The management of early stage Hodgkin's Lymphoma: assessing the use of radiotherapy.

1. The management of early stage Hodgkin's Lymphoma:assessing the use of radiotherapy. CESAR RODRIGUEZ VALDES, M.D. JAMES GRAHAM BROWN CANCER CENTER DEPARTMENT OF INTERNAL MEDICINE

2. Learning Objectives • Review the management of early stage Hodgkin Lymphoma over the past decade. • Discuss recent studies analyzing the role of radiation and of chemotherapy in efficacy of treatment. • Evaluate new radiation techniques currently being used. • Analyze the impact of therapy on long term effects in patients.

3. General overview of concepts • Favorable: • No bulky disease • No B symptoms • Unfavorable: • Stage IA, IB, IIA with: • 3 or more lymph node sites • Bulky mediastinal mass • Extra-nodal extension • Elevated ESR • Stage IIB with more than three nodes and elevates ESR. • Early stage disease: Stage I and II

4. General overview of concepts (cont’d) Types of radiation: Mantle field Para-aortic Inverted Y

5. General overview of concepts (cont’d) • Types of radiation: • Intensity-modulated radiotherapy (IMRT) • Deep-inspiration breath-hold radiotherapy (DIBH)

6. General overview of concepts (cont’d) • Hodgkin’s lymphoma affects 8,500 new patients each year. • (2-3 per 100,000) • One of the most common malignancies in young adults in the third decade. • Before 1990, standard treatment involved pathologic staging and sub-total lymphoid irradiation. • 20-30% of patients where upstaged from original clinical staging. • No survival advantage in pathologic staging vs.clinical staging when treating with radiation.

7. Let the unrest lead to experiments

8. Journal of Clinical Oncology, Vol 19, No 22, 2001

9. Press et al (cont’d) Phase III randomized intergroup trial 6 weeks • Patients were assessed on an annual basis with imaging studies for remission status • CR, CRu, partial response, stable disease, progressive disease

10. Study was closed with 80% of target population. • CMT arm showed superior FFS on interim analysis.

11. Press et al (cont’d) • Overall response: (CR + CRu + PR) - CMT showed to be superior arm. p:0.004 • Failure free survival STLI vs. CMT

12. Press et al (cont’d) • Toxicities

13. Press et al (cont’d) • Conclusions: • 3 cycles of doxorubicin/vinblastin followed by STLI is a well tolerated regimen that produces a superior FFS than STLI alone. • Overall survival superiority can’t be determined in this study. • Good overall survival and FFS can be obtained without laparotomy or splenectomy in limited stage HL.

15. HD-7 Trial (cont’d) • Study design: • 650 patients with favorable early stage HL • Multicenter randomized study: Germany, Switzerland, Czech Republic, Italy • Purpose: • To investigate whether combined-modality treatment (CMT) with 2 cycles of ABVD followed by extended field radiotherapy (IF-RT) is superior to EF-RT alone.

16. HD-7 Trial (cont’d) 316 pts 311 pts

17. HD-7 Trial (cont’d)

18. HD-7 Trial (cont’d) • Freedom from treatment failure • Overall survival

19. HD-7 Trial (cont’d) • Secondary malignancies

20. HD-7 Trial (cont’d) • Conclusions: • There was superior FFTF (88% vs 67%) with CMT compared to radiation only mainly due to fewer relapses (3% vs 22%). • There is no benefit on overall survival or response rates between treatment arms. • CMT is not associated with more acute or long term toxicities. • ABVD with radiation has become the standard of treatment.

21. Problems with standard treatment With advances in treatment, overall survival has increased to 90% in early stage disease, leading to the appearance of complications from treatment on the long run. (mostly attributed to radiation)

22. Problem with current treatment (cont’d)

23. So what is being done to improve this?

25. HD 10 Study (cont’d) • Purpose: • To determine if it is possible to reduce the intensity of treatment in early stage HL without affecting outcome. • Freedom of treatment failure and overall survival. • Study design: • Multicenter randomized trial: Germany, Switzerland, Czech Republic, Austria, and the Netherlands. • 1370 patients with favorable early stage HL

26. HD 10 Study (cont’d) • Study design - 1:1:1:1 randomization - Comparison of similar arms was made for each modality.

27. Patient characteristics

28. HD 10 Study (cont’d) • Chemotherapy doses • Radiation doses CR: 99% vs 97.4% CR: 96.5% vs 96.8%

29. HD 10 Study (cont’d) • High dose vs. low dose Complete remission: 96.3% vs 96.3%

30. HD 10 Study (cont’d) • Overall survival between high doses vs. low doses

31. HD 10 Study (cont’d) • Adverse effects: • There was more grade III and IV toxicity in the group that received 4 cycles of chemotherapy compared to 2 cycles. (51.7% vs 33.2%) • Hair loss, hematologic, infectious. • Higher doses of radiation presented with more grade III and IV toxicity as well (8.7% vs 2.9%). • Dysphagia and mucositis.

32. HD 10 Study (cont’d) • Conclusions: • Results show noninferiority for both fewer cycles of chemotherapy and lower doses of radiation. • Note: caution should be made considering the wide confidence interval of 6%. • 2 cycles of ABVD and 20 Gy of radiation resulted in less acute toxicity. • Long term toxicities can’t be assessed in this study.

33. What if we remove the radiation?

35. MSKCC Study (cont’d) • Purpose: • To determine if combined modality therapy is superior to chemotherapy alone. • Complete remission duration, freedom from progression and overall survival • Study: • Stage IA, IB, IIA, IIB, IIIA • No bulky disease 152 patients • ABVD + RT • 76 patients • 3600 cGy • Mantle or inverted Y ABVD x 6 cycles - 76 patients

36. MSKCC Study (cont’d)

37. MSKCC Study (cont’d)

38. MSKCC Study (cont’d)

39. MSKCC Study (cont’d)

40. MSKCC Study (cont’d)

41. MSKCC Study (cont’d) • Conclusions: • No differences were seen in the treatment outcomes between CMT and chemotherapy alone. • No statistical significance in CR duration, FFP, survival. • Long-term side effects not measurable at this time. • Results coincide with studies performed in Spain and Argentina. • Caveats: • Sample size was too small to detect a difference of less then 20% in outcomes. • The radiation used and number of cycles of chemotherapy are no longer used.

43. The Cochrane Collaboration • Background: evaluate the importance of radiotherapy after noticing adverse effects such as secondary malignancies. • Objective: compare chemotherapy alone with combined modality treatment (CMT) with respect to response rate, progression-free survival and overall survival. • Study: 5 randomized controlled studies (1245 patients) • Mexico B2H031, Argentina GATLA, CALGB 7751, EORTC-GELA H9-F, MSKCC #90-44

44. The Cochrane Collaboration (cont’d) • Selection criteria: • Randomized controlled studies comparing chemotherapy alone with CMT using same chemotherapy regimen. • Early favorable and early unfavorable stages comprising more than 80% of patient population. • Documentation of OS, tumor control and response rate. • Endpoints: • Overall survival, overall response rate and complete response.

45. The Cochrane Collaboration (cont’d)

46. The Cochrane Collaboration (cont’d)

47. The Cochrane Collaboration (cont’d)

48. The Cochrane Collaboration (cont’d)

49. The Cochrane Collaboration (cont’d) • Conclusions • Meta analysis shows that adding radiotherapy to chemotherapy improves tumor control and overall survival at 5 years. • Rates of complete response remain the same between both arms. • Long term side effects still can’t be evaluated and require more time.

50. What are the current guidelines?