Radiotherapy in the Modern Era in the Management of Langerhans Cell Histiocytosis

Rupen Garg, BS

EXPERT'S PERSPECTIVE:

Bradford Hoppe, MD, MPH

Associate Professor, University of Florida Proton Therapy Institute

Why is this article contemporary?

One concern for utilizing radiotherapy (RT) is the potential for toxicity, especially the late sequelae including musculoskeletal growth abnormalities and second malignancies that have been reported. Considering there are no clearly defined roles for conformal radiation techniques such as intensity-modulated radiation therapy (IMRT) in treating LCH, this study retrospectively reviewed 16 patients with histologically confirmed Langerhans cell histiocytosis (LCH) treated with radiation therapy between July 1983 and October 2013 at the Johns Hopkins Hospital. With regards to local control and overall survival, both conformal and conventional radiotherapy techniques provided excellent results in the management of LCH. These results also showed that conformal radiotherapy techniques employ significantly lower radiation dose to critical normal structures, such as temporal lobes, hippocampus, lens and hypothalamus/pituitary axis, compared to conventional techniques.

By utilizing modern and contemporary radiotherapy approaches, the reduction in critical structures can be achieved without sacrificing excellent clinical outcomes. Ultimately, this approach appears to improve the therapeutic ratio for children and young adults with this disease. Approximately 60% of LCH patients present in the head and neck where excess radiation dose could have significant long-term sequelae.

Younger patients are more vulnerable and radiosensitive than adults, and thus, this population merits more consideration for sparing of normal organs. These results support the use of contemporary, conformal radiation techniques. IMRT should be considered in pediatric and young adult patients receiving RT for LCH particularly given the long-term survival of these patients. Future research could evaluate using proton therapy to reduce the radiation dose further to the critical structures.

Abstract

Objective

Methods

Results

Conclusions

Radiotherapy has been shown to be effective in treating Langerhans cell histiocytosis (LCH) with no clearly defined role for conformal radiation techniques such as intensity-modulated radiotherapy (IMRT). The goal of this study was to evaluate clinical outcomes and radiation dose to critical normal structures in patients treated for LCH with conventional and conformal radiotherapy techniques.Sixteen patients (mean age 27.4 years, range 1-48 years) with 21 lesions treated with radiotherapy for LCH were retrospectively reviewed. The 6 IMRT-treated patients were replanned using conventional techniques and mean radiation doses to critical structures were compared using dose volume histograms (DVHs).After a median follow-up of 46.6 months (range, 3.0-341.9 months), 15 of 16 patients were alive with stable disease. Local control was 88% with IMRT and 90% with conventional radiotherapy at 5 years. One patient died after 28.5 years of follow- up due to progression of disease. All patients tolerated treatment with mild, acute toxicities. No late toxicities were reported at last follow-up. The median dose was 18 Gy (range, 7.5-4 Gy). DVH analysis showed that IMRT delivered less mean radiation dose to critical normal structures including the parotid glands, cochleae, temporal lobes, and hippocampi compared to conventional radiotherapy techniques. Mean ipsilateral parotid dose for skull-based lesions was 17 ± 0.9 Gy for IMRT and 21 ± 1.3 Gy for conventional techniques (P = 0.016). Mean temporal lobe dose was reduced in all 6 IMRT plans by up to 29% compared to conventional techniques (P = 0.021).IMRT reduces the mean radiation dose delivered to critical normal structures and should be considered in LCH treatment when radiotherapy is indicated, particularly given the expected, long-term survival of these patients.

Introduction Langerhans cell histiocytosis (LCH) is a rare disorder characterized by proliferation of myeloid dendritic cells expressing the antigens CD1a and CD207.¹ The accumulation of LCH cells results in single or multiple osteolytic bone lesions in 80% of cases, but other organ systems may also be involved including the skin, lymph nodes, lungs, liver, bone marrow, spleen, or central nervous system.² While the exact incidence of LCH is unknown, it is estimated that the annual incidence of LCH is 5 to 6 cases per million children.³ It is predominantly a disease of childhood with a peak incidence in children 1 to 3 years of age.^4,5,6 However, LCH may also be seen in adults.^7,8

Management of LCH is based on risk stratification according to extent of disease and involvement of risk organs (bone marrow, liver, or spleen).^9,10 Treatment consists of many options ranging from observation, surgical treatment of bone lesions, systemic or topical steroids, chemotherapy, and radiation therapy (RT). [¹¹] The role of radiotherapy in LCH is generally reserved for symptomatic lesions with risk of fracture, functional abnormality, or cosmetic disfiguration.11 Patients receiving radiotherapy for bony manifestations have good outcomes with a local control rate of over 90%.^12,13 Radiotherapy has also been reported to be effective in recently diagnosed diabetes insipidus (DI) secondary to LCH of the pituitary gland but not for longstanding DI, although alternative interventions are currently recommended to avoid radiation exposure to the brain.^14,15

Materials and MethodsPatients

Radiation Treatment

However, there is no literature specifically discussing conformal radiation techniques such as intensity-modulated radiotherapy (IMRT) for treatment of LCH. Conformal techniques allow for administration of radiation to the site of disease while limiting additional radiation dose to surrounding normal tissue. The aim of the present study is to review the experience of patients treated with radiotherapy for LCH at a tertiary center. The primary objectives of the study are to report on clinical response rates for LCH treated with either conventional or conformal radiation techniques. In addition, dose distributions for IMRT and conventional techniques are compared with each other by analyzing dose-volume histograms for 6 different lesions that were planned using both techniques.Between July 1983 and October 2013, 16 patients with histologically confirmed LCH, treated with radiation therapy at our institution, were retrospectively reviewed after approval from our institutional review board. A total of 21 sites of disease were treated with radiotherapy for these 16 patients. Data were obtained from electronic medical records and paper charts and included age at diagnosis, sex, presenting symptoms, location of disease, alternative types of therapy used in treatment, radiotherapy dose and technique, toxicity, local recurrence, distant recurrence, overall survival, and date of last follow-up. The mean age at the start of radiotherapy was 27.4 years (range, 1-48 years). Of the 16 patients, 8 were female and 8 were male. Table 1 summarizes patient characteristics.The median dose of radiotherapy was 18 Gy (range, 7.5-24 Gy) delivered by external beam to the site of disease. Indications for radiotherapy included unresectable disease, sites of pain, and recurrent disease. Table 2 summarizes the radiation techniques and toxicities.

Table 1. Summary of Patient Characteristics

Abbreviations: N indicates number; CNS, central nervous system.

Dose-Volume Analysis

Statistical Analysis

Table 2. Radiation Planning, Technique, and Toxicity

Abbreviations: Fr = fraction; AP = anterior-posterior; PA = posterior-anterior; 3DCRT = 3-dimensional conformal radiation therapy; IMRT = intensity- modulated radiation therapy; IGIMRT = image guided intensity-modulated radiation therapy.

Results

Clinical Outcomes

Pattern of failure was defined as either local or distant (outside of the irradiated volume). Local control (LC) was defined as the time from the last day of radiation therapy to first local failure. Progression-free survival (PFS) was measured from the last day of radiation therapy to first recurrence of disease (ie, local or distant metastasis). Overall survival (OS) was measured from the last day of radiation therapy to the date of death or last follow-up. Radiotherapy toxicity was assessed by reviewing the patient’s radiation treatment records for on-treatment visits and follow-up notes. Toxicity was rated based on National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.Six sites initially treated with IMRT were replanned using conventional techniques. Three sites were intracranial that were replanned with opposed-lateral beams. Three sites were skull-base lesions that were replanned using 3-dimensional conformal radiotherapy (3D-CRT). Dosimetric analyses were conducted by comparing the initial IMRT plans to the corresponding conventional plans. Mean dose to critical normal structures was evaluated.GraphPad Prism 6 (GraphPad Software, Inc, San Diego, CA) was used to perform statistical analysis and to calculate survival rates based on the Kaplan-Meier method. Comparisons of curves were performed with a log-rank (Mantel-Cox) test. A P-value of ≤0.05 was considered statistically significant.Twenty-one sites were treated with radiation. Ten sites received conformal radiotherapy (IMRT or 3D-CRT) and 11 sites received conventional RT. The median duration of follow-up from date of diagnosis was 46.6 months (range, 3.0-341.9 months) and 15 of 16 patients were alive with stable disease at the time of last follow-up. Nine patients (56%) had disease limited to osseous lesions at the time of diagnosis, 4 patients had soft tissue disease (25%) and 3 patients had both osseous and soft-tissue disease (19%). Eight patients were treated with surgery (50%) and 9 patients (56%) received chemotherapy. Eight patients (50%) developed endocrine involvement during the course of their disease. Six patients developed diabetes insipidus, 3 developed panhypopituitarism, and 2 patients developed primary hypothyroidism due to tablthyroidectomy for disease involvement of the thyroid. All 6 patients with diabetes insipidus were diagnosed with DI prior to receiving RT. Three of those patients with DI went on to receive RT to the pituitary. None of those 3 patients showed a reduction in desmopressin dosage following RT. Detailed patient characteristics are shown in Table 3.Results from this study showed no statistically significant difference in local failure rate for patients receiving conformal radiation techniques compared to conventional radiation techniques. Estimated local control at 5 years was 88% for the conformal group and 90% for the conventional group (Figure 1). Overall, 9 of 10 sites treated with conformal RT had local control and 10 of 11 sites treated with conventional RT had local control. Local control was better in pediatric patients than adults (100% vs 87%).

Table 3. Patient Characteristics, Treatment Details, and Patterns of Recurrence for 16 Patients With LCH

*Received ABVD chemotherapy for concurrently diagnosed HD Abbreviations: LCH = Langerhans cell histiocytosis; Pt = patient; RT = radiotherapy; CT = chemotherapy; DI = diabetes insipidus; AMS = altered mental status; CNS = central nervous system; ABVD = Adriamycin, Bleomycin, Vinblastine, Dacarbazine.

Dose-Volume Analyses

Local failure rate for the 3 radiation dose groups also showed a similar trend. Estimated local control at 5 years for 0-10 Gy, >10-20 Gy, and >20 Gy was 83%, 88%, and 100%, respectively. Overall, 4 of 10 sites in the conformal RT group and 3 of 11 sites in the conventional RT group developed either local or distant recurrences. PFS was not significantly different between the two radiation techniques. Overall survival was 100% for both radiation technique groups at 10 years. One patient in the conventional RT group died after 28.5 years of follow-up due to disease progression.Six sites initially treated with IMRT were replanned using more conventional techniques. Three intracranial lesions were replanned using opposed-lateral beams and three skull-based lesions were replanned using 3D-CRT. DVH results showed IMRT delivered less mean radiation dose to critical normal structures including the parotid glands, cochleae, temporal lobes, and hippocampi compared to conventional radiotherapy techniques. Table 4 reports percent mean dose reduction to critical structures by IMRT compared to conventional techniques. Mean temporal lobe dose was reduced in all six IMRT plans by up to 29% compared to conventional techniques (P = 0.021).

Table 4. Percent Reduction of Mean Dose to Critical Structures Using IMRT

Abbreviations: IMRT = intensity-modulated radiation therapy.

Toxicities

Discussion

Mean ipsilateral parotid dose for the 3 skull-based lesions was 17 ± 0.9 Gy for IMRT and 21 ± 1.3 Gy for conventional techniques (P = 0.016). IMRT and conventional techniques delivered similar radiation doses to the whole brain and brainstem. When utilizing IMRT, the mean RT dose to the lens and to the hypothalamic/pituitary axis remained low at 1.85 Gy (range 0.43-3.8 Gy) and 5.39 Gy (range 0.36-8.9 Gy), respectively.Irradiation was tolerated well by most patients overall. Several patients experienced mild, acute RT-related toxicities. The most common toxicity was grade 1 or 2 fatigue, which was experienced by 4 patients. Three patients experienced grade 1 or 2 pain while on treatment and 2 patients developed grade 1 nausea. No secondary malignancies were observed, with a median follow-up of 46.6 months. One patient was diagnosed with concurrent Hodgkin lymphoma involving the left axilla while undergoing radiation treatment for LCH involving the right iliac wing and lumbar spine; the patient subsequently received adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy. No other late toxicities were observed.LCH is a rare cancer that is most commonly seen in the pediatric population. The role of RT in LCH has decreased over time with current indications including sites where surgery would result in significant morbidity, painful lesions that are unresponsive to surgery, and recurrent lesions. ^11,16,17 We report on the outcomes for patients treated at a single institution with RT in an effort to assess the role of conventional versus conformal radiation techniques. Asymptomatic lesions confined to one organ system are usually best managed by observation.¹⁸ In contrast, multiple organ involvement carries a much poorer prognosis.¹¹

There has been a trend towards less use of RT for management of LCH due to better understanding of prognostic factors and grouping of patients by predicted outcomes.¹⁸

However, RT may still be indicated, especially in older patients, for local relapse after surgery, sites at risk of collapse if treated by curettage, compromise of critical structures such as the spinal cord requiring rapid response, or for pain relief.¹⁹

Several studies report favorable local control rates for LCH following RT. A meta-analysis of osseous lesions conducted by Olschewski et al¹² estimated LC to be 96% for single-system disease and 92% for multi-system disease. Another study reported a local control rate of 91.4% for disease sites across all organ systems.¹¹ Our study demonstrated favorable local control rates with 89% overall LC and 100% LC for osseous lesions.

LCH may be more responsive to treatment in younger patients. Selch et al²⁰ reported higher rates of local control in pediatric patients than in adults (100% vs 72%). The reason for this more benign disease course in children remains unclear and could be a result of small sample size (22 patients and 56 sites), but may also signify increased radiosensitivity in pediatric patients. In our study, local control was 100% in pediatric patients and 87% in adults (not statistically different).

As LCH is a radiosensitive disease, establishing the optimal number of fractions and total dose are important questions that have been addressed. Special attention must be paid to radiation dose to endochondral ossification centers, as these areas are radiosensitive. According to the literature, bone lesions were more likely to relapse following radiation doses below 450 cGy. These relapses were thought to be due to insufficient doses.²¹ Current dose recommendations represent a wide range between 6 and 30 Gy for best local control rates.¹¹ Selch et al recommended more specific dose ranges depending on disease site. That study also reported improved clinical outcomes with megavoltage than orthovoltage treatment. Patients in our study received radiation doses ranging from 7.5 Gy to 24 Gy and were all treated in the megavolt energy range. Median dose was 18.3 Gy in pediatric patients and 18.0 Gy in adults. Local control rate was not statistically significant across radiation doses in our study (P = 0.66) although this may be due to the low number of patients in our series. Previous studies have shown no difference in LC when evaluating a range of RT doses.^11,17 Jahraus et al22 demonstrated that patients treated with RT fractionation at values of 1.8 Gy or greater have better clinical outcomes. All patients in our study were treated with a radiation dose fraction of 1.8 Gy or higher.

All patients in our series with DI who received RT to the pituitary had longstanding DI (greater than 1 year). None of these patients showed improvement of their DI based on desmopressin dose requirements. This is consistent with previous studies that show RT given to recently diagnosed DI may be beneficial, but RT given to longstanding DI (greater than 2 weeks) is futile.¹⁵

One of the concerns with RT treatment in this group of long-term survivors is the potential for RT toxicity. In general, acute radiation toxicities are a less likely complication in the treatment for LCH than in other diseases due to the low-dose range of RT. However, late sequelae including musculoskeletal growth abnormalities and second malignancies have been reported.^11,19 No patients in this study experienced late toxicity from treatment, which is consistent with previous studies reporting excellent late toxicity profiles following RT for LCH.¹² There were no second malignancies with a median follow-up time of 46.6 months.

This is consistent with low rates of second malignancies reported in previous studies. Greenberg et al19 reported a second malignancy induction rate of 3.9% with median follow- up of 8.5 years for patients treated with RT for LCH.

This study investigates clinical outcomes for LCH between conformal radiation techniques such as IMRT and conventional radiation techniques. Nine out of 10 sites (90%) treated with conformal techniques experienced local control versus 10 out of 11 sites (91%) treated with conventional radiation techniques. In both groups treated with IMRT and conventional radiation techniques, radiotherapy was well tolerated. No secondary malignancies were discovered in either group after 46 months; however, the long-term effects of IMRT for reducing second cancer risks is also not clear. IMRT often employs more radiation fields and thus, there is a potential for a larger volume of normal tissue to receive lower doses.²³

However, despite the use of IMRT, doses to such radiosensitive structures such as at the lens of the eye, remained low. Whether additional areas exposed to low doses of radiation could be a risk for secondary malignancies remains unclear, and long-term follow-up with IMRT use must be obtained particularly for children. Ultimately, electron therapy for superficial lesions could be considered. For example, in our study, 2 patients were treated with electrons for a total of 4 sites, showing no acute toxicity or late complications after 46 months of follow- up. However, lesions with deeper extension often require photon techniques and this study demonstrates that IMRT can be advantageous in this setting.

While our study and other previous studies have shown RT to provide excellent clinical outcomes in the treatment of LCH, special attention must be paid to utilizing radiotherapy techniques that limit dose to critical normal structures such as the temporal lobes and hippocampus. Radiotherapy to the temporal lobes may result in memory, language, motor, and executive function deficits.²⁴

Modest doses to the hippocampus may lead to cognitive impairment, and conformal avoidance of this structure has been shown to preserve memory.^25,26 Gondi et al²⁶ conducted a single-arm phase II study that compared patients treated with whole brain radiation therapy (WBRT) considering hippocampal avoidance with a historical control group with WBRT alone. Of 42 patients analyzed at 4 months, mean relative decline in Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) from baseline to 4 months was 7.0% (95% CI, —4.7% to 18.7%), significantly lower compared to historical controls (P <.001).

Also, Deng et al²⁷ demonstrated evidence for the important role for adult hippocampal neurogenesis in learning and memory by finding that newborn neurons associated with hippocampal functions may contribute to mnemonic function in mice models. Reducing the dose to these critical structures is especially important in the treatment of LCH given the long-term survival of these patients. Dosimetric comparison of treatment plans in this study shows IMRT delivers less dose to critical intracranial normal structures compared to conventional techniques.

Conclusion

Limitations of this series include the retrospective nature of the study and the limited number of patients. It is important to note that many LCH lesions resolve spontaneously, and 9 of 16 patients in our cohort received systemic therapy at some point for their disease. Therefore, clinicians must be cognizant of the variable natural history of LCH and the impact of systemic therapies when evaluating the efficacy of radiotherapy in the resolution of LCH lesions. Although further follow-up is required to investigate potential late effects of radiotherapy such as growth abnormalities, neurocognitive dysfunction, and secondary malignancies, our median follow-up to date has not demonstrated evidence of significant late sequelae. There are certainly risks associated with RT when administered to young patients, but these risks should be weighed against the potential morbidity associated with salvage treatment in the setting of disease recurrence. Given the potential long-term morbidity associated with radiotherapy in children, candidates for RT should be carefully selected.Radiotherapy has been shown to be effective in the treatment of LCH. However, the role of conformal radiotherapy techniques compared with conventional techniques has not been well studied. This study demonstrates IMRT delivers less radiation dose to critical normal structures compared to conventional RT while providing similar local control and overall survival. RT was well tolerated in our patient cohort, with expected acute toxicities and without significant long-term side effects. IMRT should be considered in all patients receiving RT for Langerhans cell histiocytosis, particularly given the long-term survival of these patients.

ABOUT THE AUTHORS

Temple University School of Medicine (RG), Philadelphia, PA. Johns Hopkins School of Medicine (QC, YZ, AEM, SAT), Baltimore, MD. University of Washington (JZ), Seattle, WA, Ronald A. Matricaria Institute of Molecular Medicine at Phoenix Children’s Hospital, University of Arizona (RJA), Phoenix, AZ.

Address correspondence to: Stephanie A. Terezakis, MD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Department of Radiation Oncology and Molecular Radiation Sciences, 401 N. Broadway, Baltimore, MD 21231; Phone: (443) 287-7889, Fax: (410) 502-1419. E-mail: stereza1@jhmi.edu

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