Recent advances in radiotherapy for head and neck cancers.
Advancements in surgery have made it possible to resect cancers that had previously been regarded as incurable. Similarly, new developments in radiation oncology have helped improve the outlook for patients with locally advanced or recurrent head and neck cancers. Among these advancements are refinements in altered fractionation, three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, stereotactic radiosurgery and fractionated stereotactic radiotherapy, neutron-beam radiotherapy, charged-particle radiotherapy, and intra-operative radiotherapy. These recent developments have allowed radiation oncologists to escalate the dose of radiation delivered to tumors while minimizing the dose delivered to surrounding normal tissue. Additionally, more continues to be learned about the optimum delivery of chemotherapy. This article provides an update on the status of these new developments in the treatment of head and neck cancers.
Cancers of the head and neck region constitute 3% of all cancers; approximately 40,000 new cases occur each year in the United States. Smoking is the most common cause of head and neck cancers.  Alcohol abuse and poor oral hygiene are other common risk factors.  The role of genetic abnormalities is just now beginning to be elucidated. For example, p53 gene mutations are frequently observed in patients with head and neck cancers. [3,4] Infection with Epstein-Barr virus or human papillomavirus types 6, 11, 16, or 18 might also play a role in the development of head and neck malignancies. [2,5]
Patients with head and neck cancer should be placed under the care of a multidisciplinary team whose members can provide not only prospective treatment recommendations, but deliver dental care along with nutritional, psychological, and social support. The aims of a multidisciplinary approach are to maximize the duration of disease-free and overall survival while minimizing morbidity.
Several recent advances have been made in radiation techniques and planning for these patients, and more continues to be learned about chemotherapy. In this article, we discuss this important progress.
Radiotherapy has been used to treat cancer for more than a century. The dose of radiation is typically expressed in terms of gray (Gy) units (1 Gy = 100 cGy = 100 rads), which denote the amount of energy deposited in tissue per unit of mass (J/kg).
The most common method of delivering external-beam radiotherapy (EBRT) is by linear accelerators, which produce photons (x-rays). These machines use a penetrating, high-energy (4 to 6 MV) x-ray beam to minimize the dose of radiation that is delivered to the skin. In contrast, electrons and superficial x-rays are more limited in their depth of tissue penetration, and they are suitable only for treating superficial lesions. Radiation therapy can also be delivered via brachytherapy, which involves the implantation of radioisotopes such as iridium 192 ([Ir.sup.192]) or cesium 137 ([Cs.sup.137]) directly into unresectable cancers. During brachytherapy, gamma rays are emitted by the radioactive source, and they have the same biologic effect as x-rays.
For a given degree of tumor-cell killing, the delivery of multiple small doses of radiation (fractionation) carries a lower risk of late complications than does the delivery of a single large dose. For this reason, fractionation has been a cornerstone of radiotherapy since the 1920s. In general, 44 to 50 Gy of radiation, delivered in increments of 1.8 to 2.0 Gy per fraction, are administered to regions that have a risk of 15% or more of harboring microscopic disease.  Between 66 and 70 Gy are usually prescribed for primary tumors measuring 2 cm or less.  When radiotherapy alone is delivered to a patient with more advanced disease, doses of 70 Gy or more are necessary to control the primary tumor and involved nodes. 
As a rule of thumb, the dose of radiation required for locoregional control increases as tumor size increases. In patients with lymphadenopathy, EBRT alone can control more than 90% of neck nodes that measure 2 cm or less.  EBRT at doses of 70 Gy or more sterilizes only approximately 80% of nodes that measure 2 to 3 cm.  Lymph nodes that are larger than 3 cm are rarely controlled with EBRT alone; they usually require a planned neck dissection. An exception to this general rule applies to lymph node metastases of nasopharyngeal and tonsillar carcinomas; these metastases are more radiosensitive than are metastases that spread from primary tumors at other sites.
There has recently been an increase in interest in altered fractionation schedules that differ from the traditional once-daily approach. Locoregional control in advanced head and neck cancers is suboptimal when radiotherapy alone is administered on a once-daily schedule. For radio-biologic reasons, altered fractionation schedules--in which two or three doses of radiation are delivered daily (at least 6 hours apart to minimize toxicity)--have been actively explored in the treatment of advanced head and neck cancers.
Hyperfractionation. Hyperfractionation typically refers to twice-daily delivery. Overall, hyperfractionation delivers a higher total dose than once-daily fractionation in approximately the same amount of treatment time; radiation is delivered in more, but smaller, doses. By using a smaller dose per fraction than once-daily fractionation, hyperfractionation allows for the delivery of a higher total dose while remaining within the tolerance of late-responding tissues. As a result, hyperfractionation can decrease the risk of late complications while achieving the same or better tumor control as once-daily delivery.
Accelerated fractionation. Accelerated fractionation is a means of decreasing the overall duration of treatment in an effort to reduce the repopulation of tumor cells in rapidly proliferating cancers. Repopulation (tumor-cell regeneration) tends to increase over time when the overall duration of treatment is protracted. By reducing the overall duration of treatment and thereby retarding repopulation, the likelihood of tumor control can be increased.
Concomitant-boost technique. A variant of accelerated fractionation is the concomitant-boost technique. With this technique, treatment is delivered once daily for the first 3.5 weeks and then twice daily during the final 2 to 2.5 weeks, when tumor cells can begin to repopulate more rapidly.
Accelerated hyperfractionation. Accelerated hyperfractionation has also been studied as a way of increasing tumor-cell killing without increasing the risk of late complications. This hybrid regimen incorporates features of both accelerated fractionation and hyperfractionation.
Numerous trials have suggested that the different types of altered fractionation have advantages over conventional once-daily dosing. [8-14] For example, the European Organization for Research and Treatment of Cancer conducted a prospective, randomized trial to compare twice-daily radiotherapy with 80.5 Gy in 70 fractions versus once-daily radiotherapy with 70 Gy in 35 to 40 fractions in patients with stage II or III oropharyngeal carcinoma (excluding carcinomas of the base of the tongue).  The researchers found that locoregional control at 5 years was better with the twice-daily treatment (59 vs 40%; p = 0.007). There was also a trend toward better overall survival at 5 years with altered fractionation (40 vs 30%; p = 0.08). There was no difference in late toxicity between the two arms.
Similar locoregional control and overall survival rates have been observed in patients with slightly more advanced disease (stage III or IV) whose treatment included the concomitant-boost technique. [9,10] The Radiation Therapy Oncology Group recently reported the findings of its prospective, randomized, 2-year comparison of once-daily fractionation, hyperfractionation, and two variants of accelerated fractionation.  This study included 1,113 patients who had stage Ill or IV cancer of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx or stage II cancer of the base of the tongue and hypopharynx. The investigators reported that patients who were treated with either hyperfractionation or a concomitant-boost technique experienced significantly better locoregional control (p = 0.045 and p = 0.050, respectively) than did those who were treated with once-daily fractionation. The differences in overall disease-free survival rates were not statistically significant, but there was a trend in favor of the two altered fractionation treatments (p = 0.067 and p = 0.054, respectively.)
Three-dimensional conformal radiotherapy. When early-stage disease is treated with radiotherapy, radiation oncologists have traditionally used two or three fields. For patients with more advanced disease, they have typically used a three-field technique that includes coverage of the primary site and the regional lymph nodes. The three fields typically include two opposed lateral fields that are matched with a low anterior neck field (figure 1).
Recent technical advances have led to the development of techniques that differ from these traditional two- and three-field approaches, and these newer techniques have been used increasingly in an attempt to raise the likelihood of cure. One of these techniques is three-dimensional conformal radiotherapy (3D-CRT). With 3D-CRT, sophisticated computer programming is used to determine the optimal beam shape and field arrangement. In addition, a new device, the multileaf collimator, allows for the collimation of the x-ray beam during treatment. The tumor and the regions at risk for microscopic extension are contoured on each axial computed tomography (CT) slice. The tumor volume is then visualized in three dimensions. A physicist and dosimetrist work together to construct a beam arrangement that will deliver the desired therapeutic dose to the tumor volume while minimizing the amount of radiation that will be delivered to the adjacent normal tissues.
The use of 3D-CRT has been investigated as a treatment for several head and neck cancers, including skull base tumors. For example, Leibel et al compared 3D-CRT plans with conventional two-dimensional radiotherapy plans in 15 patients with nasopharyngeal carcinoma.  They found that the 3D-CRT plans were superior to the two-dimensional plans in terms of both tumor control and reduction of normal-tissue complications. The probability of tumor control was 15% higher with 3D-CRT. Emami et al also demonstrated that 3D-CRT treatment plans were superior to conventional radiotherapy plans for patients with head and neck cancer.  Moreover, Perez et al reported that acute toxicity with 3D-CRT for head and neck cancer was comparable to or less than that observed with conventional radiotherapy. 
Multileaf collimators significantly shorten the daily treatment time required to administer 3D-CRT.  Gademann et al reported promising results with 3D-CRT in 195 patients who had tumors of the head, neck, or brain.  After a median followup of 22 months, 95% of patients treated with 3D-CRT throughout their entire course of radiotherapy were still alive, versus 86% of those who received 3D-CRT only during their final weeks of radiotherapy. As was the case in other studies, [15,20] Gademann et al found that morbidity with 3D-CRT compared favorably with that of conventional radiotherapy.
Latz et al described the outcomes of 13 patients whose clival chordomas were treated with 3D-CRT to a median dose of 70 Gy.  After a median followup of 32 months, 12 of the 13 patients (92.3%) were still alive. The local control rate was 69%. Only one patient developed endocrine dysfunction that required hormone replacement. No complication involving the optic pathway, cranial nerves, or brainstem was observed.
Intensity-modulated radiation therapy. Under computer guidance, "dynamic" multileaf collimators can change their shape during treatment, thereby giving rise to intensity-modulated radiation therapy (IMRT). IMRT can deliver radiation more conformally than 3D-CRT can, which allows for the delivery of higher doses. IMRT differs from 3D-CRT in that each x-ray beam is broken up into many "beamlets," and the intensity of each beamlet can be adjusted individually. As a result, IMRT has a significant advantage over 3D-CRT in inverse planning, which is the process by which a physicist, using a computer program, starts with the dose distribution desired by the radiation oncologist and works backward to determine the intensity of every beamlet necessary to achieve that distribution. By contrast, treatment planning with 3D-CRT is an exercise in trial and error.
With the aid of the multileaf collimator, IMRT fields can treat targets more efficiently because they allow the physician to better conform the high-dose region to the tumor. As a result, a higher dose of radiation can be safely delivered to the tumor. Several studies have demonstrated the feasibility and potential advantages of IMRT in the treatment of head and neck cancers. [15, 22-24] The results of preliminary clinical studies by various investigators have been promising. [25-27]
IMRT is especially useful in treating tumors of the nasal cavity, ethmoid sinus, sphenoid sinus, and base of the skull, areas where the risks of optic neuropathy and retinopathy following conventional radiotherapy are relatively high (figures 2, 3, and 4). In a study of nasal cavity, ethmoid sinus, and sphenoid sinus cancers, Parsons et al reported that 33% of patients treated with radiotherapy alone developed unilateral blindness between 17 and 90 months after treatment. 
Stereotactic radiosurgery and fractionated stereotactic radiotherapy. Stereotactic radiosurgery provides the precise delivery of a single large dose of radiation to a target that typically measures less than 3.5 cm in diameter. The procedure can be administered by a linear accelerator, gamma knife, or cyclotron. By limiting treatment to a small target, the physician can ensure a steep fall-off in the amount of radiation that is administered to adjacent normal tissue. A stereotactic frame is used to immobilize the patient's head during treatment. This frame also serves as a reference marker, allowing for precise target localization in a three-dimensional space. Stereotactic radiosurgery has been used to treat skull base tumors and nasopharyngeal carcinomas. [29, 30]
Like fractionated EBRT, fractionated stereotactic radiotherapy has also been developed. [31, 32] This technique involves the use of a relocatable head frame that can be placed in different positions during multiple daily treatments.  One drawback to this technique is that the relocatable frame does not allow for quite the same degree of accuracy as does a fixed frame. Consequently, approximately 2 mm of additional normal tissue (e.g., cranial nerves) is included in the high-dose region. Even so, by delivering several small doses rather than a single large dose, the physician can minimize the risk of cranial nerve palsies when irradiating skull base tumors such as acoustic neuromas and pituitary adenomas, particularly larger tumors (e.g., 3 to 5 cm). [33-36]
Neutron-beam radiotherapy. The Radiation Therapy Oncology Group in North America and the Medical Research Council in England jointly conducted a randomized trial to compare fast neutron-beam radiotherapy with conventional photon-beam radiotherapy in patients with incompletely resected or inoperable salivary gland cancers.  The trial was stopped after only 32 patients had been enrolled because the results showed that the fast-neutron group had experienced significantly better locoregional control. After 10 years of followup, that improvement remains significantly better (65 vs 15%; p = 0.009). However, there was no statistically significant difference in overall survival (15 vs 25%; p>0.05). Most of the failures in the neutron group were attributable to distant metastases, while most failures in the conventional radiotherapy group were the result of locoregional recurrences. Moreover, the neutron group experienced a greater incidence of severe complications, which helps explain why this treatment approach has not gained in popularity. Because locoregional control is more likely to be achieved in patients with salivary gland cancers no larger than 4 cm, initial surgical resection is advocated whenever possible.  The installation of modem neutron machines and the use of three-dimensional treatment planning at selected institutions should help reduce the relatively high incidence (11%) of severe complications with neutron-beam radiotherapy.
Charged-particle radiotherapy. A small number of facilities around the world deliver radiation with charged particles such as protons and heavy ions (figure 5). Unlike the case with photon and gamma-ray therapy, most of the energy delivered during charged-particle radiotherapy is absorbed at the end of the particles' path through tissue (the Bragg peak phenomenon). The dose unit for these charged particles is called a Gy equivalent (GyE). Charged-particle therapy has not gained much in popularity, in part because the equipment costs tens of millions of dollars to purchase and maintain. Also, there is only a limited number of indications (e.g., unresectable skull base and cervical spine tumors and choroidal melanomas) for which charged-particle therapy is more advantageous than traditional radiotherapeutic techniques. In the case of skull base tumors, the advantage of charged-particle radiotherapy is that it allows for the deposition of highly localized energy within the tumor as it spares the adjacent normal structures.
Since the 1980s, physicians at the Massachusetts General Hospital, Harvard Cyclotron Laboratories, Lawrence Berkeley Laboratories, and elsewhere have reported their extensive experience in treating skull base tumors with charged-particle radiotherapy. [40-46] In 1999, Munzenrider and Liebsch updated their experience in using combined photon-proton radiotherapy for chordomas and low-grade chondrosarcomas of the skull base and cervical spine in patients treated between 1975 and 1998.  Of the 621 patients (52% men) who were analyzed, 60% had chordomas and 40% had chondrosarcomas; 84% had skull base tumors and 16% had cervical spine tumors. Local control was defined as the absence of tumor enlargement on followup imaging in addition to neurologic stability or improvement.
Munzenrider and Liebsch found that among the patients who had skull base tumors, local recurrence-free survival at 10 years was significantly higher among those who had chondrosarcomas than those who had chordomas (94 vs 54%; p[less than]0.000l). Likewise, overall 10-year survival was significantly higher among those with chondrosarcomas (88 vs 54%; p[less than]0.0001). Among the patients with chondrosarcomas, there was no difference in outcomes between the genders; among those with chordomas, men tended to fare better than women. The probabilities of brainstem or cervical spinal cord injury were 8 and 13% at 5 and l0 years postirradiation, respectively. The probability of temporal lobe injury was 13% at 5 years postirradiation. Optic neuropathy developed in 4.4% of patients. Fifteen of 33 patients (45.5%) who were evaluated prospectively had developed a hearing deficit between 2 and 5 years postirradiation. Almost two-thirds of patients who received 62.7 GyE or more to the inner ear or the auditory nerve experienced a progressi ve and severe hearing loss. Therefore, Munzenrider and Liebsch concluded that any dose delivered to the inner ear should be limited to no more than 62 GyE.
In two reports of charged-particle radiotherapy conducted at the Lawrence Berkeley Laboratory in California, Castro et al  and Berson et a1  published the results of their experience in treating the skull base tumors of 223 patients with either helium or neon. Their 5-year local control rate was 63%, and 5 year overall survival was 75%.
In the treatment of skull base and cervical spine tumors, the results of charged-particle radiotherapy do compare favorably with those of conventional radiotherapy. However, because charged-particle radiotherapy is expensive and inaccessible, 3D-CRT appears to be a better option for the treatment of skull base tumors. [21,47-49] IMRT also shows promise for these tumors.
Intraoperative radiation therapy. During intraoperative radiation therapy (IORT), a single large dose of radiation is delivered in the operating suite after the tumor bed and adjacent normal organs have been defined (figure 6). IORT typically involves the administration of electrons rather than photons. With electrons, the dose of radiation falls off rapidly with depth, and the physician is thus able to spare normal underlying tissues. The typical dose of IORT is 12 to 20 Gy in a single delivery. Because of the rapid fall-off of the radiation dose with depth, IORT has been investigated as a treatment for head and neck cancer, especially locally advanced or recurrent disease. [50-52]
Freeman et al studied IORT outcomes in 104 patients with head and neck cancer.  Forty of these patients underwent surgery and IORT as an initial treatment, while the remainder received IORT for recurrent disease. Doses ranged from 15 to 20 Gy. After 2 years, the local control rate was 54%. Patients who had microscopic disease experienced better local control than those with gross disease. The complication rate was 14%. All of the patients who had experienced complications had undergone radiotherapy previously.
In another report, Rate et al published the outcomes of 47 patients with recurrent head and neck cancer who underwent resection and IORT.  The 2-year actuarial local control rate was 62%, and the 2-year survival was 55%. Toita et al also reported the outcomes of 25 patients with advanced or recurrent head and neck cancer who were treated with surgery and IORT.  The 2-year control rate in the IORT port was 55% for microscopic disease, but 0% for gross disease. The 2-year complication rate was 33%, and there was a higher incidence of complications at doses of 20 Gy and higher.
Initial studies of patients with recurrent or metastatic head and neck cancers typically looked at chemotherapy alone, and the results were disappointing. [53,54] Next, researchers conducted studies of chemotherapy administered prior to radiotherapy in patients with previously untreated, locally advanced cancers, and two of these randomized trials have been widely quoted by proponents of this approach. [55-57]
One of these was a trial conducted by the Department of Veterans Affairs Laryngeal Cancer Study Group. [55,56] The VA investigators suggested that natural speech preservation is possible in approximately two-thirds of patients with stage III or IV cancer who undergo three cycles of neoadjuvant 5-fluorouracil and cisplatin chemotherapy followed by EBRT. Patients were randomized to undergo either (1) neoadjuvant chemotherapy and EBRT or (2) total laryngectomy, neck dissection, and postoperative EBRT. After a median follow up of 33 months, the surgical approach resulted in significantly better locoregional control (p = 0.0005); there was also a trend toward greater disease-free survival (p = 0.11). However, there was no difference in overall survival between the two groups, due in part to the need for surgical salvage of chemoradiation failures.
The other widely quoted study reported the preliminary results of a phase III trial conducted by the European Organization for Research and Treatment of Cancer.  In this study, patients with piriform sinus cancer were treated with either (1) two or three cycles of induction 5-fluorouracil and cisplatin chemotherapy followed by radiotherapy or (2) surgery and postoperative radiotherapy. Local control rates were similar in the two arms--83% in the chemotherapy/radiotherapy group and 88% in the surgery/radiotherapy group. Regional control rates were also similar--77 and 81%, respectively. In the chemotherapy/radiotherapy arm, the incidence of distant metastasis was lower (25 vs 36%; p = 0.04), and the median survival was greater (44 vs 25 mo; p = 0.006). The results of this study suggest that organ preservation is possible without a decrement in overall survival.
A recent review  and a meta-analysis of prospective, randomized trials have suggested that while chemotherapy improves local control, it does so at the cost of increased morbidity. Nevertheless, chemotherapy can lead to an improvement in overall survival when it is administered concurrently with, rather than prior to, radiotherapy. [58,59] In a phase III randomized study of patients with nasopharyngeal carcinoma, Al-Sarraf et al compared radiotherapy alone with radiation plus concurrent cisplatin chemotherapy for three cycles, followed by 5-fluorouracil and cisplatin for three additional cycles.  The radiation doses in both arms were 70 Gy in 35 to 39 fractions, once a day, 5 days per week. At 3 years, the progression free survival was significantly better in the combined-modality group than in the radiotherapy-alone group (69 vs 24%; p[less than]0.001); the 3-year overall survival rate was better as well (76 vs 46%; p[less than]0.001). Based on these findings, the standard of care for stage III or IV nasopharyngeal carcinoma is considered to be radiotherapy with concurrent cisplatin, followed by 5-fluorouracil and cisplatin.
In the past few years, chemotherapy delivered concomitantly with altered fractionation radiotherapy has been investigated in patients with advanced head and neck cancer. [61-63] Brizel et al at Duke University reported the results of a randomized trial wherein the outcome of twice-daily radiotherapy and concurrent 5-fluorouracil and cisplatin chemotherapy was superior to that of twice-daily radiotherapy alone.  One hundred sixteen patients with advanced head and neck cancer were analyzed in this study, which had a median followup of 41 months. At 3 years, locoregional control among patients in the combined-modality group was significantly better than that in the radiotherapy-alone group (70 vs 44%; p=0.01).=0.01). There was also a trend toward greater relapse-free survival (61 vs 41%) and overall survival (55 vs 34%) in the combined-modality group.
De Serdio et al reported promising results with twice-daily radiotherapy and concurrent carboplatin chemotherapy in 52 stage Ill and IV head and neck cancer patients.  At 52 months, local control and cause-specific survival rates were 72 and 59%, respectively, and the neck control rate was 95%. Because the acute toxicity of chemotherapy with concomitant twice-daily radiotherapy can be severe, this approach should be limited to patients younger than 75 years of age who are able to take care of their own needs.
Preliminary results with radioprotectors such as amifostine  and glutamine  and chemopreventive agents such as 13-cis retinoic acid [66,67] and interferon alfa [66,67] have also been encouraging. All of these advances make this an exciting time for physicians who are involved in the multidisciplinary management of head and neck cancers.
The authors thank Mike Mulan, PhD, of the Department of Radiation Oncology at the Duke University Medical Center in Durham, N.C., for providing figure 5, and Karen Fu, MD, of the Department of Radiation Oncology at the University of California, San Francisco, for figure 6. The authors also thank Peggy Gravitte for her secretarial assistance.
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|Comment:||Recent advances in radiotherapy for head and neck cancers.|
|Author:||Forster, Kenneth M.|
|Publication:||Ear, Nose and Throat Journal|
|Date:||Oct 1, 2001|
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