Radiotherapy dose fractionation in Pediatric Langerhans cell histiocytosis.

To the Editor: Langerhans cell histiocytosis (LCH) is an uncommon disease characterized by idiopathic proliferation of dendritic histiocytes, most commonly diagnosed in children younger than 20 years of age. Though LCH is radioresponsive, the use of radiation has been restricted in children, due to concerns about growth, developmental, and other late toxicities and the availability of less toxic treatment. Nonetheless, situations arise in which critical structures are threatened or primary therapy fails, and the risks of using radiotherapy (RT) are outweighed by probable benefit. (1,2) Modern series have used RT doses of 600 to 1,000 cGy, (1-3) however, proper dose fractionation is poorly established, with no published results correlating fraction size with clinical outcome. Thus, we retrospectively analyzed outcomes according to the RT dose fraction used.

Pediatric RT patients with a diagnosis of LCH were identified at our institutions. "Pediatric" was defined as age younger than 18 years at the time of treatment. Patient confidentiality was maintained at all times, and approval was obtained from the primary institution's institutional review board. Various parameters were considered; however, the present analysis is based on RT dose per fraction only.

A scoring system characterized the degree of response to RT, with a low score representing a more favorable response. The physician submitting the data assigned the appropriate score within each of three categories: initial radiographic response, initial clinical response, and status at last follow-up. Radiographic response was scored on a 4-point system: 1 point for complete radiographic resolution, 2 points for greater than 50% reduction in lesion volume, 3 points for less than 50% reduction, and 4 points for unchanged lesions. Clinical response was scored on a 4-point system, with 1 point for complete symptom resolution, 2 points for incomplete relief, 3 points for no change, and 4 points for symptom progression during treatment. Status at last follow-up was scored on a 4-point system, with 1 point for patients alive without disease; 2 points for patients alive with residual symptoms but no progression; 3 points for patients alive with progressive disease; and 4 points for patients dead of disease. Statistical analyses were performed by using the unpaired Student t test. Twenty-four patients were included, with a median follow-up of 28 months. Subjects were ethnically diverse and ranged in age from 18 days to 14 years. Fifteen had limited stage disease and nine had disseminated disease. Nineteen had bone involvement only, whereas five had extraosseous disease. Total radiotherapy dose delivered ranged from 300 to 2000 cGy in fractions of 50 to 300 cGy. All but one were treated with megavoltage equipment. Initial radiographic response ranged from complete resolution to unchanged (1 to 4 points), and initial clinical response ranged from complete resolution to unchanged (1 to 3 points). Long-term outcomes were similarly varied.

Fractions of 180 cGy or greater (principally 180 to 200 cGy) yielded superior results, with an average clinical response score of 1.29 (a score of one represented complete symptom resolution), whereas those treated with less than 180 cGy (range, 50 to 150 cGy) fractions had an average score of 2.10 (a score of 2 represented incomplete symptom resolution). This average difference of nearly one clinical response point was statistically significant (P = 0.013). Whereas numeric averages for initial radiographic response favored 180 cGy per fraction or greater both for the group as a whole and for patients with bone involvement only, neither comparison reached statistical significance. No statistically significant difference was detected in status at last follow-up.

The role of RT in LCH has been declining for decades, as our understanding of the disease process has evolved. Nonetheless, it is important when administered in carefully selected patients. Contrary to commonly held feelings that RT poses an unacceptable risk of secondary malignancy, other more commonly used therapies have been implicated more often than radiotherapy. (4)

Dose fractionation in the radiotherapy of LCH is a little-studied and poorly understood matter. Published recommendations vary greatly without objective data. (1,5) Our analysis sought to provide concrete evidence on which to base fraction size. Although we believe that we have helped form a more evidence-based approach to dose fractionation in this setting, it is essential to point out that variables such as chemotherapy and surgery could not be controlled, given the small number of patients. It is conceivable that the addition of chemotherapy to the smaller fraction regimens could yield results comparable to those schemes using 180 cGy per fraction or greater. Nonetheless, our recommendation is that for treatments using radiotherapy alone, 180 cGy per fraction be used.

References

1. Halperin EC, Constine LS, Tarbell NJ, Kun LE. Langerhans' cell histiocytosis, in: Pediatric Radiation Oncology. 3rd edition, Philadelphia, Lippincott Williams & Wilkins, 1999, pp 422-445.

2. Ladisch S, Gadner H. Treatment of Langerhans cell histiocytosis: evolution and current approaches. Br J Cancer 1994;70:S41-S46.

3. Gramatovici R, D'Angio GJ. Radiation therapy in soft-tissue lesions in histiocytosis X (Langerhans' cell histiocytosis). Med Pediatr Oncol 1988;16:259-262.

4. Haupt R, Fears TR, Heise A, et al. Risk of secondary leukemia after treatment with etoposide (VP-16) for Langerhans' cell histiocytosis in Italian and Austrian-German populations. Int J Cancer 1997;71:9-13.

5. Slater JM, Swarm OJ. Eosinophilic granuloma of bone. Med Pediatr Oncol 1980;8:151-164.

Christopher D. Jahraus, MD

Department of Radiation Medicine

University of Kentucky Medical Center

Lexington, KY

Suzanne Russo, MD

Department of Radiation Oncology

University of Alabama School of Medicine 

Birmingham, AL

Jose Penagaricano, MD

Division of Radiation Oncology

University of Arkansas for Medical Sciences 

Little Rock, AR

Anupam Routh, MD

Department of Radiation Oncology

University of Mississippi Medical Center 

Jackson, MS

William St Clair, MD, PhD

Department of Radiation Medicine

University of Kentucky Medical Center

Lexington, KY

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