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Radiotherapy in Pediatric Hodgkin Lymphoma

Radiotherapy in Pediatric Hodgkin Lymphoma. Tasha Mcdonald , MD Department of Radiation Medicine June 18, 2008. OVERVIEW. Case presentation Risk-groups Early/favorable risk Unfavorable risk Toxicities Future directions. Case presentation.

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Radiotherapy in Pediatric Hodgkin Lymphoma

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  1. Radiotherapy in Pediatric Hodgkin Lymphoma Tasha Mcdonald, MD Department of Radiation Medicine June 18, 2008

  2. OVERVIEW • Case presentation • Risk-groups • Early/favorable risk • Unfavorable risk • Toxicities • Future directions

  3. 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

  4. Outside PET 1/22/08

  5. Outside CT Chest 1/22/08

  6. 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

  7. OHSU PET 3/7/08

  8. OHSU CT Chest 3/7/08

  9. 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.

  10. OHSU PET 4/28/08

  11. OHSU CT Chest 4/28/08

  12. 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

  13. RT Plan evaluation

  14. RT field with pre-chemo volume shown

  15. RT AP field with post-chemo volume

  16. 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 therapy1,2 • Low-dose RT (15-25 Gy) following chemotherapy was shown to produce excellent EFS and OS3-5 • Chemotherapy followed by low-dose RT became the standard therapy • The most recent trials use risk-adapted and/or response-adapted therapy

  17. Risk groups • Division into groups based on factors shown to influence outcome • Histology • Clinical stage • B symptoms • Bulky disease

  18. 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

  19. 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

  20. Treatment and outcomes in early stage pediatric Hodgkin disease

  21. Early stage/favorable riskResponse-adapted approach • SDS group study6,7: 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%): 15Gy IFRT • German HD958,9: 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 MDH9010: 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

  22. Early stage/favorable riskExclusion of RT • POG 862511: 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 594212: 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

  23. 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 EFS13,14 • RT continues to be standard therapy in this risk group (unless on protocol)

  24. Treatment and outcomes in intermediate/advanced stage pediatric Hodgkin disease

  25. Intermediate and advanced stage disease • POG15: 8 cycles of MOPP/ABVD +/- total-nodal irradiation • No diff by intent-to-treat analysis • CCG 52116: 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-958,9: 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%

  26. RT Planning • Historical mantle field and total nodal irradiation

  27. RT Fields

  28. 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

  29. 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

  30. Late Toxicity of Radiotherapy • Growth abnormalities17 • Bone and soft-tissue hypoplasia in prepubertal children • Thyroid sequela18,19 • 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

  31. Late Toxicity • Cardiovascular disease20,21 • Atherosclerotic heart disease • Valvular dysfunction • Pericardial disease • Pulmonary toxicity22 • Decrease in pulmonary function tests • Sterility/Infertility: limit dose to ovaries to 3Gy • Increase incidence of secondary cancers23-25 • 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

  32. 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 cancer26

  33. 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

  34. 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,andimidazolevs MOPP. Cancer 36: 252-9, 1975. • Donaldson SS et al. HD: Treatment with low dose radiation and chemotherapy. Front RadiatTherOncol 16: 122-33, 1981. • Hunger SP et al. ABVD/MOPP and low-dose IFRT in pediatric HD. J ClinOncol12:2160-6, 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 ClinOncol9: 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 ClinOncol 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 ClinOncol25:332–337, 2007 .

  35. 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 ClinOncol18:1500–1507, 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 PediatrHematolOncol 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 ClinOncol22:4541–4550, 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.

  36. 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 ClinOncol15:2769–79, 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 ClinOncol8(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 ClinEndocrinolMetab85:3227-3232, 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 ClinOncol 23:18-21, 2000.

  37. References • Bhatia S et al. Second cancers after pediatric Hodgkin’s disease. J ClinOncol16(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 ClinOncol21:4386-4394, 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 NatlCancerInst97:1428-1437, 2005.

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