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

    1. 1. TASHA MCDONALD, MD DEPARTMENT OF RADIATION MEDICINE JUNE 18, 2008 Radiotherapy in Pediatric Hodgkin Lymphoma
    2. 2. OVERVIEW <ul><li>Case presentation </li></ul><ul><li>Risk-groups </li></ul><ul><li>Early/favorable risk </li></ul><ul><li>Unfavorable risk </li></ul><ul><li>Toxicities </li></ul><ul><li>Future directions </li></ul>
    3. 3. Case presentation <ul><li>L.S.: 18 yo girl presented in 1/08 with 2 months of fatigue, fever, chills, sweats and 10 lb weight loss </li></ul><ul><li>Developed difficulty swallowing and enlarged neck nodes and SOB when lying down </li></ul><ul><li>On exam: palpable cervical LAD </li></ul><ul><li>Underwent US of the neck 1/3/08: irregular 2.3x2.3 x3.4cm nodule in right neck. </li></ul><ul><li>LN biopsy on 1/4/08 at Kaiser: nodular sclerosing Hodgkin disease </li></ul>
    4. 4. Outside PET 1/22/08
    5. 5. Outside CT Chest 1/22/08
    6. 6. Case presentation <ul><li>Stage IIB NSHD </li></ul><ul><ul><li>No subdiaphragmatic disease </li></ul></ul><ul><ul><li>Bone marrow bx was negative </li></ul></ul><ul><li>Started on COG AHOD 0031 protocol and received 2 cycles of ABVE-PC </li></ul><ul><li>Re-imaged on 3/7/08 and determined to be a slow early responder per protocol </li></ul>
    7. 7. OHSU PET 3/7/08
    8. 8. OHSU CT Chest 3/7/08
    9. 9. Case presentation <ul><li>Randomized to the augmented therapy arm to receive DECA x 2 followed by 2 more cycles of ABVE-PC </li></ul><ul><li>CT and PET on 4/28/08 (before the ABVE-PC) showed a 66% reduction tumor size </li></ul><ul><li>Finished chemotherapy and scheduled to start RT on 5/23/08. </li></ul>
    10. 10. OHSU PET 4/28/08
    11. 11. OHSU CT Chest 4/28/08
    12. 12. RT Guidelines for AHOD0031 Protocol <ul><li>IFRT for all pts except those who achieve rapid early response after 2 cycles of chemo AND CR after 4 cycles of chemo. </li></ul><ul><li>IFRT with 21 Gy in 14 fxs given with AP:PA fields </li></ul><ul><li>RT to start w/in 4 weeks of last chemo cycle </li></ul><ul><li>GTV = LN>1.5 cm; CTV = anatomical compartment of LN; PTV = 1.0 cm margin to CTV </li></ul><ul><li>RT fields adapted to response of chemo are not permitted except if treating the mediastinum </li></ul>
    13. 13. RT Plan evaluation
    14. 14. RT field with pre-chemo volume shown
    15. 15. RT AP field with post-chemo volume
    16. 17. History <ul><li>Treated with full-dose (35-45 Gy) extended-field RT w/ excellent disease control but significant late toxicity </li></ul><ul><li>Chemotherapy (MOPP or ABVD) was shown to salvage relapsed disease after RT and improve DFS when used as part of initial therapy 1,2 </li></ul><ul><li>Low-dose RT (15-25 Gy) following chemotherapy was shown to produce excellent EFS and OS 3-5 </li></ul><ul><li>Chemotherapy followed by low-dose RT became the standard therapy </li></ul><ul><li>The most recent trials use risk-adapted and/or response-adapted therapy </li></ul>
    17. 18. Risk groups <ul><li>Division into groups based on factors shown to influence outcome </li></ul><ul><ul><li>Histology </li></ul></ul><ul><ul><li>Clinical stage </li></ul></ul><ul><ul><li>B symptoms </li></ul></ul><ul><ul><li>Bulky disease </li></ul></ul>
    18. 19. Risk groups <ul><li>Prognostic stratification (not uniformly agreed on): </li></ul><ul><ul><li>Low-risk/favorable: Stage I or II, no B symptoms, no bulky disease and disease in fewer than 3 nodal regions </li></ul></ul><ul><ul><li>Intermediate-risk: Stage IB, IIB (or bulky disease and extranodal involvement) and sometimes IIIA </li></ul></ul><ul><ul><li>High-risk: Stage IIIB, IVA/B </li></ul></ul>
    19. 20. Early stage/favorable risk <ul><li>Goal = limit treatment-related toxicity and maintain success of therapy </li></ul><ul><li>Efficacy of various strategies is relatively equivalent </li></ul><ul><ul><li>~90% or better EFS or PFS </li></ul></ul><ul><ul><li>~95% OS </li></ul></ul><ul><li>Treatment: 2-4 cycles of chemotherapy +/- involved field RT </li></ul><ul><ul><li>Response-adapted approach: Response to the first cycles of chemotherapy determines inclusion of additional chemo or dose of RT </li></ul></ul>
    20. 21. Treatment and outcomes in early stage pediatric Hodgkin disease
    21. 22. Early stage/favorable risk Response-adapted approach <ul><ul><li>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 </li></ul></ul><ul><ul><ul><li>PR (53%): 25 .5 Gy IFRT </li></ul></ul></ul><ul><ul><ul><li>CR (47%): 15 Gy IFRT </li></ul></ul></ul><ul><ul><li>German HD95 8,9 : OPPA or OEPA for two cycles </li></ul></ul><ul><ul><ul><li>CR (27%): observation </li></ul></ul></ul><ul><ul><ul><li>PR with >75% reduction (53%): 25 Gy IFRT </li></ul></ul></ul><ul><ul><ul><li><75% reduction (~5%): 20-30 Gy IFRT + 5 Gy boost to >50 ml residual </li></ul></ul></ul><ul><ul><li>French MDH90 10 : 4 cycles of VBVP </li></ul></ul><ul><ul><ul><li>>70% response (85%): 20 Gy IFRT </li></ul></ul></ul><ul><ul><ul><li><70% response: 1 or 2 more cycles of OPPA and 20 or 40 Gy IFRT </li></ul></ul></ul><ul><ul><li>Despite the differences in treatment, all these studies had a EFS or PFS of 93% or better </li></ul></ul>
    22. 23. Early stage/favorable risk Exclusion of RT <ul><li>POG 8625 11 : Laparotomy-staged IA-IIIA disease </li></ul><ul><ul><li>4 cycles of MOPP/ABVD OR 2 cycles of MOPP/ABVD plus 25.5 Gy IFRT </li></ul></ul><ul><ul><li>EFS (83% vs 91%) and OS (94% vs 97%) were statistically equivalent </li></ul></ul><ul><li>CCG 5942 12 : Clinically staged I-II disease </li></ul><ul><ul><li>4 cycles of COPP/ABV </li></ul></ul><ul><ul><li>CRs randomized to observation vs. 21 Gy IFRT </li></ul></ul><ul><ul><li>Stopped early after interim analysis indicated superiority of RT arm (EFS 85% vs 93%) but OS was 100% in both arms </li></ul></ul>
    23. 24. Intermediate and advanced stage disease <ul><li>More intensified regimens with a combination of diverse chemotherapeutic agents </li></ul><ul><li>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 </li></ul><ul><li>RT continues to be standard therapy in this risk group (unless on protocol) </li></ul>
    24. 25. Treatment and outcomes in intermediate/advanced stage pediatric Hodgkin disease
    25. 26. Intermediate and advanced stage disease <ul><li>POG 15 : 8 cycles of MOPP/ABVD +/- total-nodal irradiation </li></ul><ul><ul><li>No diff by intent-to-treat analysis </li></ul></ul><ul><li>CCG 521 16 : 6 cycles MOPP alternating with 6 cycles of ABVD vs 6 cycles of ABVD with 21 Gy extended-field RT </li></ul><ul><ul><li>Equivalent outcome </li></ul></ul><ul><ul><li>EFS 77% vs 87%, P = .09; OS 84% vs 90%, P=.45 </li></ul></ul><ul><li>German HD-95 8,9 : 2 cycles of OPPA or OEPA +2-4 cycles of COPP </li></ul><ul><ul><li>>70% reduction in tumor volume: No RT </li></ul></ul><ul><ul><li><70% reduction: IFRT </li></ul></ul><ul><ul><li>OS equivalent but EFS with RT =92% vs with chemo alone = 69% </li></ul></ul>
    26. 27. RT Planning <ul><li>Historical mantle field and total nodal irradiation </li></ul>
    27. 28. RT Fields
    28. 29. IFRT <ul><li>IFRT requires careful evaluation of pre- and post-chemotherapy volumes </li></ul><ul><li>CTV encompasses post-chemo mediastianal width laterally and pre-chemo extent in sup/inf direction </li></ul><ul><li>An anterior laryngeal block can be used if it does not shield involved nodes </li></ul><ul><li>If the axillae are to be treated humeral head blocks are used </li></ul><ul><li>CT based planning allows evaluation of adequate CTV coverage and normal tissue dose </li></ul>
    29. 30. IFRT <ul><li>Whole-heart irradiation indications: pericardial involvement/invasion </li></ul><ul><li>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 </li></ul><ul><li>If the pelvis needs to be treated the ovaries should be relocated and the dose should be limited to <3 Gy </li></ul><ul><li>When treating a male, ensure on a daily basis that the scrotum is not in the pelvic field </li></ul>
    30. 31. Late Toxicity of Radiotherapy <ul><li>Growth abnormalities 17 </li></ul><ul><ul><li>Bone and soft-tissue hypoplasia in prepubertal children </li></ul></ul><ul><li>Thyroid sequela 18,19 </li></ul><ul><ul><li>Hypothyroidism </li></ul></ul><ul><ul><li>Hyperthyroidism </li></ul></ul><ul><ul><li>Benign and malignant thyroid nodules </li></ul></ul><ul><ul><li>17% of children treated with RT dose <26 Gy had thyroid abnormalities compared to 78% with >26 Gy </li></ul></ul>
    31. 32. Late Toxicity <ul><li>Cardiovascular disease 20,21 </li></ul><ul><ul><li>Atherosclerotic heart disease </li></ul></ul><ul><ul><li>Valvular dysfunction </li></ul></ul><ul><ul><li>Pericardial disease </li></ul></ul><ul><li>Pulmonary toxicity 22 </li></ul><ul><ul><li>Decrease in pulmonary function tests </li></ul></ul><ul><li>Sterility/Infertility: limit dose to ovaries to 3Gy </li></ul><ul><li>Increase incidence of secondary cancers 23-25 </li></ul><ul><ul><li>Late effects study group: 30 yr cumulative incidence of SC = 26.3% in pts dx’ed before age 16 </li></ul></ul><ul><ul><li>Breast cancer was most elevated solid cancer </li></ul></ul>
    32. 33. Late Toxicity <ul><li>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 </li></ul><ul><ul><li>Second solid cancer risk appears to be dose dependent with patients w/ <23 Gy mediastinal RT with lower risk of developing breast cancer 26 </li></ul></ul>
    33. 34. Future Directions <ul><li>Improve the technique of response-adapted therapy </li></ul><ul><li>Incorporate functional imaging into evaluating treatment response and RT planning </li></ul><ul><li>Improve upon late toxicities AND determine the effects of decreased dose IFRT on late toxicities </li></ul><ul><li>Refine risk categories </li></ul><ul><li>Improve treatment regimen for high-risk disease </li></ul>
    34. 35. References <ul><li>Devita VT Jr et al. Combination chemotherapy in the treatment of advanced HD. Ann Intern Med 73: 881-95. 1970 </li></ul><ul><li>Bonadonna G et al. Combination chemotherapy of HD with adriamycin, bleomycin,vinblastine,and imidazole vs MOPP. Cancer 36: 252-9, 1975. </li></ul><ul><li>Donaldson SS et al. HD: Treatment with low dose radiation and chemotherapy. Front Radiat Ther Oncol 16: 122-33, 1981. </li></ul><ul><li>Hunger SP et al. ABVD/MOPP and low-dose IFRT in pediatric HD. J Clin Oncol 12:2160-6, 1994. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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 . </li></ul>
    35. 36. References <ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>Friedmann AM et al. Treatment of unfavorable childhood HD with VEPA and low-dose, involved-field radiation. J Clin Oncol 20:3088–3094, 2002. </li></ul>
    36. 37. References <ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>Willman KY, Cox RS, Donaldson SS: Radiation induced height impairment in pediatric HD. IJROBP 28(1): 85–92, 1994. </li></ul><ul><li>Constine LS ,et al. Thyroid dysfunction after radiotherapy in children with Hodgkin’s disease. Cancer 53:878-883, 1984. </li></ul><ul><li>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. </li></ul><ul><li>Hancock SL, et al. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA 270: 1949-1955, 1993. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul>
    37. 38. References <ul><li>Bhatia S et al. Second cancers after pediatric Hodgkin’s disease. J Clin Oncol 16(7):2570–2572, 1998. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>Travis LB,et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl CancerInst 97:1428-1437, 2005. </li></ul>

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