Radiotherapy in Pediatric Hodgkin Lymphoma
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Radiotherapy in Pediatric Hodgkin Lymphoma

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  • Response to the first cycles of chemotherapy determines inclusion of additional chemo or dose of RT SDS: Stanford, Dana Farber, St Jude VAMP: vinblastine, doxorubicin, methotrexate and prednisone OPPA: vincristine, procarbazine, prednisone and doxorubicin OEPA: vincristine, etoposide, prednisone and doxorubicin VBVP: vinblastine, bleomycin, etoposide, prednisone

Radiotherapy in Pediatric Hodgkin Lymphoma Radiotherapy in Pediatric Hodgkin Lymphoma Presentation Transcript

  • TASHA MCDONALD, MD DEPARTMENT OF RADIATION MEDICINE JUNE 18, 2008 Radiotherapy in Pediatric Hodgkin Lymphoma
  • OVERVIEW
    • Case presentation
    • Risk-groups
    • Early/favorable risk
    • Unfavorable risk
    • Toxicities
    • Future directions
  • Case presentation
    • L.S.: 18 yo girl presented in 1/08 with 2 months of fatigue, fever, chills, sweats and 10 lb weight loss
    • Developed difficulty swallowing and enlarged neck nodes and SOB when lying down
    • On exam: palpable cervical LAD
    • Underwent US of the neck 1/3/08: irregular 2.3x2.3 x3.4cm nodule in right neck.
    • LN biopsy on 1/4/08 at Kaiser: nodular sclerosing Hodgkin disease
  • Outside PET 1/22/08
  • Outside CT Chest 1/22/08
  • Case presentation
    • Stage IIB NSHD
      • No subdiaphragmatic disease
      • Bone marrow bx was negative
    • Started on COG AHOD 0031 protocol and received 2 cycles of ABVE-PC
    • Re-imaged on 3/7/08 and determined to be a slow early responder per protocol
  • OHSU PET 3/7/08
  • OHSU CT Chest 3/7/08
  • Case presentation
    • Randomized to the augmented therapy arm to receive DECA x 2 followed by 2 more cycles of ABVE-PC
    • CT and PET on 4/28/08 (before the ABVE-PC) showed a 66% reduction tumor size
    • Finished chemotherapy and scheduled to start RT on 5/23/08.
  • OHSU PET 4/28/08
  • OHSU CT Chest 4/28/08
  • RT Guidelines for AHOD0031 Protocol
    • IFRT for all pts except those who achieve rapid early response after 2 cycles of chemo AND CR after 4 cycles of chemo.
    • IFRT with 21 Gy in 14 fxs given with AP:PA fields
    • RT to start w/in 4 weeks of last chemo cycle
    • GTV = LN>1.5 cm; CTV = anatomical compartment of LN; PTV = 1.0 cm margin to CTV
    • RT fields adapted to response of chemo are not permitted except if treating the mediastinum
  • RT Plan evaluation
  • RT field with pre-chemo volume shown
  • RT AP field with post-chemo volume
  •  
  • History
    • Treated with full-dose (35-45 Gy) extended-field RT w/ excellent disease control but significant late toxicity
    • Chemotherapy (MOPP or ABVD) was shown to salvage relapsed disease after RT and improve DFS when used as part of initial therapy 1,2
    • Low-dose RT (15-25 Gy) following chemotherapy was shown to produce excellent EFS and OS 3-5
    • Chemotherapy followed by low-dose RT became the standard therapy
    • The most recent trials use risk-adapted and/or response-adapted therapy
  • Risk groups
    • Division into groups based on factors shown to influence outcome
      • Histology
      • Clinical stage
      • B symptoms
      • Bulky disease
  • Risk groups
    • Prognostic stratification (not uniformly agreed on):
      • Low-risk/favorable: Stage I or II, no B symptoms, no bulky disease and disease in fewer than 3 nodal regions
      • Intermediate-risk: Stage IB, IIB (or bulky disease and extranodal involvement) and sometimes IIIA
      • High-risk: Stage IIIB, IVA/B
  • Early stage/favorable risk
    • Goal = limit treatment-related toxicity and maintain success of therapy
    • Efficacy of various strategies is relatively equivalent
      • ~90% or better EFS or PFS
      • ~95% OS
    • Treatment: 2-4 cycles of chemotherapy +/- involved field RT
      • Response-adapted approach: Response to the first cycles of chemotherapy determines inclusion of additional chemo or dose of RT
  • Treatment and outcomes in early stage pediatric Hodgkin disease
  • Early stage/favorable risk Response-adapted approach
      • SDS group study 6,7 : single arm study; 4 cycles of VAMP followed by IFRT with RT dose determined by response to first 2 cycles
        • PR (53%): 25 .5 Gy IFRT
        • CR (47%): 15 Gy IFRT
      • German HD95 8,9 : OPPA or OEPA for two cycles
        • CR (27%): observation
        • PR with >75% reduction (53%): 25 Gy IFRT
        • <75% reduction (~5%): 20-30 Gy IFRT + 5 Gy boost to >50 ml residual
      • French MDH90 10 : 4 cycles of VBVP
        • >70% response (85%): 20 Gy IFRT
        • <70% response: 1 or 2 more cycles of OPPA and 20 or 40 Gy IFRT
      • Despite the differences in treatment, all these studies had a EFS or PFS of 93% or better
  • Early stage/favorable risk Exclusion of RT
    • POG 8625 11 : Laparotomy-staged IA-IIIA disease
      • 4 cycles of MOPP/ABVD OR 2 cycles of MOPP/ABVD plus 25.5 Gy IFRT
      • EFS (83% vs 91%) and OS (94% vs 97%) were statistically equivalent
    • CCG 5942 12 : Clinically staged I-II disease
      • 4 cycles of COPP/ABV
      • CRs randomized to observation vs. 21 Gy IFRT
      • Stopped early after interim analysis indicated superiority of RT arm (EFS 85% vs 93%) but OS was 100% in both arms
  • Intermediate and advanced stage disease
    • More intensified regimens with a combination of diverse chemotherapeutic agents
    • Goal of minimizing treatment-related toxicity is still important but studies that reduced alkylating agents and anthracyclines with limited IFRT lead to decreased EFS 13,14
    • RT continues to be standard therapy in this risk group (unless on protocol)
  • Treatment and outcomes in intermediate/advanced stage pediatric Hodgkin disease
  • Intermediate and advanced stage disease
    • POG 15 : 8 cycles of MOPP/ABVD +/- total-nodal irradiation
      • No diff by intent-to-treat analysis
    • CCG 521 16 : 6 cycles MOPP alternating with 6 cycles of ABVD vs 6 cycles of ABVD with 21 Gy extended-field RT
      • Equivalent outcome
      • EFS 77% vs 87%, P = .09; OS 84% vs 90%, P=.45
    • German HD-95 8,9 : 2 cycles of OPPA or OEPA +2-4 cycles of COPP
      • >70% reduction in tumor volume: No RT
      • <70% reduction: IFRT
      • OS equivalent but EFS with RT =92% vs with chemo alone = 69%
  • RT Planning
    • Historical mantle field and total nodal irradiation
  • RT Fields
  • IFRT
    • IFRT requires careful evaluation of pre- and post-chemotherapy volumes
    • CTV encompasses post-chemo mediastianal width laterally and pre-chemo extent in sup/inf direction
    • An anterior laryngeal block can be used if it does not shield involved nodes
    • If the axillae are to be treated humeral head blocks are used
    • CT based planning allows evaluation of adequate CTV coverage and normal tissue dose
  • IFRT
    • Whole-heart irradiation indications: pericardial involvement/invasion
    • Splenic irradiation is indicated in pts with splenic involvement but renal dose must be limited to mean <10.5 Gy or keep 2/3rds of the kidney to <15 Gy
    • If the pelvis needs to be treated the ovaries should be relocated and the dose should be limited to <3 Gy
    • When treating a male, ensure on a daily basis that the scrotum is not in the pelvic field
  • Late Toxicity of Radiotherapy
    • Growth abnormalities 17
      • Bone and soft-tissue hypoplasia in prepubertal children
    • Thyroid sequela 18,19
      • Hypothyroidism
      • Hyperthyroidism
      • Benign and malignant thyroid nodules
      • 17% of children treated with RT dose <26 Gy had thyroid abnormalities compared to 78% with >26 Gy
  • Late Toxicity
    • Cardiovascular disease 20,21
      • Atherosclerotic heart disease
      • Valvular dysfunction
      • Pericardial disease
    • Pulmonary toxicity 22
      • Decrease in pulmonary function tests
    • Sterility/Infertility: limit dose to ovaries to 3Gy
    • Increase incidence of secondary cancers 23-25
      • Late effects study group: 30 yr cumulative incidence of SC = 26.3% in pts dx’ed before age 16
      • Breast cancer was most elevated solid cancer
  • Late Toxicity
    • Toxicities of higher dose RT are well documented but it is less clear what toxicities will exist with 15-25 Gy bc many toxicities are dose and volume dependent
      • Second solid cancer risk appears to be dose dependent with patients w/ <23 Gy mediastinal RT with lower risk of developing breast cancer 26
  • Future Directions
    • Improve the technique of response-adapted therapy
    • Incorporate functional imaging into evaluating treatment response and RT planning
    • Improve upon late toxicities AND determine the effects of decreased dose IFRT on late toxicities
    • Refine risk categories
    • Improve treatment regimen for high-risk disease
  • References
    • Devita VT Jr et al. Combination chemotherapy in the treatment of advanced HD. Ann Intern Med 73: 881-95. 1970
    • Bonadonna G et al. Combination chemotherapy of HD with adriamycin, bleomycin,vinblastine,and imidazole vs MOPP. Cancer 36: 252-9, 1975.
    • Donaldson SS et al. HD: Treatment with low dose radiation and chemotherapy. Front Radiat Ther Oncol 16: 122-33, 1981.
    • Hunger SP et al. ABVD/MOPP and low-dose IFRT in pediatric HD. J Clin Oncol 12:2160-6, 1994.
    • Weiner MA et al. Intensive chemotherapy and low-dose RT for the treatment of advanced-stage HD in pediatric patients: A POG study. J Clin Oncol 9: 1591-98, 1991.
    • Donaldson SS et al. VAMP and low-dose, IFRT for children and adolescents with favorable, early-stage HD: results of a prospective clinical trial. J Clin Oncol 20:3081–3087, 2002.
    • Donaldson SS et al. Final results of a prospective clinical trial with VAMP and low-dose IFRT for children with low-risk HD. J Clin Oncol 25:332–337, 2007 .
  • References
    • Ruhl U et al. Response adapted RT in the treatment of pediatric HD: an interim report at 5 years of the German GPOH-HD 95 trial. IJROBP , 51: 1209–1218, 2001.
    • Ruhl U et al. Abstract at ASTRO, 46th annual meeting: German GPOH-HD 95 trial: Treatment results and analysis of failures in pediatric HD using combination chemotherapy with and without RT. IJROBP 60:S131, 2004.
    • Landman-Parker Jet al. Localized childhood HD: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose RT-results of the French MDH90. J Clin Oncol 18:1500–1507, 2000.
    • Kung FH et al. POG 8625: a randomized trial comparing chemotherapy with chemoradiotherapy for children and adolescents with stages I, IIA, IIIA1 HD: a report from the COG. J Pediatr Hematol Oncol 28:362–368, 2006.
    • Nachman JB et al. Randomized comparison of IFRT and no RT for children with HD who achieve a complete response to chemotherapy. J Clin Oncol 20(18):3765–3771, 2002.
    • Hudson MM et al. Risk-adapted, combined-modality therapy with VAMP/COP and response-based, IFRT for unfavorable pediatric HD. J Clin Oncol 22:4541–4550, 2004.
    • Friedmann AM et al. Treatment of unfavorable childhood HD with VEPA and low-dose, involved-field radiation. J Clin Oncol 20:3088–3094, 2002.
  • References
    • Weiner MA et al. Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal RT in the treatment of HD in pediatric patients: a POG study. J Clin Oncol 15:2769–79, 1997.
    • Fryer CJ et al. Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional RT in advanced HD in children: a report from the Children’s Cancer Study Group. J Clin Oncol 8(12):1971–1980, 1990.
    • Willman KY, Cox RS, Donaldson SS: Radiation induced height impairment in pediatric HD. IJROBP 28(1): 85–92, 1994.
    • Constine LS ,et al. Thyroid dysfunction after radiotherapy in children with Hodgkin’s disease. Cancer 53:878-883, 1984.
    • Sklar C, et al. Abnormalities of the thyroid in survivors of HD: Data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85:3227-3232, 2000.
    • Hancock SL, et al. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA 270: 1949-1955, 1993.
    • Hull MC, et al. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of HD treated with RT. JAMA 290:2831-2837, 2003.
    • Villani F, et al. Late pulmonary effects in favorable stage I and IIA HD treated with radiotherapy alone. Am J Clin Oncol 23:18-21, 2000.
  • References
    • Bhatia S et al. Second cancers after pediatric Hodgkin’s disease. J Clin Oncol 16(7):2570–2572, 1998.
    • Bhatia S, et al. High risk of subsequent neoplasms continues with extended follow-up of childhood HD: Report from the Late Effects Study Group. J Clin Oncol 21:4386-4394, 2003.
    • Metayer C, et al. Second cancers among long-termsurvivors of Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol 18:2435-2443, 2000.
    • Travis LB,et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl CancerInst 97:1428-1437, 2005.