sábado, 29 de junio de 2019

Langerhans Cell Histiocytosis Treatment (PDQ®) 7/7 —Health Professional Version - National Cancer Institute

Langerhans Cell Histiocytosis Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Langerhans Cell Histiocytosis Treatment (PDQ®)–Health Professional Version



Treatment of Adult LCH

Standard Treatment Options

The lack of clinical trials limits the ability to make evidence-based recommendations for adult patients with Langerhans cell histiocytosis (LCH).
Most investigators have previously recommended treatment according to the guidelines for the treatment of childhood LCH. It is unclear, however, whether adult LCH responds as well as the childhood form of the disease. In addition, the drugs used in the treatment of children are not as well tolerated when used in adults. Excessive neurologic toxicity from vinblastine, for example, prompted closure of the LCH-A1 trial.
A consensus opinion reported on the evaluation and treatment of adult patients with LCH.[1] Discussion continues, particularly with regard to optimal first-line therapy, with some experienced clinicians preferring to start with vinblastine and prednisone and others with alternative therapy, such as single-agent cytosine arabinoside or cladribine.[2][Level of evidence: 3iiiC]

Treatment of pulmonary LCH

It is difficult to judge the effectiveness of various treatments for pulmonary LCH because patients can recover spontaneously or have stable disease without treatment.
Treatment options for adult patients with pulmonary LCH include the following:
  1. Smoking cessation. Smoking cessation is mandatory because of the apparent causal effect of smoking in pulmonary LCH.[3] Most adult patients with LCH have gradual disease progression with continued smoking. The disease may regress or progress with the cessation of smoking.[4] A study of 27 patients with pulmonary LCH observed that 52% of patients improved after a mean follow-up period of 14 months; most patients improved with smoking cessation, and some patients improved with steroid treatment. Four patients (15%) had stable disease at a mean follow-up of 26 months, and nine patients (33%) demonstrated disease progression during the mean follow-up of 22 months.[5]
  2. Steroid therapy. It is not known whether steroid therapy is efficacious in the treatment of adult pulmonary LCH because reported case series did not control for smoking cessation.[3]
  3. Chemotherapy. Some patients have been reported to respond to cladribine therapy.[3,6]
  4. Lung transplantation. Lung transplantation may be necessary for adults with extensive pulmonary destruction from LCH.[7] This multicenter study reported 54% survival at 10 years posttransplant, with 20% of patients having recurrent LCH that did not impact survival; longer follow-up of these patients is needed.[7] Another study confirmed an approximate 50% survival at 10 years and improved hemodynamic changes associated with pulmonary arterial hypertension, but did not alter pulmonary function testing or incidence of pulmonary edema.[8]
The best strategy for follow-up of pulmonary LCH includes physical examination, chest radiographs, lung function tests, and high-resolution computed tomography (CT) scans.[9]

Treatment of bone LCH

Treatment options for adult patients with bone LCH include the following:
  1. Curettage followed by observation, with or without intralesional corticosteroids.As in children, adults with single-bone lesions should undergo curettage of the lesion followed by observation, with or without intralesional corticosteroids. Extensive or radical surgery leading to loss of function and disfigurement is contraindicated at any site, including the teeth or jaw bones.
  2. Systemic chemotherapy. Systemic chemotherapy will cause bone lesions to regress. A variety of chemotherapy regimens, including cladribine, have been published in the treatment of a relatively limited number of patients. (Refer to the Chemotherapy for the treatment of other single-system disease and multisystem disease section of this summary for more information.)
  3. Low-dose radiation therapy. For those failing chemotherapy, low-dose radiation therapy may be indicated and should be tried before any radical surgery that leads to extensive loss of function and disfigurement. Radiation therapy is also indicated for impending neurological deficits from vertebral body lesions or visual problems from orbital lesions. Two series have reported the following:
    • A German cooperative radiation therapy group reported on a series of 98 adult patients with LCH, most of whom (60 of 98) had only bone lesions, and 24 had multisystem disease including bone, treated with radiation therapy.[10][Level of evidence: 3iiiDiv] Of 89 evaluable patients, 77% achieved a complete remission, 9% developed an infield recurrence, and 15.7% (14 of 89) experienced a progression outside the radiation field(s).
    • A retrospective analysis of 80 patients treated with radiation therapy alone reported a 77% complete remission rate and a 12.5% partial remission rate, with 80% long-term control noted in adults. No adverse late effects were reported.[11]
  4. Bisphosphonate therapy. Case reports and case series have described the successful use of bisphosphonates, both intravenous pamidronate and oral zoledronate, in controlling severe bone pain in patients with multiple osteolytic LCH bone lesions.[12-14] A multi-institutional review of bisphosphonate therapy in children and adults with LCH found that most adult patients were given oral zoledronic acid, and most pediatric patients were given pamidronate.[15] Because of the increased toxicity of chemotherapy in adults, bisphosphonate therapy could be used before chemotherapy in multifocal bone disease. Response of other organs, such as skin and soft tissue, to bisphosphonate therapy has been reported.[16]
  5. Anti-inflammatory agents with trofosfamide. Another approach using anti-inflammatory agents (pioglitazone and rofecoxib) coupled with trofosfamide in a specific timed sequence was successful in two patients who had disease resistant to standard chemotherapy treatment.[17]

Treatment of single-system skin disease

Treatment options for adult patients with single-system skin disease include the following:
  1. Surgical excision. Localized lesions can be treated by surgical excision, but as with bone, mutilating surgery, including hemivulvectomy, should be avoided unless the disease is refractory to all available therapy.
  2. Topical therapy. Topical therapies are described in greater detail in the childhood isolated skin involvement section of this summary and include the following:
    • Topical or intralesional corticosteroid.
    • Topical tacrolimus.
    • Topical imiquimod.[18,19]
    • Psoralen and long-wave ultraviolet A radiation (PUVA) and UVB. Therapies such as PUVA/UVB may be more useful in adults because long-term toxicity may be reduced.[20,21]
  3. Systemic therapy. Systemic therapy for severe skin LCH includes oral methotrexate, hydroxyurea, oral thalidomide, oral interferon-alpha, or combinations of interferon and thalidomide.[22-24] Interferon and thalidomide are also used to treat chronic adult skin LCH.[25] Recurrences may occur after treatment is stopped but may respond to re-treatment.
    Oral isotretinoin has induced remission in some refractory cases of skin LCH in adults.[26]
Chemotherapy is generally used for skin LCH associated with multisystem disease in adults.

Chemotherapy for the treatment of other single-system disease and multisystem disease

Evidence (chemotherapy for the treatment of other single-system disease [not mentioned above] and multisystem disease):
  1. A single-center, retrospective review of 58 adult patients with LCH reported on the efficacy and toxicities of treatment with vinblastine/prednisone, cladribine, and cytarabine.[27]
    • Patients treated with vinblastine/prednisone had the worst outcome, with 84% not responding within 6 weeks or relapsing within a year.
    • The no-response/relapse rate was 59% for cladribine and 21% for cytarabine.
    • Grade 3 or 4 neurologic toxic effects occurred in 75% of patients treated with vinblastine.
    • Grade 3 or 4 neutropenia occurred in 37% of patients treated with cladribine and in 20% of patients receiving cytarabine.
  2. A report on the treatment of adult patients with either vindesine and prednisone or cyclophosphamide, etoposide, vindesine, and prednisone showed that more than 70% of patients relapsed with either regimen.[28][Level of evidence: 3iiiDiii]
  3. Etoposide has been used with some success in single-system and multisystem LCH.
    • Minimal toxicity was reported with the use of prolonged oral etoposide in adults with skin LCH, while 3-day courses of intravenous etoposide (100 mg/m2/day) induced complete remission in a small number of patients with resistant single-system and multisystem disease.[29]
    • Another study at the same center found that azathioprine was the most successful drug for localized disease in adults, with the addition of etoposide for refractory and multisystem disease.[30]
  4. For patients who do not respond to front-line therapy with etoposide, cladribine is effective for adults with skin, bone, lymph node, and probably pulmonary and central nervous system (CNS) disease.[31,32]
    • The first study that used cladribine to treat refractory and recurrent skin LCH disease reported on three patients (aged 33, 51, and 57 years) who received two to four courses of cladribine at 0.7 mg/kg intravenously over 2 hours/day for 5 days.[31]
    • In a series of five adults (one untreated and four with refractory LCH treated with cladribine at the same dose noted directly above), three patients achieved a complete remission and two patients achieved a partial remission.[32]
  5. An adult lymphoma treatment regimen of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (MACOP-B) was used in three patients with multisystem LCH and four with single-system multifocal bone LCH from 1995 to 2007. Total duration of therapy was 12 weeks.[33]
    • Response was seen in all patients, two with partial response and five with complete response.
    • Three recurrences were seen after therapy was stopped.
    • Despite the small number of patients and the retrospective nature of the study, MACOP-B may be useful as salvage therapy in adult patients with LCH and deserves further study.[34]
  6. Neurodegenerative CNS disease. A case report suggests some benefit to treating neurodegenerative CNS LCH disease with infliximab, a tumor necrosis factor (TNF)-alpha inhibitor.[35] However, the TNF inhibitors infliximab and etanercept have limited ability to cross the blood-brain barrier. Thalidomide, which also has anti-TNF activity, has been effective in adults with skin and bone LCH.[22,36] One study reported an improvement in ataxia in a patient with LCH who was treated with vemurafenib.[37]
  7. Pituitary LCH. A report of stereotactic radiosurgery for the treatment of pituitary LCH in adults showed efficacy in reducing the masses.[38] However, radiation therapy is not considered the standard of care for children with pituitary involvement. Systemic chemotherapy with cytarabine and cladribine have been the preferred treatments.[39,40]

Targeted therapies for the treatment of single-system and multisystem disease

Early reports on the use of targeted therapies for LCH patients with low-risk or high-risk LCH sites include the following:
  1. Tyrosine kinase inhibitors. Imatinib mesylate was effective in the treatment of four adult patients with LCH who had skin, lung, bone, and/or CNS involvement.[41,42] Another adult patient with LCH did not respond to imatinib mesylate.[43]
  2. MAP2K/ERK pathway inhibitors. The finding that most patients with LCH have BRAFand other RAS pathway mutations led to several reports of good responses to vemurafenib, a BRAF V600E inhibitor, in adult patients with LCH, Erdheim-Chester (ECD) disease, or mixed ECD/LCH, as well as in severe cutaneous LCH.[44,45]
    Of four patients with LCH who were treated with vemurafenib on the VE-BASKET (NCT01524978) trial, one patient had a complete response and three patients had partial responses.[37] Early results of targeted inhibitor therapy are encouraging, but many questions remain, particularly the optimal duration of therapy and the reactivation rate after therapy is discontinued. A BRAF inhibitor in combination with a MEK inhibitor have been shown to be effective in patients with melanoma who have BRAF mutations (with reduced toxicity), and this combination may be effective in patients with LCH.[44] A number of clinical trials of BRAF and other RAS pathway inhibitors in adults and children with LCH are ongoing.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Girschikofsky M, Arico M, Castillo D, et al.: Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis 8: 72, 2013. [PUBMED Abstract]
  2. Grobost V, Khouatra C, Lazor R, et al.: Effectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis. Orphanet J Rare Dis 9: 191, 2014. [PUBMED Abstract]
  3. Tazi A: Adult pulmonary Langerhans' cell histiocytosis. Eur Respir J 27 (6): 1272-85, 2006. [PUBMED Abstract]
  4. Mogulkoc N, Veral A, Bishop PW, et al.: Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking cessation. Chest 115 (5): 1452-5, 1999. [PUBMED Abstract]
  5. Kim HJ, Lee KS, Johkoh T, et al.: Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-pathology comparisons and evolutional changes at CT. Eur Radiol 21 (7): 1406-15, 2011. [PUBMED Abstract]
  6. Lorillon G, Tazi A: How I manage pulmonary Langerhans cell histiocytosis. Eur Respir Rev 26 (145): , 2017. [PUBMED Abstract]
  7. Dauriat G, Mal H, Thabut G, et al.: Lung transplantation for pulmonary langerhans' cell histiocytosis: a multicenter analysis. Transplantation 81 (5): 746-50, 2006. [PUBMED Abstract]
  8. Le Pavec J, Lorillon G, Jaïs X, et al.: Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies. Chest 142 (5): 1150-1157, 2012. [PUBMED Abstract]
  9. Abbritti M, Mazzei MA, Bargagli E, et al.: Utility of spiral CAT scan in the follow-up of patients with pulmonary Langerhans cell histiocytosis. Eur J Radiol 81 (8): 1907-12, 2012. [PUBMED Abstract]
  10. Olschewski T, Seegenschmiedt MH: Radiotherapy of Langerhans' Cell Histiocytosis : Results and Implications of a National Patterns-of-Care Study. Strahlenther Onkol 182 (11): 629-34, 2006. [PUBMED Abstract]
  11. Kriz J, Eich HT, Bruns F, et al.: Radiotherapy in langerhans cell histiocytosis - a rare indication in a rare disease. Radiat Oncol 8: 233, 2013. [PUBMED Abstract]
  12. Arzoo K, Sadeghi S, Pullarkat V: Pamidronate for bone pain from osteolytic lesions in Langerhans'-cell histiocytosis. N Engl J Med 345 (3): 225, 2001. [PUBMED Abstract]
  13. Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001. [PUBMED Abstract]
  14. Brown RE: Bisphosphonates as antialveolar macrophage therapy in pulmonary langerhans cell histiocytosis? Med Pediatr Oncol 36 (6): 641-3, 2001. [PUBMED Abstract]
  15. Chellapandian D, Makras P, Kaltsas G, et al.: Bisphosphonates in Langerhans Cell Histiocytosis: An International Retrospective Case Series. Mediterr J Hematol Infect Dis 8 (1): e2016033, 2016. [PUBMED Abstract]
  16. Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011. [PUBMED Abstract]
  17. Reichle A, Vogt T, Kunz-Schughart L, et al.: Anti-inflammatory and angiostatic therapy in chemorefractory multisystem Langerhans' cell histiocytosis of adults. Br J Haematol 128 (5): 730-2, 2005. [PUBMED Abstract]
  18. O'Kane D, Jenkinson H, Carson J: Langerhans cell histiocytosis associated with breast carcinoma successfully treated with topical imiquimod. Clin Exp Dermatol 34 (8): e829-32, 2009. [PUBMED Abstract]
  19. Taverna JA, Stefanato CM, Wax FD, et al.: Adult cutaneous Langerhans cell histiocytosis responsive to topical imiquimod. J Am Acad Dermatol 54 (5): 911-3, 2006. [PUBMED Abstract]
  20. Rieker J, Hengge U, Ruzicka T, et al.: [Multifocal facial eosinophilic granuloma: successful treatment with topical tacrolimus]. Hautarzt 57 (4): 324-6, 2006. [PUBMED Abstract]
  21. Vogel CA, Aughenbaugh W, Sharata H: Excimer laser as adjuvant therapy for adult cutaneous Langerhans cell histiocytosis. Arch Dermatol 144 (10): 1287-90, 2008. [PUBMED Abstract]
  22. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007. [PUBMED Abstract]
  23. Steen AE, Steen KH, Bauer R, et al.: Successful treatment of cutaneous Langerhans cell histiocytosis with low-dose methotrexate. Br J Dermatol 145 (1): 137-40, 2001. [PUBMED Abstract]
  24. Zinn DJ, Grimes AB, Lin H, et al.: Hydroxyurea: a new old therapy for Langerhans cell histiocytosis. Blood 128 (20): 2462-2465, 2016. [PUBMED Abstract]
  25. Chang SE, Koh GJ, Choi JH, et al.: Widespread skin-limited adult Langerhans cell histiocytosis: long-term follow-up with good response to interferon alpha. Clin Exp Dermatol 27 (2): 135-7, 2002. [PUBMED Abstract]
  26. Tsambaos D, Georgiou S, Kapranos N, et al.: Langerhans' cell histiocytosis: complete remission after oral isotretinoin therapy. Acta Derm Venereol 75 (1): 62-4, 1995. [PUBMED Abstract]
  27. Cantu MA, Lupo PJ, Bilgi M, et al.: Optimal therapy for adults with Langerhans cell histiocytosis bone lesions. PLoS One 7 (8): e43257, 2012. [PUBMED Abstract]
  28. Duan MH, Han X, Li J, et al.: Comparison of vindesine and prednisone and cyclophosphamide, etoposide, vindesine, and prednisone as first-line treatment for adult Langerhans cell histiocytosis: A single-center retrospective study. Leuk Res 42: 43-6, 2016. [PUBMED Abstract]
  29. Tsele E, Thomas DM, Chu AC: Treatment of adult Langerhans cell histiocytosis with etoposide. J Am Acad Dermatol 27 (1): 61-4, 1992. [PUBMED Abstract]
  30. Chu T: Langerhans cell histiocytosis. Australas J Dermatol 42 (4): 237-42, 2001. [PUBMED Abstract]
  31. Saven A, Foon KA, Piro LD: 2-Chlorodeoxyadenosine-induced complete remissions in Langerhans-cell histiocytosis. Ann Intern Med 121 (6): 430-2, 1994. [PUBMED Abstract]
  32. Pardanani A, Phyliky RL, Li CY, et al.: 2-Chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis. Mayo Clin Proc 78 (3): 301-6, 2003. [PUBMED Abstract]
  33. Derenzini E, Fina MP, Stefoni V, et al.: MACOP-B regimen in the treatment of adult Langerhans cell histiocytosis: experience on seven patients. Ann Oncol 21 (6): 1173-8, 2010. [PUBMED Abstract]
  34. Gadner H: Treatment of adult-onset Langerhans cell histiocytosis--is it different from the pediatric approach? Ann Oncol 21 (6): 1141-2, 2010. [PUBMED Abstract]
  35. Chohan G, Barnett Y, Gibson J, et al.: Langerhans cell histiocytosis with refractory central nervous system involvement responsive to infliximab. J Neurol Neurosurg Psychiatry 83 (5): 573-5, 2012. [PUBMED Abstract]
  36. Sander CS, Kaatz M, Elsner P: Successful treatment of cutaneous langerhans cell histiocytosis with thalidomide. Dermatology 208 (2): 149-52, 2004. [PUBMED Abstract]
  37. Diamond EL, Subbiah V, Lockhart AC, et al.: Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study. JAMA Oncol 4 (3): 384-388, 2018. [PUBMED Abstract]
  38. Hong WC, Murovic JA, Gibbs I, et al.: Pituitary stalk Langerhans cell histiocytosis treated with CyberKnife radiosurgery. Clin Neurol Neurosurg 115 (5): 573-7, 2013. [PUBMED Abstract]
  39. Dhall G, Finlay JL, Dunkel IJ, et al.: Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer 50 (1): 72-9, 2008. [PUBMED Abstract]
  40. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993. [PUBMED Abstract]
  41. Montella L, Insabato L, Palmieri G: Imatinib mesylate for cerebral Langerhans'-cell histiocytosis. N Engl J Med 351 (10): 1034-5, 2004. [PUBMED Abstract]
  42. Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010. [PUBMED Abstract]
  43. Wagner C, Mohme H, Krömer-Olbrisch T, et al.: Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol 145 (8): 949-50, 2009. [PUBMED Abstract]
  44. Haroche J, Cohen-Aubart F, Emile JF, et al.: Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 121 (9): 1495-500, 2013. [PUBMED Abstract]
  45. Charles J, Beani JC, Fiandrino G, et al.: Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation. J Am Acad Dermatol 71 (3): e97-9, 2014. [PUBMED Abstract]

Changes to This Summary (06/13/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood and adult Langerhans cell histiocytosis. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Langerhans Cell Histiocytosis Treatment are:
  • Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
  • Thomas G. Gross, MD, PhD (National Cancer Institute)
  • Kenneth L. McClain, MD, PhD (Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital)
  • Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Langerhans Cell Histiocytosis Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389240]
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  • Updated: June 13, 2019
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