumors of different sites was steep and varied with the clinical situation, an optimum dose needed to be determined for each site and stage of disease. Sixth, conservative surgical resection could be combined with modest doses of

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radiation yielding an improved quality of life over that achievable with either modality alone [8]. During the early years of megavoltage cancer treatment, radiotherapists depending largely on their clinical assessment of patient tolerance and tumor response developed fractionation schemes and therapeutic dose levels for different tumor sites. As the late complications of radiation therapy became apparent, tolerance doses for different tissues were defined. With few exceptions [9], head and neck tumors were treated with 180-200 cGy daily fractions, 5 days per week to total doses in excess of 6,000 cGy. The addition of the electron beam, a less penetrating form of megavoltage irradiation, to the radiotherapeutic armamentarium facilitated the treatment of the posterior cervical lymphatics, while sparing the underlying spinal cord [ 10,111. Computerized treatment planning and the ability to “mix” electron and photon beams of different energies enable radiotherapists to deliver higher doses of irradiation to small volumes of normal tissues [12]. Mandibular necrosis, though most often seen following interstitial treatment of oral cavity lesions, remained a major limitation for therapy of the oral cavity with external beam irradiation as well. Its association with dental caries was recognized early, and until the 1970s full mouth extractions prior to radiation therapy were common. The development of a vigorous program of dental prophylaxis and fluoride gel therapy developed by Daly et al. [ 131 has dramatically lowered the incidence of this devastating complication. The one site in the head and neck where radiotherapy has been the sole treatment for virtually every stage of cancer is the nasopharynx. As tumors of this area are usually asymptomatic until late, most patients present with advanced disease. Eighty percent of patients presenting at M.D.A.C.C. had cervical lymphadenopathy [14]. In 1972, Moench and Phillips [15] identified a dose-response relationship for nasopharyngeal carcinoma (NPC), suggesting that an NSD [ 161 of 1,750 ret, roughly equivalent to 6500 cGy given in 7 weeks, gave an 80% local control rate. Their study and that of Meyer and Wang [ 171 found no difference in control rates for squamous cell carcinoma and lymphoepithelioma. Conversely, Chen and Fletcher [ 181 observed a 3 1% incidence of local recurrence for squamous cell carcinoma and a 12% incidence for lymphoepithelioma. Hoppe et al. reported very similar local failure rates of 33 and lo%, respectively [19]. Mesic et a]. [20] reviewed the results of radiotherapy for NPC at M.D. Anderson Hospital, comparing two time periods, 1954 through 1971 and 1972 through 1977. The major treatment difference between these two time periods was the addition of 500-750 cGy boost to the nasopharynx in the later

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Toonkel

[33]. Unlike NPC, vocal cord cancer, causing an early symptom (hoarseness), presents most often with localized disease. Lymph node and distant metastases are uncommon. While primary surgical therapy of early vocal cord cancer results in cure rates approaching 100% [34], this is often associated with the loss of speech or at best a sacrifice of voice quality. For this reason, fractionated radiation therapy is most often first line treatment for patients with T, and T, disease 1351. Our own experience with 3-year minimum follow-up on 124 patients with T, disease showed only 9 (7%) failures, of which 4 patients were salvaged with subsequent surgery. Of 35 patients with T, lesions, 4 (11%) showed local recurrence or persistence and 3 of these were also salvaged surgically. Two of the 13 failures subsequently developed uncontrolled nodal recurrences, suggesting a role for the addition of ipsilateral neck dissection to partial or total laryngectomy for failed patients. These results are echoed by reports of larger series in the literature shown in Table I1 136-391. Much more controversial is the management of patients with a fixed vocal cord (T, disease). The initial local control for these patients when treated by radiation therapy alone is considerably less than that achieved for patients with mobile cords, despite the use of higher doses. Mendenhall et al. (401 report an initial control rate of 61% for T, patients correlating successful treatment with both higher total doses and a shorter overall treatment time. The disease was also controlled above the clavicles in 83% of patients with the addition of surgical salvage. Harwood et al. [41] report that 52% of patients with T,NdT,N, disease retained a functional larynx for 5 years after initial treatment with radiation therapy. The as yet unresolved issue is whether overall survival is jeopardized by delaying laryngectomy for radiation failure [42,43]. While our current policy is to recommend laryngectomy for those patients showing a poor response at a “preoperative” dose level, strategies designed to improve the initial results of radiation treatment, including the use of neoadjuvant or concurrent chemotherapy and altered fractionation schemes (multiple daily treatStage ments), are being tested. Between 1978 and 1986, 21 patients with T, lesions IV received total tumor doses of 6,440 to 7,990 cGy with twice daily 120 cGy fractions at the University of Florida. Five of 6 local failures were successfully salvaged 1 I by laryngectomy . An additional patient required laryngectomy for laryngeal necrosis resulting in a determinant 0 survival of 86% with 67% of patients retaining laryngeal function [44]. The Veterans Administrative Cooperative study [45] 19 randomizes patients with moderately advanced and ad20 vanced (T, and T,) laryngeal carcinoma, to be treated by

years. This was delivered with a high-energy X-ray beam (1 8-25 MV) through parallel opposed portals, minimizing the lateral dose absorbed by the temporomandibular joints. The control rate for T , and T2 lesions increased from 76 to 94% in the later years without an accompanying increase in the complication rate. Specifically, with more careful treatment planning, no major CNS complications were seen in the later time period. Table I shows representative survival rates for NPC continuing to improve through the 1970s and 1980s 121-241. Major advances in the field of diagnostic imaging now enable radiotherapists to tailor treatment plans to individual disease extent and anatomic features. Computerized tomography (CT) has improved the visualization of the parapharyngeal soft tissues and the basal foramena from that available from plain radiographs. Yet the more recently developed magnetic resonance imager (MRI) has already proved superior to CT for detailing intracranial extension of NPC [25-271. Further improvement in the local control of nasopharyngeal and other head and neck tumors can be expected, as these imaging modalities are incorporated into computerized radiotherapy treatment planning systems [28] (Figs. 1 and 2). As up to 50% of patients with Nz and N, disease will develop distant metastases [29], it is doubtful that these improvements will have a major impact on overall survival rates. The development of effective systemic therapy for NPC must still be a major research priority as currently available drug regimens have not been shown to improve survival [30]. Reirradiation of local recurrence by high-energy external beam and/or placement of intracavitary radioactive sources directly into the nasopharynx can result in worthwhile palliation and occasional long-term control [24,31,321. On the other end of the oncologic spectrum from the nasopharynx is carcinoma of the glottic larynx, the most common of head and neck malignancies with over 12,000 new cases reported in the United States in 1988 TABLE I. NPC: 5-Year Disease-Free Survival Reference

Moensch and Phillips, 1972 1151 Ho, 1978 [21] Huang. 1980 1221 Baker and Wolfe. 1980 [ 2 3 ] Hsu and TU. 1983 1241

Stage

Stage

I

I1

Stage 111

67 68

62 50

21 28

65

46

23

61

19

19

81

15

48

Advances in Radiotherapy

41

Fig. 1. Treatment planning MRI of patient with recurrent squamous cell carcinoma metastatic from the skin of the left ear to cervical lymph nodes and recurrent in soft tissue of the left neck following radical neck dissection. Axial image shows tumor volume well encompassed by 5,500 cGy isodose line using a mixed beam of 10 MeV

electrons and cobalt-60 photons. The spinal cord is receiving less than 2,500 cGy. (Reproduced from Magnetic Resonance lmaging 6:315319, Toonkel et al., “MRI assisted treatment planning for radiation therapy of the head and neck,” 1988, with permission of Pergamon Press.)

either surgery with postoperative radiotherapy if indicated or ‘‘induction chemotherapy” with cisplatin and 5-W, followed by surgery for patients with less than complete response or conventional radiotherapy for complete responders. The most recent update of this experience [45] reports that 109 patients in the induction chemotherapy arm have completed treatment. Twenty-two patients underwent laryngectomy because of poor chemotherapeutic response and an additional 17 patients required salvaged laryngectomy for recurrence after radiation. While the frequency of relapse was similar in the surgery and chemotherapy/radiotherapy arms (32 vs 33%) and the 2 year projected survival was equivalent (64 vs 69%), an intact larynx was preserved in 57% of patients in the chemotherapy/radiotherapy arm. Similar results have been reported from Memorial Sloan Kettering Cancer Center [46] (M.S.K.C.C.) using cisplatin and bleomycin and induction and treating all patients without progression with radiotherapy. The current treatment policy at M.D.A.C.C. for patients with T, and T4 lesions of the larynx, hypopharynx,

and base of tongue, whose tumors would required total laryngectomy for local control, is induction chemotherapy with 3 courses of cisplatin and continuous infusion of bleomycin and 5-FU. Patients who achieve a complete or near complete response are treated with twice daily radiotherapy to total doses of 7,200 cGy for complete responders to chemotherapy and 7,660 cGy for partial responders [47]. The role of chemotherapy in advanced head and neck cancers is discussed in detail elsewhere in this volume. Metastatic squamous cancer to cervical lymphatics from any site in the upper aerodigestive tract has represented a major impediment to cure. Treating No patients with oral tongue carcinoma by partial glossectomy only [48], Spiro and Strong observed nodal recurrences in 29% of patients with T, tumors, 43% with T,, and 77% with T, lesions. Radical neck dissection was capable of salvaging only 35% of these patients. Northrop et al. [49] observed the development of contralateral neck disease in 34% of patients treated by neck dissection and maintaining continuous control of their primary lesions.

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Toonkel

Fig. 2. Treatment planning MRI using a coronal image offset through the plane of the spinal cord for patient described in Figure 1. Note that although the entire tumor is well encompassed by the 5 , 5 0 0 cCy isodose line now the spinal cord near the inferior field margin is

receiving just under 4,500 cGy. (Reproduced from Magnetic Res“MRI assisted treatment planning for radiation therapy of the head and neck,” 1988, with permission of Pergamon Press.)

onance Imaging 6:315-319, Toonkel et al.,

TABLE 11. Radiation Therapy for Cancer of the Vocal Cord Stage

Number

% Controlled by radiotherapy (%)

Ultimate control (%)

T, T2

332 175

89 74

98 94

Princess Margaret Hospital ( 1982) [37]

TI T*

57 1 316

87 68

96 80

Massachusetts General Hospital (1983) [38]

TI T2

723 173

90 69

97 86

TI T2

171 108

93 74

97 94

Institution M.D. Anderson Hospital (1980) [36]

University of Florida (1988) [39]

The efficacy of radiotherapy for the control of subclinical disease is apparent when the results of elective neck irradiation are reviewed. Barkley et al. [50] reported that ipsilateral neck failure developed in only 1 patient and contralateral recurrence in only 2 patients of a total of 50 initially No patients receiving complete neck irradiation with controlled primary lesions in the oro-

pharynx, hypopharynx, or supraglottic larynx. Mendenhall et a]. [51] reported control of occult neck diseases in 98% of 103 irradiated patients. In both of these studies, a tumor dose of 5,000 cGy was prescribed over 5 weeks to the neck. Evaluating the results of radical neck dissection for patients with clinically involved lymph nodes of various

Advances in Radiotherapy

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head and neck primary sites, Strong [52] reported a neck 2-3 weeks after completion of radiotherapy (4-6 weeks recurrence rate of 37% when lymph nodes were positive after neck irradiation). For the occasional patient showat one level and 72% when mutiple levels were involved. ing poor response to treatment, all radiotherapy would be Twenty-four percent of these patients also showed failure discontinued at preoperative dose levels and both the prmary and the neck disease managed surgically. to control the disease at the primary site. With the continued modernization of the technical asSchneider et al. [53] reviewing the ability of radiopects of radiation therapy including improvements in patherapy to control grossly metastatic neck nodes showed tient immobilization, tumor localization, and dose deliva failure rate of 19% for N, disease and 34% for N, ery systems, and the interinstitutional differences in both disease. For the N, patients, a dose of at least 6,500 cGy surgical and radiotherapy techniques, it has been difficult was required and the more bulky nodes failed with even higher doses. These dose levels are associated with a to assess the actual therapeutic gain of combined therapy for patients with head and neck cancer. At M.S.K.C.C., high degree of subcutaneous fibrosis. By contrast, when surgery, most often utilizing a func- 74% of advanced head and neck cancer patients with tional neck dissection, and lower doses of postoperative unsatisfactory surgical margins [55] and 72% of patients radiotherapy (5,000-6,OOOcGy) were combined, Bark- with multiple level cervical node involvement, [52] ley et al. [50] reports no case of ipsilateral neck recur- failed above the clavicles when treated by radical surgery rence in 46 N, patients. Three N,, patients failed in the alone. Fewer than 25% of these patients survived 5 years contralateral neck. Clearly, the combination of radiother- [56]. Similar patients treated at the same institution after apy and surgery substantially improved the rate of neck 1975, when a consistent policy of postoperative radiodisease control and by depending on radiotherapy for therapy was in use, were reported to have a failure rate control of subclinical disease, the modified neck dissec- above the clavicles of only 15% and a projected 5 year tion gave much better cosmetic and functional results relapse-free survival rate of 50%. A 20% rate of distant with lower doses of radiation, avoiding posttreatment metastases was seen, essentially the same as that reported for the earlier studies, but now representing the fibrosis. A major controversy in combined modality treatment major cause of treatment failure. Additionally, the risk of of neck disease has been the sequencing of the surgery developing a new cancer now overtakes the relapse rate and radiotherapy. Proponents of preoperative irradiation by 4 years after therapy and continues to increase with a theorize that tumor sterilization will decrease the likeli- positive slope [56]. A similar change in failure patterns hood of dissemination by operative manipulation at the was seen in an autopsy study from M.D.A.C.C. Luna time of surgery. While one retrospective evaluation [54] and Dimery [57] compared the causes of death of 420 did suggest a lower rate of distant metastases for patients patients treated in one of two time periods, 1955-1965 or irradiated preoperatively, a randomized study of the 1973-1983. Death from uncontrolled disease above the RTOG showed no survival differences comparing pre- clavicles decreased from 30 to 15% in the later period. and postoperatively treated patients. Another theoretical Fatal complications of therapy decreased from 24.7 to advantage for preoperative radiotherapy is the presence 10.5% and the median survival of those patients who died of disease increased from 6 to 14.5 months. In this of a relatively well oxygenated tumor bed. For those patients whose primaries are to be treated study, death from distant metastases increased from 17 to surgically, we prefer postoperative treatment as the acute 32.3%; death from unrelated nonmalignant causes intolerance to radiotherapy is improved following the sur- creased from 14.7 to 27.7% while death from second gical removal of painful lesions of the oral cavity or primary malignancies remained constant at 14.2%. These studies indicate that although we are approachpharynx. Additionally, surgical staging provides details of disease spread that has both prognostic and therapeutic ing maximum control rates with combined local therasignificance. Lesions of borderline operability can often pies, it is unlikely that further improvement will be transbe rendered resectable by preoperative radiotherapy, but lated into overall survival benefits until effective treatthese patients may also benefit from neoadjuvant sys- ments for distant spread and second primary cancers are temic regimens. Patients with primary tumors amenable available [58].Until such time, efforts to improve the to radiotherapeutic control but with advanced neck dis- functional results of head and neck cancer management ease, commonly T, or T,, N2-3 pharyngeal or supraglot- with organ preservation will rely on continued improvetic lesions, are preferably treated with radiotherapy first. ments in radiation treatment. As mentioned above, If a good response is seen at the primary site, the fields promising results are being seen for advanced cancers are reduced off of the neck nodes at a “preoperative” using neoadjuvant chemotherapy to reduce the tumor dose level, and the primary lesion carried to more radical burden and improve the oxygenation of residual tumor dose levels. This would be followed by neck dissection prior to radiation therapy. The RTOG has recently

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Toonkel

opened a study of concomitant chemotherapy and radiotherapy testing the hypothesis that cisplatin will sensitize tumor cells to the effects of irradiation. Hyperthermia is also emerging as an effective adjuvant to radiation therapy for advanced disease. Experimental studies have shown that heat potentiates radiation cell killing [5943]. Heat is also selectively lethal for cells in a low pH environment like necrotic hypoxic tumors, where ionizing irradiation is least effective. Several centers have reported improved local control rates for superficially advanced malignancies with combined hyperthermic treatment and radiotherapy over that achievable by radiotherapy alone [64-68]. Alterations of conventional fractionation schemes of radiation therapy are based on fundamental principles of radiobiology. As late radiation injury to fixed postmitotic cells is related to the dose of irradiation per fraction, as well as the total dose, hyperfractionation was developed using multiple daily exposures of lower than conventional doses of radiation separated by 3 4 hours, to deliver higher than conventionally prescribed total doses. Horiot et al. [69] reporting for the EORTC studied 366 N,, oropharyngeal cancer randompatients with T, ized to receive conventional treatment to a total dose of 7,000 cGy in 7 weeks versus twice daily treatments to a total dose of 8,050 cGy in 70 fractions during an equivalent time period. Patients were entered on study from February 1980 through March 1987. As of March 1987, with 293 patients entered and a median follow up of 189 weeks, a significant improvement in 3 year localregional control, 59 versus 4396, was seen favoring the patients treated twice daily. Greater differences were seen in those patients with a 901100 Kamofsky index including a 3-year survival advantage of 65 vs 45%. Despite the higher total dose, there was no difference in the later rate of radiotherapy complications. Similar findings were observed by Datta et al. [70] for 212 T2-, N,, head and neck cancer patients randomized to receive conventional therapy of 6,600 cGy versus b.i.d. treatment to 7,920 cGy. After 2 years, 62.7% of the twice daily treated patients showed no evidence of disease, compared with only 32.9% in the conventional treatment arm. Although acute reactions were more severe with 2 fractions per day, again, late complications were equivalent. While an improvement in Iocal-regional control was seen for these hyperfractionated regimens, the finding of actual survival benefit seen over conventional treatment is quite encouraging. The observation that tumor clonagens can repopulate during prolonged courses of radiotherapy [7 1-73] has led to clinical trials of accelerated fractionation. Again, using multiple fractions per day in an effort to avert late complications, accelerated fractionation schemes deliver conventional total doses of irradiation in a shortened

overall duration of treatment. Using intensive short courses of multiple daily fractions of 180-200 cGy, most investigators have found very severe acute reactions limiting both treatment volumes and total dose to approximately 5,500 cGy. As expected, this dose level fails to improve upon local control rates obtained by conventional schedules [74]. Wang [75] at Massachusetts General Hospital initiated a modified accelerated fractionation regimen in 1979. Using 2 daily fractions of 160 cGy , conventional total doses were delivered with the addition of a 2 week break near the middle of the treatment course to allow for settling of acute mucosal reactions. A comparison of results of this treatment regimen with historical controls treated prior to 1970 shows a significant improvement in local control rates (69 versus 46%) [76]. A type of accelerated fractionation schedule referred to as concomitant boosting was pioneered by Knee et al. [77] at M.D. Anderson Hospital for patients with head and neck tumors showing extremely rapid growth, appearance of disease prior to initiation of planned postoperative radiotherapy, or actual tumor progression during conventional treatment. These patients were treated to a smaller field-within-a-field with a second daily fraction of 120-150 cGy, 2-3 times per week with a 3-6 hour intertreatment interval, resulting in the delivery of 7,000-7,400 cGy in 6 weeks. In this unfavorable group, the finding of a 65% 2-year local control rate prompted the initiation of randomized study of 3 different concomitant boost schedules in 1984. Ang et al. [78] will report that patients with advanced cancers of the oropharynx and nasopharynx, receiving concomitant boost treatment during the last 2-2% weeks of conventional therapy, have better 2-year control rates following radiotherapy (79% primary control, 75% neck control) and surgical salvage (86% primary control, 89% neck control) than patients receiving a similar boost treatment, either early on in the treatment course or evenly spaced throughout conventional therapy. The use of accelerated and/or hyperfractionated radiation schedules has opened a therapeutic window of opportunity in the treatment of advanced head and neck cancer patients. Results from these well-conceived trials indicate that substantial improvement in local-regional control (and perhaps survival) rates has been achieved without subjecting patients to systemic therapy and not requiring additional expensive radiation modalities. With the approach of the twenty-first century, radiation therapy will continue to play a major role in the management of cancers of the head and neck. The development of predictive assays of radioresponsiveness 1791 will enable radiation oncologists to choose novel fractionation schemes and/or combinations of chemo-

Advances in Radiotherapy

therapy or hyperthermia and radiation to optimize results for the individual patient, much as they now choose energies and combinations of external and interstitial therapy. This optimization will require even closer cooperation in the design of clinical trials and in individualized patient management among medical, surgical, and radiation oncologists.

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