Despite great strides forward in the organ preservation treatment of head and neck cancer, recurrent disease in the inoperable patient afflicted with squamous cell carcinoma of the head and neck (SCCHN) often remains challenging. Re-excision is usually limited by radiation effect of prior treatment, or a history of a prior resection. For these patients, systemic therapy, re-irradiation, and other supportive care are often the only available options.

Systemic therapy alone is typically considered the standard palliative treatment option for recurrent SCCHN patients. Re-irradiation of the head and neck can be fraught with hazards due to normal tissue tolerance saturation from prior radiation treatments. Little available normal tissue tolerance will often result in a sub-optimal treatment plan. Older palliative radiation regimens such as ”quad-shot“ therapy require considerable expertise in treating these types of patients in order to be administered safely.

This interesting single institutional study by Patel et al is contemporary as it addresses the use of low-dose fractionated radiation therapy (LDFRT) in addition to cetuximab and docetaxel in patients in this unique situation. The investigators used a regimen as follows: cetuximab 400mg/m2 was given as loading dose only on day 1 of week 1 and then, subsequently, in 250 mg/m

 weekly doses on day 1 of each following week (weeks 2 to 7). Docetaxel 20 mg/ m

 was administered weekly on day 1 from week 2 to 7. Radiotherapy consisted of 0.5 Gy/fraction twice a day at least 6 hours apart on days 2 and 3 of weeks 2 to 7 for a total dose of 12 Gy. Patel at al suggest that this regimen is well-tolerated, however the benefit may be marginal.

For this appropriate subset of patients, LDFRT and chemotherapy may offer transient palliation accompanied by low treatment related morbidity.

In this phase II study, cetuximab 400 mg/m

 was given in the usual loading dose only on day 1 of week 1 and then, subsequently, in 250mg/m

 weekly doses on day 1 of each following week (weeks 2-7). Docetaxel 20 mg/m

 was administered weekly on day 1 from week 2-7. Radiotherapy consisted of 0.5 Gy/fraction BID at least 6 hours apart on days 2 and 3 of weeks 2-7 for a total dose of 12 Gy.

Nine patients were screened, 5 patients were enrolled, and 4 patients were treated between October 2013 through February 2015. After completion of salvage treatment per protocol, at 1 month follow up, partial response was seen in 2 patients (50%), stable disease in 1 patient (25%), and progressive disease in 1 (25%) patient. By 6 months, all patients had progressive disease, 1 patient (25%) completed a full course of re-irradiation, and 1 patient (25%) received further chemotherapy for progression. Treatment-related morbidity was limited to diffuse grade 1 skin toxicity reported in all patients. The Data Safety and Monitoring Board suggested closing this protocol as clinical response approached the predefined futility endpoint for complete response.

Low-dose radiotherapy in addition to docetaxel and cetuximab was well tolerated although treatment effects were transient. More durable treatment options may exist for definitive treatment; however, this protocol may offer palliation to select patients.

Local/regional failure after definitive radiotherapy (RT) remains a significant problem particularly in advanced stage head and neck cancer.1-3 Approximately 50% to 60% of patients who fail initial definitive treatment will die as a direct consequence of locally or regionally recurrent disease.

Surgical salvage is sometimes successful, but not always feasible due to disease extent, location, or patient comorbidities.

For these patients, systemic therapy, re-irradiation, and supportive care may be the only remaining options.

Historically, prior to when re-irradiation was not yet commonly used, systemic therapy alone was considered the remaining palliative treatment option for inoperable patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). Use of platinum-based chemotherapy has been associated with response rates of less than 50% and a median overall survival (OS) of 6-8 months.

 More recently, cetuximab therapy has demonstrated improved response rates and survival in platinum-refractory SCCHN compared with historical controls.

 In a study of 442 patients randomized to receive a platinum-based chemotherapy and fluorouracil with or without cetuximab, the addition of cetuximab significantly prolonged the median OS to 10.1 months versus 7.4 months in the control arm.

 Furthermore, the same authors reviewed 3 separate phase II trials in patients with recurrent or metastatic SCCHN who progressed on platinum-based therapies and found that the addition of cetuximab led to additional improvement in response rates from 10-13%.

 The authors concluded that cetuximab may prolong survival in patients with SCCHN who fail first-line therapy.

Re-irradiation of the head and neck may be fraught with difficulties in relation to concerns regarding normal tissue tolerance and, sometimes, tumor radioresistance.

 More recently, preclinical and clinical data have shown that re-irradiation is feasible and may provide improved disease control translating into superior survival in subsets of patients; albeit, in the setting of potentially high toxicity profile.

Various types of RT delivery, such as conventionally fractionated therapy, hyperfractionation, brachytherapy, and stereotactic body RT have been attempted with and without concurrent chemotherapy in this group of patients.

In appropriately selected patients who are able to undergo re-irradiation, there is usually an improved disease response compared to systemic therapy alone; however, there also continues to be a notable risk of treatment related morbidity with such combination therapy.

In contrast to the paucity of treatment options for patients in the loco-regionally recurrent and unresectable setting, there have been numerous developments in the primary treatment of SCCHN. Low-dose fractionated RT (LDFRT) is a novel approach that has been utilized in the treatment of loco-regionally very advanced SCCHN as a means of decreasing the toxicity of re-irradiation. LDFRT resulted in more effective cell-kill than was predicted by the linear quadratic model in preclinical studies, possibly, through both the hyper-radiation sensitivity (HRS) phenomenon and/or through potentiating the effect of chemotherapy.

 Early work by groups such as Joiner and colleagues showed an initial phase of HRS in head and neck cell lines that were exposed to doses less than 1 Gy, specifically around 0.5 Gy.

 In this low dose region there exists a paradoxical increase in tumor cell kill compared with higher doses. It is hypothesized that HRS does not cause the initiation of DNA repair mechanisms that would otherwise arrest these cells for repair in the G2 phase. As such, these damaged cells ultimately undergo cellular death.

The use of LDFRT along with chemotherapy has also demonstrated a chemo-potentiating role. In vitro data initially revealed that LDFRT potentiates the effects of the paclitaxel in both wild type and mutant 

 Furthermore, LDFRT in both cell lines caused an up-regulation in the pro-apoptotic protein, BAX, and a down-regulation in anti-apoptotic proteins, BCL-2 and NF-kB. The combined effects of LDFRT and docetaxel therapy on the growth of SCCHN were also evaluated in the nude mouse model to elicit the HRS phenomenon present in G2/M cell cycle.

 Combination therapy showed a significant improvement in both tumor regression and local control. Additionally, molecular analysis of resected tumor specimens demonstrated that Bax levels were elevated with concomitant increase in cytochrome c release to the cytosol in the LDFRT and docetaxel group. These findings strongly suggest that LDFRT can be used in combination with docetaxel to potentiate the effects of docetaxel on tumor regression through an apoptotic mode of death. As such, the G2/M cell cycle arrest by docetaxel appears to be an important component of the enhanced apoptotic effect of LDFRT + docetaxel combined treatment.

The aforementioned in vitro and in vivo studies also led to a clinical trial: Gleason et al evaluated 39 patients with loco-regionally advanced SCCHN in a phase II clinical trial treated with induction paclitaxel, carboplatin, and LDFRT every 21 days for 2 cycles.25 RT consisted of 80 cGy BID on days 1 and 2 to a total dose of 640 cGy. Initial results were promising and showed a response rate of 90% at the primary disease site and 69% at the nodal site.26 Five-year follow-up was similar to historical controls showing an OS of 62% and progression-free survival (PFS) of 58%. In this study, treatment-related toxicity was minimal.

Our novel approach to treat recurrent SCCHN was based on the following 5 hypotheses, extrapolated from the aforementioned data: 1) LDFRT would be utilized to sensitize chemotherapy 2) low dose HRS response would be significantly enhanced in docetaxel-induced G2/M cell cycle arrest, 3) LDFRT would render enhanced BAX activation mediated mode of apoptotic cell death 4) cetuximab would help arrest the cells in G1/G0 phase leading to p21-mediated mode of cell death, and 5) the toxicity profile would be expected to be minimal. The purpose of this study is to describe our initial exploratory experience with LDFRT in addition to docetaxel and cetuximab in the setting of recurrent SCCHN.

Study and patient characteristics / eligibility criteria This study was Institutional Review Board approved, Investigational New Drug exempt, and Health Insurance Portability and Accountability Act compliant. In addition to having loco-regional recurrence in the head and neck, all patients fulfilled all the following inclusion criteria: 1) Eastern Cooperative Oncology Group (ECOG) performance status of 0—2, 2) histo-pathologically confirmed recurrence of SCCHN, 3) not candidates for surgical salvage treatment due to unresectability, and 4) a period of at least 6 months from the completion of prior RT. Exclusion criteria included distant metastases outside the head and neck, primary in the nasopharynx or salivary glands, other invasive malignancies, or medical illnesses impairing ability to receive treatment.

The plan was to enroll 25 evaluable patients and follow them for a minimum of 2 additional years. The primary objective was to show an improvement of response rate of 40% with chemotherapy alone to 70% with the addition of LDFRT. Considering the possibility that 5% of study-eligible patients will not be evaluable, we aimed to enroll 27 patients to ensure an analysis set of 25 patients who would be evaluable for efficacy. This sample size would provide reasonable precision in estimating the overall response rate (ORR) as preliminary evidence that the proposed docetaxel-cetuximab-LDFRT treatment is efficacious in this population. ORR is defined as rate of patients achieving complete response (CR) or partial response (PR). Secondary objectives consisted of a safety profile along with an estimate of PFS and OS.

Cetuximab 400mg/m2 IV was administered as a loading dose 1 week prior to RT and then cetuximab 250mg/m

 IV was given weekly on day 1 of weeks 2 to 7. Docetaxel 20mg/ m2 IV was given weekly on day 1 of week 2 to 7. LDFRT consisted of 0.5 Gy/fraction BID via intensity modulated radiotherapy at least 6 hours apart on day 2 and 3 of weeks 2 to 7 for a total dose of 12 Gy. Total therapy lasted for a total of 7 weeks. Figure 1 reviews the treatment schema.

 Patients were assessed weekly in the Department of Radiation Oncology. Every week, complete blood counts, and chemistries were evaluated to evaluate hematologic toxicity. NCI-Common terminology criteria for adverse events (CTCAE) version 4.0 was utilized for documentation of toxicity.

Follow-up visits consisting of history and physical examination were performed at 1, 3, 6, and 9 months. Four weeks after treatment a CT or MRI of the head and neck were obtained. Response was evaluated by the treating physician defined as follows : CR was defined as disappearance of the target lesions, PR was defined as at least a 30% decrease in size of the lesion, progressive disease (PD) was defined as at least a 20% increase in the size of the lesion, and stable disease (SD) was defined as insufficient changes to qualify for the aforementioned end points of PR or PD. Patients that had less than a CR were recommended for further treatment with RT or chemotherapy at the discretion of the treating physician.

Proposals were set in place for the Data Safety Monitoring Committee (DSMC) to stop the trial bases on response or toxicity data. These guidelines were developed using Bayesian methods that could be applied at any phase of enrollment without advance specification of the number of interim analyses to be performed. Under these methods, a prior probability is assigned to possible values for response and toxicity data. As data on treated patients becomes available, the probability distributions are revised and the resulting posterior probability becomes the basis for recommending either continuation or termination of the study.

Patients Between October 2013 and February 2015, 9 patients were screened for this institutional study to receive LDFRT, cetuximab, and docetaxel. Four patients were found to be ineligible for the study as 1 patient had metastatic disease on further work up, 1 patient had a poor performance status, 1 patient elected hospice, and 1 patient died prior to enrollment.

Five patients were enrolled in this study; however, 4 patients were ultimately treated as 1 patient was found to have a poor performance status and was not recommended for further treatment at the discretion of the treating physician. Table 1 lists the characteristics of the patients included in this study. All patients were male. Primary disease sites were the larynx, in 2 patients, floor of mouth in 1 patient, and the tonsillar fossa in another. 

Only 1 patient received surgery as treatment for their primary tumor followed by RT consisting of 66 Gy whereas 3 patients received definitive chemoradiation consisting of cisplatin 100mg/m2 q3 weeks and RT dose of 70 Gy to their primary tumor. Time from end date of definitive primary treatment to therapy for recurrent disease ranged from 13 to 26 months. Four patients completed the reirradiation protocol and were able to tolerate treatment.

All the patients had grade 1 fatigue attributed to both chemotherapy and radiotherapy treatment. All patients had grade 1 rash ascribed to chemotherapy. There was no grade 2 or higher toxicity.

At 1 month follow up, PR was seen in 2 patients (50%), SD in 1 patient (25%), and PD in 1 (25%) patient. By 6 months, all patients had PD. One patient (25%) underwent a second course of re-irradiation consisting of 58 Gy in 2 Gy/ fraction as salvage treatment at progression and 1 patient (25%) underwent chemotherapy. Table 2 summarizes treatment response. Given that the accumulating data suggested that the ORR was no better than 40%, the DSMC recommended early discontinuation due to lack of efficacy as previously outlined.

To our knowledge, this is the first study to evaluate the use of LDFRT with chemotherapy in patients with recurrent SCCHN. The primary endpoint for assessing efficacy was overall response rate. The secondary objectives were treatment- related acute and long-term toxicities and estimate of PFS and OS. In this exploratory analysis, we found an initial 75% rate of stable or responsive disease. The treatment effect was transient, with all patients experiencing PD at 6 months. The treatment was tolerated well with all patients experiencing grade 1 fatigue and rash and no reported grade 2 or higher toxicity. The DSMC suggested closing this protocol early as results were approaching the predefined futility endpoint.

 In the setting of nonsurgical treatment options for patients with recurrent SCHHN, there is a paucity of randomized data evaluating the comparative benefit of treatment options. Provider treatment biases as demonstrated in part by selection of healthier patients into surgical series as well as the heterogeneity present in the remaining patient population may account for this dearth of comparative clinical data. Consequently, national phase III studies such as RTOG 0421, a randomized trial designed to evaluate concurrent re-irradiation and chemotherapy versus chemotherapy alone in patients with recurrent head and neck cancer, were closed early due to inadequate patient accrual. Even after overcoming the challenge of enrolling patients, there are numerous difficulties in maintaining a clinical trial within this select, chronically ill, and unstable population. Nine patients were originally screened, but only 4 were treated due to rapidly deteriorating functional status of the excluded patients. Furthermore, this trend of incomplete clinical trial data continues as this trial was closed early.

Prior to our protocol design, a study evaluating LDFRT, paclitaxel, and carboplatin in patients with primary locally advanced SCCHN was initially reported by Arnold et al.26 In their study, the response rate was initially high at the primary site and nodal site. Our study was in part motivated by these developments; however, more recently these originally promising results were published as a 5-year follow-up with the mature data matching historic data in respect to DFS and OS.25 In the recurrent SCHHN setting, the treatment effect with LDFRT and chemotherapy appears to be more transient as seen with our experience. This reason may be in part due to a lower threshold for DNA repair due to previous treatment or even an inherent and selected radioresistance in cells surviving a previous full course of radiotherapy.

Early work with LDFRT unveiled the concept of HRS in which low doses of radiation paradoxically increased tumor cell kill as compared to conventional doses.23 Hypothetically, HRS related damage is below the threshold of DNA repair initiation that would otherwise be recognized (eg, double strand damage that occurs after conventional doses). As such, the cell undergoes an apoptotic death.25 Depending on the study, this area of HRS is described as being in the <1 Gy range usually described broadly from 0.1—0.8 Gy region of the cell survival curve.22-24 Notably this area of HRS is swiftly followed by an area of increased radioresistance (IRR). IRR is thought to represent repair mechanism initiation after a dose active increase in ATM activity and G2 checkpoint function.27 As such, radiation induced damage triggers activation of repair mechanisms in the region of IRR. Some studies have described this area of IRR being present in the 0.3&mdash;1 Gy range.24,27 As such, it is plausible that 0.5 Gy may be too high of a dose to take advantage of HRS and may even conversely fall into an area of IRR.

This is also the first study to use cetuximab and docetaxel in conjunction with LDFRT in patients with recurrent SCCHN. We based the use of cetuximab on the favorable response seen in patient receiving cetuximab in the recurrent setting while docetaxel was chosen due to the potentiating effect of LDFRT based upon the aforementioned in vitro and in vivo clinical data.14,22,25,28 Although the potentiating effect of docetaxel is well described, there could be more of a potentiation role with other chemotherapeutic agents. It appears that LDFRT and both chemotherapeutic agents were very well tolerated compared to published experiences of multidrug chemotherapy regimens alone.10,11,29 From our single institutional experience, patients with loco-regionally recurrent unresectable SCCHN should be treated with more established RT techniques as they may not optimally benefit from this protocol.2,8 In patients with more limited options, as those presenting with metastatic disease, LDFRT with cetuximab and docetaxel may offer transient palliation with minimal morbidity.

Although there have been numerous improvements in the primary treatment of SCCHN, treatment of recurrent disease in inoperable patients is challenging. From our single- institutional experience, low-dose RT in addition to cetuximab and docetaxel is well-tolerated in patients with recurrent SCCHN. More long-term treatment options may exist in patients with recurrent SCCHN; however, for a select group of patients, LDFRT and chemotherapy may offer transient palliation in the setting of low morbidity.

Department of Radiation Oncology, University of Miami, Miami FL (VNP, HJN, MAS, LMF, NME, MCA). Department of Biostatistics, University of Miami, Miami FL (DK). Department of Otolaryngology, University of Miami, Miami, FL (CI). Department of Medical Oncology, University of Miami, Miami, FL (DW).

Supported by a research grant from the American Cancer Society (Grant # IRG9827710). Sylvester Comprehensive Cancer Center provided resources and the use of facilities to support this research investigation.

 Matthew C. Abramowitz, MD, Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, 1275 NW 14th St. Miami, FL, 33136. E-mail: mabramowitz@med.miami.edu

Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. 

Marur S, Forastiere AA. Head and neck squamous cell carcinoma: update on epidemiology, diagnosis, and treatment. 

. 2016;91(3):386-396. doi: 10.1016/j.mayocp.2015.12.017.

Strom T, Wishka C, Caudell JJ. Stereotactic body radiotherapy for recurrent unresectable head and neck cancers. 

Hong WK, Bromer RH, Amato DA, et al. Patterns of relapse in locally advanced head and neck cancer patients who achieved complete remission after combined modality therapy. 

Zafereo M. Surgical salvage of recurrent cancer of the head and neck. 

. 2014;16(5):386. doi: 10.1007/s11912-014-0386-0.

Strojan P, Corry J, Eisbruch A, et al. Recurrent and second primary squamous cell carcinoma of the head and neck: when and how to reirradiate. 

. 2015;37(1):134-150. doi: 10.1002/hed.23542.

Wong SJ, Machtay M, Li Y. Locally recurrent, previously irradiated head and neck cancer: concurrent re-irradiation and chemotherapy, or chemotherapy alone? 

Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. 

. 2015;33(29):3305- 3313. doi: 10.1200/JCO.2015.62.0963.

Ho AS, Kraus DH, Ganly I, Lee NY, Shah JP, Morris LG. Decision making in the management of recurrent head and neck cancer. 

. 2014;36(1):144- 151. doi: 10.1002/hed.23227.

Colevas AD. Chemotherapy options for patients with metastatic or recurrent squamous cell carcinoma of the head and neck. 

Colevas AD. Systemic Therapy for Metastatic or Recurrent Squamous Cell Carcinoma of the Head and Neck. 

Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. 

Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. 

. 2008;359(11):1116-1127. doi: 10.1056/NEJMoa0802656

Vermorken JB, Herbst RS, Leon X, Amellal N, Baselga J. Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. 

. 2008;112(12):2710-2719. doi: 10.1002/cncr.23442.

Soltys B, Wiazzane N, Mirjolet C, et al. [Reirradiations of head and neck cancers: state of the concept and ways of development]. 

 2013;17(5-6):508-512. doi: 10.1016/j.canrad.2013.07.142.

Peponi E, Balta S, Tasiou I, et al. Reirradiation for recurrent head and neck carcinoma. 

Chen AM, Phillips TL, Lee NY. Practical considerations in the re-irradiation of recurrent and second primary head-and-neck cancer: who, why, how, and how much? 

. 2011;81(5):1211-1219. doi: 10.1016/j. ijrobp.2011.06.1998.

Cacicedo J, Navarro A, Alongi F, et al. The role of re-irradiation of secondary and recurrent head and neck carcinomas. Is it a potentially curative treatment? A practical approach. 

. 2014;40(1):178-189. doi: 10.1016/j.ctrv.2013.08.002.

Mouttet-Audouard R, Gras L, Comet B, Lartigau E. Evidence based and new developments in re-irradiation for recurrent or second primary head and neck cancers. 

. 2012;20(2):137-141. doi: 10.1097/MOO.0b013e3283506a52.

Riaz N, Hong JC, Sherman EJ, et al. A nomogram to predict loco-regional control after re-irradiation for head and neck cancer. 

. 2014;111(3):382-387. doi: 10.1016/j.radonc.2014.06.003.

Spring PM, Arnold SM, Shajahan S, et al. Low dose fractionated radiation potentiates the effects of taxotere in nude mice xenografts of squamous cell carcinoma of head and neck. 

Dey S, Spring PM, Arnold S, et al. Low-dose fractionated radiation potentiates the effects of Paclitaxel in wild-type and mutant p53 head and neck tumor cell lines. 

Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: current status and possible mechanisms. 

Marples B, Collis SJ. Low-dose hyper-radiosensitivity: past, present, and future. 

. 2008;70(5):1310-1318. doi: 10.1016/j. ijrobp.2007.11.071.

Gleason JF, Jr., Kudrimoti M, Van Meter EM, et al. Low-dose fractionated radiation with induction chemotherapy for locally advanced head and neck cancer: 5 year results of a prospective phase II trial. 

Arnold SM, Regine WF, Ahmed MM, et al. Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. 

Krueger SA, Collis SJ, Joiner MC, Wilson GD, Marples B. Transition in survival from low-dose hyper-radiosensitivity to increased radioresistance is independent of activation of ATM Ser1981 activity.

Specenier PM, Vermorken JB. Recurrent head and neck cancer: current treatment and future prospects. 

. 2008;8(3):375-391. doi: 10.1586/14737140.8.3.375.

Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. 

Articles

This study evaluates low dose radiotherapy in combination with docetaxel and cetuximab in patients with recurrent, unresectable squamous cell carcinoma of the head and neck initially treated with definitive chemo-radiation therapy.

Radiation for Chemo-Sensitization: A Phase II Trial of Cetuximab and Docetaxel With Low-Dose Fractionated Radiation for Recurrent Unresectable Locally Advanced Head and Neck Carcinoma

Associate Professor, University of Florida Proton Therapy Institute

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.

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 (

 = 0.016). Mean temporal lobe dose was reduced in all 6 IMRT plans by up to 29% compared to conventional techniques (

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.

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.

 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.

 It is predominantly a disease of childhood with a peak incidence in children 1 to 3 years of age.

Management of LCH is based on risk stratification according to extent of disease and involvement of risk organs (bone marrow, liver, or spleen).

 Treatment consists of many options ranging from observation, surgical treatment of bone lesions, systemic or topical steroids, chemotherapy, and radiation therapy (RT). [

] 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%.

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.

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. 

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.

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.

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 

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 

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

. 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.

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 

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

Abbreviations: IMRT = intensity-modulated radiation therapy.

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 (

 = 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. 

 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.

 In contrast, multiple organ involvement carries a much poorer prognosis.

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.

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.

Several studies report favorable local control rates for LCH following RT. A meta-analysis of osseous lesions conducted by Olschewski et al

 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.

 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 al

 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.

 Current dose recommendations represent a wide range between 6 and 30 Gy for best local control rates.

 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 (

 = 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.

 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.

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.

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.

 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.

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.

Modest doses to the hippocampus may lead to cognitive impairment, and conformal avoidance of this structure has been shown to preserve memory.

 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 (

 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.

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.

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.

 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

Allen CE, Li L, Peters TL, el. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. 

. 2010;184(8):4557-4567. doi: 10.4049/jimmunol. 0902336.

Grois N, Pötschger U, Prosch H, et al; DALHX- and LCH I and II Study Committee. Risk factors for diabetes insipidus in Langerhans cell histiocytosis. 

Howarth DM, Gilchrist GS, Mullan BP, Wiseman GA, Edmonson JH, Schomberg PJ. Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome. 

Ghanem I, Tolo VT, D’Ambra P, Malogalowkin MH. Langerhans cell histiocytosis of bone in children and adolescents. 

Bhatia S, Nesbit ME Jr, Egeler RM, Buckley JD, Mertens A, Robison LL. Epidemiologic study of Langerhans cell histiocytosis in children.

Muller J, Koós R, Garami M, et al. [Experiences with Langerhans’ cell histiocytosis in children in Hungary]. 

Baumgartner I, von Hochstetter A, Baumert B, Luetolf U, Follath F. Langerhans’- cell histiocytosis in adults. 

Malpas JS, Norton AJ. Langerhans cell histiocytosis in the adult. 

Grifo AH. Langerhans cell histiocytosis in children.

. 2009;26(1):41-47. doi: 10.1177/1043454208323915.

Minkov M. Multisystem Langerhans cell histiocytosis in children: current treatment and future directions. 

. 2011;13(2):75-86. doi: 10.2165/11538540-000000000-00000

Kotecha R, Venkatramani R, Jubran RF, Arkader A, Olch AJ, Wong K. Clinical outcomes of radiation therapy in the management of Langerhans cell histiocytosis. 

 2014;37(6):592-596. doi: 10.1097/ COC.0b013e318281d6ce.

Olschewski T, Seegenschmiedt MH. Radiotherapy for bony manifestations of Langerhans cell histiocytosis. Review and proposal for an international registry. 

Olschewski T, Seegenschmiedt MH. Radiotherapy of Langerhans’ cell histiocytosis : results and implication of a national Patterns-of-Care Study. 

el-Sayed S, Brewin TB. Histiocytosis X: does radiotherapy still have a role? 

Rosenzweig KE, Arceci RJ, Tarbell NJ. Diabetes insipidus secondary to Langerhans’ cell histiocytosis: is radiation therapy indicated? 

Arceci RJ, Brenner MK, Pritchard J. Controversies and new approaches to treatment of Langerhans cell histiocytosis. 

Kriz J, Eich HT, Bruns F, et al. Radiotherapy in Langerhans cell histiocytosis - a rare indication in a rare disease. 

 2013;8:233. doi: 10.1186/1748-717X-8-233.

Greenberger JS, Crocker AC, Vawter G, Jaffe N, Cassady JR. Results of treatment of 127 patients with systemic histiocytosis (Letterer-Siwe syndrome, Schuller-Christian syndrome and multifocal eosinophilic granuloma). 

Greenberger JS, Cassady JR, Jaffe N, Vawter G, Crocker AC. Radiation therapy in patients with histiocytosis: management of diabetes insipidus and bone lesions. 

Selch MT, Parker RG. Radiation therapy in the management of Langerhans cell histiocytosis. 

Pereslegin IA, Ustinova VF, Podlyaschuk EL: Radiotherapy for eosinophilic granuloma of bone

Jahraus CD, Russo S, Peñagarícano J, Routh A, St Clair W. Radiotherapy dose fractionation in pediatric Langerhans cell histiocytosis.

Ng J, Shuryak I. Minimizing second cancer risk following radiotherapy: current perspectives. 

Cheung MC, Chan AS, Law SC, Chan JH, Tse VK. Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis. 

Raber J, Rola R, LeFevour A, et al. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. 

Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. 

. 2014;32(34):3810-3816. doi: 10.1200/ JCO.2014.57.2909.

Intensity-modulated radiotherapy reduces the mean radiation dose delivered to critical normal structures and should be considered in Langerhans cell histiocytosis treatment when radiotherapy is indicated, particularly given the expected, long-term survival of these patients.

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