• 12/24/2004
  • Avraham Eisbruch, MD
  • Medscape (medscape.com)

The superiority of radiation concurrent with chemotherapy in local/regional tumor control and disease-free survival, compared with radiation alone, has been established in several randomized studies and meta-analyses.[1] The combination of chemotherapy and radiotherapy is characterized by increased toxicity, notably acute mucositis and late dysphagia, which limit the intensity of therapy and further improvement of the therapeutic results. A new and exciting radiosensitizing strategy which has emerged in recent years for head and neck cancer is the blockage of the epidermal growth factor receptor (EGFR), which is overexpressed in the majority of head and neck carcinoma cells. Such blockage can be done by antibodies to EGFR (C225, or cetuximab), or by inhibitors of tyrosine kinase, the enzyme that is activated when EGFR is expressed. Encouraging results of phase 1/2 studies suggesting radiosensitization of head and neck cancer by cetuximab were presented several years ago.

Radiotherapy in Tandem With Cetuximab
In a special session devoted to the topic of innovations in head and neck cancer management at the 46th Annual Meeting of the American Society of Therapeutic Radiology and Oncology (ASTRO), J.A. Bonner, MD, University of Alabama, Birmingham, and colleagues[2] presented initial results of a phase 3 study of radiotherapy with and without cetuximab for locally advanced head and neck cancer. This group of investigators randomized 424 patients with stage III or IV cancer, the majority having larynx, oropharynx, and hypopharynx cancer. The 2 treatment arms were well balanced and several radiation regimens were used, including standard or altered fractionated radiation. An early analysis of the results showed no difference in mucositis. However, there was an increased rate of fever, nausea, and grade 3 skin effects in the combined-modality arm. The most important result was an improvement of approximately 11% in the 2-year survival rate in the combined arm compared with radiation alone. These are very encouraging early results. The main weakness related to this study is the lack of concurrent chemotherapy. It is not known whether the advantage of cetuximab will hold when it is added to a combined chemoradiation regimen. Until a randomized study addressing this question is available, it is unlikely that cetuximab will be adopted in routine clinical practice.

IMRT: Defining Targets of Opportunity
The delivery of highly conformal radiotherapy (intensity-modulated radiotherapy [IMRT]) has been prevalent in recent years in head and neck cancer. IMRT is especially attractive in this tumor site due to the close proximity of the targets to many critical normal tissues. In addition, the lack of breathing-related motion in the well-immobilized head and neck reduces many of the difficulties in the delivery of highly conformal treatment. The most important clinical issue in IMRT of head and neck cancer is the adequate definition and delineation of the targets. Lacking adequate target delineation might increase the risk of marginal tumor recurrences, which would not occur had wide-field standard radiation been delivered. The lack of agreement among radiotherapists on the delineation of the targets was demonstrated by several studies presented in this session.

T.S. Hong, MD, and coworkers[3] from the University of Wisconsin, Madison, presented a survey among head and neck cancer experts who were asked to delineate targets for an identical case of tonsil cancer, stage T2N1. The tonsillar gross tumor volume, which measured 3 cm, and a single 2-cm ipsilateral level 2 node, were delineated by the study designers, in order to avoid differences in the outlining of the gross tumor volume. The participants were asked to delineate the clinical target volumes (CTVs). The study authors found remarkable heterogeneity in the delineation of the CTVs. For example, two thirds of the responders would treat the bilateral neck while one third would treat only the ipsilateral neck. A 5-fold variation in CTV volumes, as well as wide variation in the specific nodal stations, was observed and the prescribed doses varied extensively among the responders. They concluded that the variation among institutions in many aspects of target definition, delineation, and dose prescription present notable challenges for comparative analysis of the existing literature as well as for the incorporation of IMRT into multi-institutional studies.

MRI Fosters Precise Targeting
A similar study of observer variation in delineation of the primary CTV of nasopharyngeal carcinoma was presented by C. Rasch, MD, and investigators[4] from the Netherlands Cancer Institute in Amsterdam. In this study, 10 observers from 6 different institutions delineated the CTVs of 10 nasopharyngeal carcinoma patients. As expected, wide variations in target delineation were observed. However, when magnetic resonance imaging (MRI) was available to the participants, target variation was reduced significantly. This study underscores the need to use MRI for target definition in nasopharyngeal or advanced paranasal sinus cancers, in which the bones at the base of the skull obscure the details of the soft tissue on CT scans.

Another interesting study addressing clinically based principles for target delineation was presented by S. Apisarnthanarax, MD, and colleagues[5] from MD Anderson Cancer Center, Houston, Texas. This group examined the extent of extracapsular tumor extension around lymph nodes containing cancer. They concluded that a 1-cm CTV margin around the gross disease will be enough to encompass all microscopic disease extension. The limitations of this study include the relatively small volumes of the lymph nodes examined (median size of 11 mm) and the lack of consideration of the shrinkage of the pathologic specimen, compared with the dimensions expected in vivo.

Where CT Scans Fall Short
The delineation of targets for IMRT is performed routinely on CT scan datasets obtained before therapy starts. It is assumed that the anatomy on that CT represents the anatomy throughout 6-7 weeks of therapy. To test this hypothesis, E.K. Hansen, MD, and a group from the University of California, San Francisco[6] retrospectively identified 13 patients with head and neck cancer who were treated with IMRT and also underwent serial CT scans during the course of therapy. They retrospectively identified 13 patients with head and neck cancer treated with IMRT who had repeated CT imaging and replanning during the course of therapy. The investigators found no significant changes in the mean volume of the gross tumor volume between the pretherapy and during-therapy scans. In comparison, significant decrease in the mean volume of the parotid glands was observed. Because of weight loss and decreased normal tissue volume, significantly higher maximal doses to the spinal cord and brain stem were observed, compared with those planned initially. The clinical significance of these findings is not clear. It is likely that patients suffering substantial weight loss during therapy are those who demonstrate changes in the delivered doses to several organs, and may require replanning. This issue deserves prospective studies.

Reviewing Fractionation and Chemotherapy Results
The addition of concurrent chemotherapy to standard radiation has demonstrated a significant advantage in local regional tumor control and disease-free survival.[1] What is the role of combined altered fractionation and concurrent chemotherapy? A study by R. Bensadoun, MD, and colleagues[7] from a cooperative French group partially addressed this issue.

This group randomized 171 patients with unresectable oropharyngeal cancer to either:

Hyperfractionated radiotherapy: 1.2 Gy/fraction twice daily to a total of 80.4 Gy in 46 days, concurrent with chemotherapy-cisplatin 100 mg/m2, continuous-infusion 5-FU 750 mg/m2 days 1-5 in the first cycle and 430 mg/m2 in the second cycle. Cycles were delivered every 3 weeks.

The same radiotherapy without chemotherapy. The results showed that the disease-free survival was significantly better in the concurrent-therapy arm: 54% vs 37%. The median survival was 17 months in the combined-modality arm vs 10 months in the radiotherapy-alone arm. As expected, the rates of grade 3-4 acute mucositis and grade 2-3 skin reaction were higher in the combined-modality arm.

A question that still has not been answered is: Does altered fractionated radiotherapy confer any benefit when compared with a course of chemotherapy administered concurrently with standard fractionated radiotherapy? The Radiation Therapy Oncology Group is planning a randomized study in order to address this issue.

Radiotherapy Risks and Benefits
Several studies addressed various complications of radiotherapy for head and neck cancer. J.D. Martin, MD, and coworkers[8] from the British Columbia Cancer Agency presented data regarding carotid artery stenosis in 40 patients who received ipsilateral irradiation. No patient had symptoms or clinical signs of carotid artery disease. Patients underwent carotid ultrasonography and CT angiography. The investigators found 13 cases of stenosis in irradiated carotid arteries compared with 5 in nonirradiated arteries (P = .03). Significant stenosis was only found in patients receiving > 50 Gy. The only statistically significant risk factor, apart from radiation, was history of smoking. No clinical data regarding strokes were available. Although significantly elevated, this risk is still relatively small. However, the data warrant advising patients about this risk.

A.T. Monroe, MD, and investigators[9] from the University of Florida, Gainesville, presented their data highlighting the risk of radiation retinopathy following hyperfractionated irradiation. In their study, 186 patients received a significant dose to the retina as a part of curative radiotherapy for cancers of the nasopharynx, paranasal sinus, and palate. They found 31 eyes that developed radiation retinopathy, resulting in monocular blindness in 25 patients, at a median of 2.6 years since radiation. Three of 72 patients (4%) receiving a retinal dose < 50 Gy developed retinopathy, compared with 25 of 30 cases developing retinopathy after receiving > 60 Gy to the retina. It seemed that hyperfractionated radiation decreased the incidence, at the same dose, compared with standard fractionated radiation. The rate of retinopathy in this study is obviously quite high. It may be related to the lack of CT-based treatment planning in the early years of the study. In addition, there is some uncertainty regarding the doses delivered, due to the same reasons. In any case, this is an important study suggesting that the maximal dose to the retina should not approach 60 Gy.

A. Blanco, MD, and coworkers[10] from Washington University, St. Louis, Missouri, presented data that showcased the relationship of the doses to the parotid glands and salivary output and the quality of life in patients receiving IMRT for head and neck cancer. This group determined that the glands receiving a mean dose of 26 Gy were most likely to retain their salivary output, and that their output increased over time. These guidelines add to a growing body of information suggesting that a mean dose to the parotid glands of < 30 Gy is likely to preserve their function and should be recommended for the planning of IMRT in head and neck cancer.

References
Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091-2098
Bonner JA, Giralt J, Harari PM, Jones C, et al. Phase III evaluation of radiation with and without cetuximab for locoregionally advanced head and neck cancer. Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 31.
Hong TS, Tome WA, Chappell RJ, Harari PM. Variation in target delineation for head and neck IMRT: An international multi-institutional study. Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 47.
Steenbakkers R, Duppen J, Fitton, I, Deurloo K, et al. Observer variation in delineation of nasopharyngeal carcinoma for radiotherapy, a 3-D analysis. Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 52.
Apisarnthanarax S, Elliott D, El Naggar AK, Asper JA, et al. Determining the magnitude of clinical target volumes (CTV) margins based on pathological examination of microscopic extracapsular extension of metastatic neck nodes. Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 48.
Hansen EK, Xia P, Quivey J, Weinberg V, Bucci MK. The roles of repeat CT imaging and re-planning during the course of IMRT for patients with head and neck cancer. Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 50.
Bensadoun R, Benezery K, Ramaioli A, Magne N, et al. Phase III multicenter randomized study of concurrent twice-a-day radiotherapy with and without cisplatin-5FU (BiRCF) in unresectable pharyngeal carcinoma. 24 months results (FNCLCC-GORTEC). Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 53.
Martin JD, Graeb D, Buckley A, Walman B, et al. Carotid artery stenosis in asymptomatic patients after ipsilateral head and neck radiotherapy. Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 95.
Monroe AT, Bhandare N, Morris CG, Mendenhall WM. Preventing radiation retinopathy with hyperfractionation. Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 96.
Blanco A, Deasy JO, El Naqa I, Franklin GE. Dose-volume modeling of salivary function in patients with head and neck cancer receiving radiation therapy. Program and abstracts of the American Society for Therapeutic Radiology and Oncology 46th Annual Meeting; October 3-7, 2004; Atlanta, Georgia. Abstract 98.