Role of radiation therapy for facial skin cancers

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1 Clin Plastic Surg 31 (2004) Role of radiation therapy for facial skin cancers Sujay A. Vora, MD a, *, Steven L. Garner, MD, FACS b,c a Department of Radiation Oncology, Mayo Clinic Scottsdale, E. Shea Blvd., Scottsdale, AZ 85259, USA b Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA c Private Practice, Santa Cruz, CA 95065, USA There are a number of treatment options for patients who develop skin cancers of the head and neck, including traditional surgical excision, Mohs surgery, cryosurgery, curettage/electrodesiccation, and radiation therapy. For early lesions, each offers excellent cure rates. Over the past 20 years, radiation therapy has been used with less frequency, primarily due to the high control rates reported with Mohs surgery, advances in plastic surgery, and physician preference. Advances in radiation therapy also may be unknown to physicians in surgical fields. Nonetheless, in appropriately selected patients, radiation therapy is a curative option that provides rates of success similar to those of other treatment options. This article reviews the radiobiologic principles, radiotherapeutic techniques, and clinical management of nonmelanoma skin carcinomas. Radiobiology Radiation is a high-energy x-ray that causes cell death by direct and indirect effects (via formed oxygen-free radicals) on DNA. Due to differences in cancer and normal tissue tolerances of radiation, cancer cells die and normal cells repair from the effects of radiation. Damage to cancer cells also is dependent on oxygen status of the tumor, daily radiation dosage (fraction size), and total dose. * Corresponding author. address: vora.sujay@mayo.edu (S.A. Vora). Fractionation is an important radiobiologic principle. It was discovered during experiments on ram testicles in the 1920s. These experiments showed that rams could not be sterilized with a single dose of radiation without excessive skin damage. However, if the radiation was given in smaller doses over a period of time, sterilization was possible without skin damage. The earliest developments of time/dose/fractionation schedules were derived empirically. Initial schemes were based on work in 1963 from Von Essen [1], who examined control rates versus incidence of skin necrosis. The regimens devised are similar to ones used today (Tables 1 and 2). Using longer fractionation schedules, the incidence of serious complications and poor cosmetic results has decreased markedly. Radiotherapeutic techniques Most early lesions are treated with orthovoltage machines ( kvp) or with linear accelerators (6 12 MeVelectrons). It is important for the radiation oncologist to understand the beam characteristics particularly the surface dose, radial dose, and depth dose. The radiation beam can be modified easily by adjusting the energy of the beam or the size of the radiation field, and with the use of bolus material that can mimic skin. Shielding using materials such as gold, lead, or tungsten is important in the protection of nearby radiosensitive normal structures such as the eye or lacrimal gland. Brachytherapy is a less commonly used technique that places radiation sources directly into tumor using catheters that are afterloaded with radiation sources such as iridium 192. The tumor /04/$ see front matter D 2004 Elsevier Inc. All rights reserved. doi: /s (03)

2 34 S.A. Vora, S.L. Garner / Clin Plastic Surg 31 (2004) Table 1 Time, dose, surface area table for 99% probability of tumor cure 1cm 2 3cm 2 10 cm 2 20 cm 2 30 cm cm 2 1 treatment (1 d) txs (2 d) txs (5 d) txs (2 wk) txs (3 wk) txs (4 wk) txs (5 wk) txs (6 wk) Dosages are given in cgy. Abbreviation: txs, treatments. Modified from Von Essen CF. A spatial model of time-dose-area relationships in radiation therapy. Radiology 1963;81: sites that generally are believed to be suitable are the lip, lip commissure, and nasal vestibule. Clinical management There are many options to treat skin cancers. The counseling physician should review all treatment options with the patient along with reasons for his or her final recommendation. The selection of treatment modalities is based on a number of selection factors. There are tumor-related factors such as size, location, growth pattern, and histology; and patient-related factors such as patient s age, medical status, personal preference, time involved, and cost. In addition, clinician s preference and referral patterns contribute to the final recommendation. However, patients with advanced disease (T4 or involved nodes) require a combined modality approach. Primary radiotherapy is an option in the treatment of most patients with squamous cell carcinomas or basal cell carcinomas of the head and neck. Acute effects during the course of radiation include erythema, dry desquamation, hyperpigmentation, moist desquamation, and epilation [2]. The degree of reaction depends on variables such as size of area treated, total dose, daily dosage, length of treatment course, degree of patient pigmentation, and medical comorbidity. Chronic or late effects from radiation include epidermal atrophy, telangiectasias, hairless and dry skin, subcutaneous fibrosis, and hyperpigmentation [2]. Treatment lengths can vary between less than 1 week to 5 to 7 weeks depending on the size and location of the tumor and the importance of good cosmetic outcome. Generally, higher daily dosages will yield more deleterious effects on the normal tissues, resulting in an inferior cosmetic outcome. Advantages to radiation include high rates of local control; the preservation of adjacent normal tissue; and the ability to treat areas where it would be difficult to obtain clear margins without functional or cosmetic loss, including the nose, lips, eyelids, and ear. Tumors involving the embryonic fusion planes (H-zone, Fig. 1) Table 2 Time, dose, surface area table for 3% probability of late skin necrosis 1cm 2 3cm 2 10 cm 2 20 cm 2 30 cm cm 2 1 treatment (1 d) txs (2 d) txs (5 d) txs (2 wk) txs (3 wk) txs (4 wk) txs (5 wk) txs (6 wk) Dosages are given in cgy. Abbreviation: txs, treatments. Modified from Von Essen CF. A spatial model of time-dose-area relationships in radiation therapy. Radiology 1963;81:881 3.

3 S.A. Vora, S.L. Garner / Clin Plastic Surg 31 (2004) surgical patients [4,5]. Therefore, young patients may find the treatment option of radiation less desirable than surgery. However, with the use of lower fraction sizes, these risks of adverse late effects may not be seen. Additional disadvantages of radiation include the inability to examine microscopic margins of tumor to ensure complete inclusion within the radiation volume, the potential risk of radiation-induced malignancies (extremely rare event), and the potential to increase future surgical complication risks if radiation is unsuccessful. Fig. 1. H-zone of face. Tumors in the shaded area have the potential for deeper invasion and further radial spread. can be treated with wide margins. Wide margins are necessary because tumors in this location can be more deeply infiltrative than they appear at the surface. Radiation is an outpatient procedure that does not require anesthesia, and may maintain normal tissue contours better than do surgical techniques. One misconception about radiation is that the cartilage of the nose and ear tolerates radiation poorly. This misconception was based on old data that used large fraction sizes and old technology [3]. The incidence of chondroradionecrosis in contemporary radiation practices is extremely low. Disadvantages of radiation include some risk of late-tissue effects of atrophy, pallor, and telangiectasias that can develop months to years after radiation. This may translate to a loss of cosmetic result. Silverman et al [4,5] and Rowe et al [6] studied cosmetic outcome of basal cell cancer patients 15 years after radiotherapy/surgery. Between the first and fifteenth years of follow-up, the percentage of radiation patients who had either an excellent or good cosmetic result declined by 20%. This decline was not seen in the Outcome data Most of the available data on results of radiation are based on retrospective studies. Rowe et al [6] reported long-term recurrence rates in previously untreated carcinoma (Table 3). Radiation therapy had results that were similar to those of other non-mohs modalities. Mohs surgery had the lowest recurrence rate (Table 4). Control rates by site are as follows: Eyelid: High local control rates have been reported by Royal Marsden Hospital, Princess Margaret Hospital, Institut Curie, and Massachusetts General Hospital with local control rates between 93% and 97% [7,8]. No apparent differences were seen in squamous cell carcinomas versus basal cell carcinomas. Complications included extropion, epiphora, and conjunctival keratinization. Nose/ears: High local control rates (91% 97%) with negligible rates of necrosis have been reported by a number of institutions [8,9]. The only prospective randomized trial was published by Avril et al [10] in Three hundred and forty-seven patients with basal cell carcinomas less Table 3 Tumor control by size, histology, and presentation Size Basal cell untreated Basal cell recurrent Squamous cell untreated Squamous cell recurrent <1 cm 64/66 (97%) 22/23 (96%) 11/11 (100%) 10/12 (83%) cm 71/75 (95%) 27/36 (75%) 19/21 (90%) 7/13 (54%) 3.1 5cm 11/13 (85%) 7/9 (78%) 7/8 (88%) 6/9 (67%) >5 cm 12/13 (92%) 1/2 (50%) 3/5 (60%) 6/11 (55%) Not specified 4/4 (100)% 1/1 (100%) 0/1 (0%) 4/6 (67%) Total 162/171 (95%) 58/71 (82%) 40/46 (87%) 33/51 (65%) From Lovett RD, et al. External irradiation of epithelial skin cancer. Int J Radiat Oncol Biol Phys 1990;19:235 42; with permission.

4 36 S.A. Vora, S.L. Garner / Clin Plastic Surg 31 (2004) Table 4 Overall outcome data by modality Recurrence rates Treatment modality Short term (<5 y) Long term (5 y) Surgical excision 2.8% (157/5560) 10.1% (264/2606) Curettage/ 4.7% (173/3664) 7.7% (274/3573) electrodesiccation Radiation therapy 5.3% (318/6072) 8.7% (410/4695) Cryotherapy 3.7% (90/2462) 7.5% (20/269) All non-mohs 4.2% (738/17,758) 8.7% (968/11,143) Mohs surgery 1.4% (5/367) 1.0% (73/7670) Data from Rowe DE, et al. Long-term recurrence rates in previously untreated carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1989;15: than 4 cm in size were randomized to radiation therapy (brachytherapy, contact, or superficial external beam radiotherapy) or surgical excision (non-mohs ). At 4 years, the local recurrence rate was 0.7% for surgery and 7.5% for radiation. Cosmetic result was rated as good in 87% surgical patients and 69% of radiation patients. The authors concluded that surgery was preferred over radiation [10]. There are some concerns, however, about the variable techniques used in the radiation arm and the extremely low failure rate seen in the surgical arm. One of the larger retrospective reviews of radiation patients was by Lovett et al [11]. They reviewed 339 patients (242 basal cell carcinoma, 97 squamous cell carcinoma). Their results for both untreated and recurrent basal cell and squamous cell carcinomas are shown in Table 3. Control rates were related to tumor size. Cosmesis was rated based on the amount of telangectasia, pigmentation change, and skin fibrosis. Patients were rated good to excellent in 92% of patients. Cosmesis had an inverse relationship to the primary lesion size, and 5.5% of patients had a complication that was related to tumor size. Complications included soft tissue necrosis, bone necrosis, and cataracts [11]. There are limited data on radiation results for locally advanced T4 lesions. Lee et al [12] reported a 67% local control rate on patients previously un- Fig. 2. (A) An 83-year-old with keratinizing squamous cell carcinoma of skin. Using 12 MeV electrons, he received 5000 cgy over 4 weeks. (B, C) One-year follow-up photos.

5 S.A. Vora, S.L. Garner / Clin Plastic Surg 31 (2004) treated and a 41% local control rate for patients with recurrent disease. When surgery as salvage was added, the 5-year local control rates were 90% (untreated) and 59% (recurrent). Poor risk factors in this group of patients included lesions with bone or nerve involvement. Thus, in this group of patients, a combined approach of surgery and radiation is preferred. Postoperative radiation therapy General indications for postoperative radiation include perineural invasion, lymph node metastasis, nodal extracapsular extension, positive margins in patients with squamous cell carcinomas, selected basal cell carcinoma patients with positive margins, and selected patients with recurrent skin carcinoma. It is critical to emphasize that patients with advanced disease that requires combined modality therapy are very different than patients who require primary treatment with respect to overall control and complication rates. When radiation is delivered to an area that has been surgically managed, there is an increased risk for wound/flap breakdown and poor healing. However, in the advanced cases, if radiation is not given, the risk of tumor relapse or progression is high. The patient should be counseled with respect to these risks and benefits. Perineural invasion is seen more often in squamous cell carcinomas and recurrent cases than in de novo basal cell carcinomas. Surgical resection including nerve generally is combined with postoperative radiation therapy. Radiation fields include the nerve pathway to the ganglion. Doses vary between 50 and 64 Gy. Even with aggressive surgery and radiation, recurrence rates still can be as high as 50% [13]. Involvement of two or more lymph nodes or extracapsular extension of tumor is an indication for radiation therapy. In these cases, doses vary between 50 and 64 Gy Postoperative radiation therapy also is recommended for patients with incomplete excision of squamous cell carcinomas in whom re-excision is ill advised or refused. A recurrence could predispose the patient to lymph node metastasis and systemic relapse that could be difficult to salvage. Thus, we prefer to treat these patients once adequate healing of the primary excision has occurred. In patients with basal cell carcinomas, it is less clear who needs immediate postoperative radiation therapy versus close observation [14]. The relapse rate is higher without radiation therapy versus immediate postoperative radiation. However, overall control rates appear to be identical when salvage treatment with radiation is included. Thus, if a compliant patient is willing to have close follow-up in an area that is not functionally or cosmetically sensitive, observation is a reasonable option. Summary Radiation therapy is one of many modalities that should be considered and explained to patients with basal cell carcinomas and squamous cell carcinomas of the head and neck (Fig. 2). Control rates for appropriately selected patients should exceed 90% and historically are comparable with most surgical resections. For locally advanced T4 lesions, a combined modality approach will give the best chance at local control. Postoperative radiation therapy is indicated in patients with advanced lesions, positive margins, lymph node metastasis, or perineural invasion. We advocate the discussion of this treatment modality with every such patient, even if the treating physician does not recommend it. Only then can a patient provide genuine informed consent for treatment. References [1] VonEssenCF. Aspatialmodeloftime-dose-arearelationships in radiation therapy. Radiology 1963;81: [2] Aerchambeau JO, et al. Pathophysiology of irradiated skin and breast. Int J Radiat Oncol Biol Phys 1995;31: [3] Traenkle H, Mulay D. Further observations on late radiation necrosis following therapy of skin cancer. Arch Dermatol 1960;81: [4] Silverman M, Kopf A, Grin C, Bart R, Levenstein M. Recurrence rates of treated basal cell carcinomas. Part 1: overview. J Dermatol Surg Oncol 1991;17: [5] Silverman M, Kopf A, Grin C, Bart R, Levenstein M. Recurrence rates of treated basal cell carcinomas. Part 4: x-ray therapy. J Dermatol Surg Oncol 1992;18: [6] Rowe DE, Carroll RJ, Day Jr CL. Long-term recurrence rates in previously untreated carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1989;15: [7] Fitzpatrick P, et al. Basal and squamous cell carcinoma of the eyelids and their treatment by radiotherapy. Int J Radiat Oncol Biol Phys 1984;10: [8] Morrison W, Garden AS, Ang KK. Radiation therapy for nonmelanoma skin carcinomas. Clin Plast Surg 1997;24(4): [9] Mazeron J, et al. Radiation therapy of carcinomas of the skin of nose and nasal vestibule: a report of 1676 cases by the Groupe Europeen de Curietherapie. Radiother Oncol 1989;13:

6 38 S.A. Vora, S.L. Garner / Clin Plastic Surg 31 (2004) [10] Avril MF, Auperin A, Margulis A, Gerbaulet A, Duvillard P, Benhamou E, et al. Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study. Br J Cancer 1997;76(1): [11] Lovett RD, et al. External irradiation of epithelial skin cancer. Int J Radiat Oncol Biol Phys 1990;19: [12] Lee W, et al. Radical radiotherapy for T4 carcinoma of the skin of the head and neck: a multivariate analysis. Head Neck 1993;15: [13] Mendenhall W, et al. Carcinoma of the skin of the head and neck with perineural invasion. Head Neck 1989; 11: [14] Pascal RP, et al. Prognosis of incompletely excised versus completely excised basal cell carcinoma. Plast Reconstr Surg 1968;41:328.