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Lalita Norasetthada, MD

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1 Lalita Norasetthada, MD
Hodgkin lymphoma Lalita Norasetthada, MD

2 Overview Limited-stage disease Advanced-stage disease
Challenging problems Pregnancy HIV infection Elderly

3 Limited-Stage HL

4 Objectives in limited-stage HL
To maximize the number of cures and minimize late toxicity, particularly cardiovascular disease and 2nd cancers by optimizing the mix of available intervention

5 Unfavorable risk factors for Stage I-II HL
GHSG EORTC NCIC Age > 50 > 40 Histology MC or LD ESR and B-Symptoms > 50 if A; > 30 if B > 50 or Any B-symptoms Mediastinal mass MMR > .33 MTR > .35 MMR > .33 or > 10 cm Nodal sites > 2 > 3 Extranodal lesion Any

6 GHSG HD7 trial EFRT vs 2 x ABVD + EFRT
7 year FFTF : 67% vs 88% 7 year OS : 92% vs 94% Engert A, et al. J Clin Oncol. 2007; 25: 3495

7 GHSG HD8 trials : COPP/ABVD & EFRT vs COPP/ABVD & IFRT in limited-stage unfavorable HL
5-year FFTF : 85.8% vs 84.2% 5-year OS : 90.8% vs 92.4% Engert A, et al. J Clin Oncol. 2003; 21: 3601

8 EORTC H8-F trial Limited-stage favorable HL
Early stage with favorable features randomly assigned to 3 MOPP-ABV plus IFRT (n = 270) STNI (n = 272) 10-year EFS : 98% vs 74% 10-year OS : 97% vs 92% Ferme C, et al. N Engl J Med. 2007; 357: 1916

9 EORTC H8-U trial Limited-stage unfavorable HL
Limited-stage with unfavorable features randomly assigned to 6 cycles MOPP-ABV plus IFRT (n = 336) 4 cycles MOPP-ABV plus IFRT (n = 333) 4 cycles MOPP-ABV plus STNI (n = 327) 10-year EFS : 84% vs 88% vs 87% 10-year OS : 88% vs 85% vs 84% Ferme C, et al. N Engl J Med. 2007; 357: 1916

10 GHSG HD10 trial : 2 vs 4 x ABVD plus 30 Gy vs 20 Gy IFRT in St I-II favorable HL
randomized between 4 x ABVD & 30 Gy IF-RT (arm A) 4 x ABVD & 20 Gy IF-RT (arm B) 2 x ABVD & 30 Gy IF-RT (arm C) 2 x ABVD & 20 Gy IF-RT (arm D) CR rate : 98.4% 2-year FFTF : 96.6% 2-year OS : 98.5% no statistical difference between arms Eich H, et al. Int J Radiat oncol Biol Phys. 2005; 63(suppl): S1

11 Involved-nodal radiation therapy combined with 2 cycles of chemotherapy in St IA-IIA non bulky HL
- Non RCT retrospective study - 95% received 2 cycles of chemoRx (67% ABVD) - EFRT : n = 127, median f/u 137 mo - IFRT : n = 96 , median f/u 89 mo - INRT < 5 cm : n = 102, median f/u 50 mo Campbell B, et al. J Clin Oncol. 2008; 26: 5170

12 1974 patients treated in 8 randomized trials comparing more vs less RT
A meta-analysis: the influence of radiotherapy and chemotherapy on long term outcome of limited-stage HL 1974 patients treated in 8 randomized trials comparing more vs less RT Reduction in RT field sized to IFRT has little if any impact on survival 1,688 patients treated in 13 randomized trials comparing RT plus CT vs RT alone Addition of CT to RT produced large effect on disease control but a small non-significant effect on overall survival Specht L, et al. J Clin Oncol. 1998; 16: 830

13 RCT for limited stage HL : NCIC-CTG & ECOG
Study schema Unfavorable limited stage HL 5-year FFP : 95% vs 88%, p=.004 N = 130 each arm in unfavorable disease with short duration of f/u as the study designed to power at 12 year f/u 5-year OS : 92% vs 95%, p=.3 Meyer C, et al. J Clin Oncol. 2005; 23: 4634

14 GHSG HD14 : BEACOPP escalated in limited unfavorable HL
BEACOPP escalated x 2 + ABVD x 2 + IFRT ABVD x 4 + IFRT 3-year FFTF 96% 90% Disease progression 1.8% 5.9% This more aggressive treatment strategy will become the new standard for early unfavorable HL patients within the GHSG Whether the improved FFTF translates into an improved overall survival must be awaited Borchmann P, et al. ASH 2008: abstract

15 ABVDx6 & RT vs ABVD alone in St I-IIIA non-bulky disease
5-year OS : 97% vs 90%, p= .08 5-year FFP : 86% vs 84% Small number of patients Straus D, et al. Blood. 2004; 104: 3483

16 EORTC/GELA H9-F trial in limited-stage favorable HL
Randomly assigned patients achieving CR after EBVP x 6 to receive either IFRT 36 Gy IFRT 20 Gy No RT The trial halted prematurely due to reaching early stopping rules IFRT Patients (no.) 4-year EFS 4-year OS 36 Gy 239 88% 98% 20Gy 209 85% 100% No RT 130 69% Eghbali H, et al. Blood. 2005; 106: Abstract #814a

17 Response adapted therapy using FDG-PET : UK NCRN Rapid trials in St I-IIA
Initial treatment : ABVD x 3 Re-assessment if NR/PD, off study If CR/PR, PET scan performed PET +ve PET -ve (21%) (79%) Randomization 4th cycle of ABVD then IFRT IFRT No further treatment Radford J, et al. ASH 2008: Abstract

18 Treatment modality for limited stage HL
Combined chemotherapy with IFRT is the standard treatment of care Favorable disease : ABVD 2-4 cycles Unfavorable disease : ABVD 4-6 cycles Chemotherapy alone can be the option in selected subgroup of patients with favorable non-bulky disease, if the long-term toxic risks of radiation are to be avoided, especially for patients younger than 40 years.

19 Advanced-stage HL

20 The landmark randomized trial by CALGB for advanced HL
MOPP (n =123) MOPP/ABVD (n=123) ABVD (n= 115) P-value CR rate 67 82 83 .006 5-year FFS 50 61 65 5-year OS 66 73 75 .28 ABVD for 6-8 months was as effective as 12 months of MOPP/ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkin's disease - ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP. Canellos GP, et al. N Engl J Med. 1992; 327: 1478

21 Intergroup trial : ABVD vs MOPP/ABVD for advanced HL
P-value CR rate (%) 80 76 .16 5-year FFS (%) 66 63 .42 5-year OS (%) 81 82 .82 Pulmonary toxicity (> gr 2) (%) 30.6 24.5 .06 Hematologic toxicity ( > gr 3) (%) 74.6 63.6 <.001 Second malignancy (no.) 28 18 .13 MDS/leukemia 11 2 .011 Duggan DB, et al. J Clin Oncol. 2003; 21: 607

22 Intergrouppo Italino; ABVD vs Modified Standford V vs MOPPEBV/CAD in advanced HL
5-year FFS : 78% vs 81% vs 54% Grade 3-4 Hematologic toxicity ABVD Stanford V MOPPEBV/CAD Neutropenia (%) 25 29 51 Thrombocytopenia (%) 1 24 Infection (%) 14 Gobbi PG, et al. J Clin Oncol. 2005; 23: 9198

23 UK NCRI Lymphoma Group Study, ISRCTN 64141244 : ABVD 6-8 + RT vs Standford V
Involved field irradiation to sites of initial bulk disease (>5cm) or splenic deposits, and to residual masses ABVD (n- 261) Standford V (n= 259) Gr III-IV Pulmonary toxicity (no.) 27 10 Gr III-IV non-pulmonary toxicity (%) 8 19 Overall response rate (%) 89 90 5-yr PFS 76 74 5-y OS 92 Johnson P, et al. ASH 2008: abstract

24 GHSG HD9 : COPP/ABVD vs escalated- dose BEACOPP vs standard-dose BEACOPP in St IIB-IV
10-year FFTF : 64% vs 70% vs 82% 10-year OS : 75% vs 80% vs 86% Diehl V, et al. N Engl J Med. 2003; 348; 2386 Diehl V, et al J Clin Oncol 2007; 25(suppl 18): LBA8015

25 GHSG HD12 final analysis : RCT comparing escalated BEACOPP x 8 vs escalated BEACOPP x 4 followed by standard-dose BEACOPP Entire cohort Escalated BEACOPP x 8 +/- RT Escalated BEACOPP x 4 Standard BEACOPP x 4 +/- RT Gr 3-4 anemia 65% 51% Gr 3-4 thrombocytopenia 5-yr OS 91% NS 5-yr FFTF 85.5% 5-yr PFS 86.2% Diehl V, et al. Blood. ASH 2008 : abstract

26 Risk-adapted BEACOPP regimen
Relapse or progression occurred in 27% of patients with interim positive PET/CT versus 2.3% of negative scans (P < .02) 5-year EFS and OS for patients with early unfavorable and standard risk vs patients with high risk : 84%, 90% vs 85%, 91% Limited stage, unfavorable/ Advanced stage, IPS <2 Advanced stage, IPS > 3 Standard BEACOPP x 2 Escalated BEACOPP x 2 Restaging with PET or Ga67 Negative : Standard BEACOPP x 4 Positive : Escalated BEACOPP x 4 Dan E, et al. Blood. 2007;109:905

27 Chemotherapy for advanced HL
ABVD x 6-8 cycles is generally recommended Escalated-dose BEACOPP x 4 should be considered for high-risk patients with an IPS score > 4 If CR : Standard-dose BEACOPP x 4 If PR : Escalated-dose BEACOPP x 4 The ongoing EORTC trial is comparing escalated BEACOPP and ABVD in advanced HL The recently completed E2496 intergroup trial compared the Stanford V regimen with ABVD + RT for advanced HL, results are awaited NCCN. Practice Guidelines in Oncology-v

28 EORTC 20884 trial : Role if IFRT in advanced HL
MOPP/ABVD x 6-8 cycles CR PR Randomization IFRT No further therapy IFRT CR; no further Rx CR; IFRT PR; IFRT 5-year EFS (%) 84 79 5-year OS (%) 91 85 87 IFRT did not improve outcome in patients achieving CR after chemotherapy Consolidative IFRT is beneficial for patients experiencing PR Aleman BMP, et al. N Engl J Med. 2003;109:2396

29 GHSG HD15 : Response adapted therapy using FDG-PET; preliminary result
Multicenter RCT in advanced HL treated with standard-dose BEACOPP x 8 or escalated-dose BEACOPP x 6 or time-condensed BEACOPP-14 x 8 IFRT was restricted to patients with PET-positive after chemotherapy Negative predictive value of PET after chemotherapy : 94% (95% CI: ) 1-year PFS : 96% vs 86% Kobe C, et al. Blood. 2008; 112 : 3989

30 Role of IFRT after chemotherapy in advanced HL
Additional IFRT is beneficial for patients with residual disease after chemotherapy IFRT is routinely recommended for patients with bulky disease Consolidative IFRT can be omitted in PET negative patients after chemotherapy

31 HIV related HL

32 HIV related HL HIV infection also increases the risk of classical Hodgkin lymphoma, with a relative risk of 8–10- fold compared to the general population A greater proportion of the subtypes (mixed cellularity, lymphocyte depleted) with less favorable prognosis compared to the general population The greater proportion of MC and LD subtypes is related to severe immunocompromise, while those with modest immunocompromise are more at risk for the NS subtype

33 Histology of HIV related cHL
LMP1 MC CD15 CD30 Grogg, et al. J Clin Path. 2007; 60 : 1365

34 HIV related HL There is coincident EBV infection, with nearly all cases showing EBER and LMP-1 expression in the HRS cells The composition of the reactive inflammatory infiltrate in HIV-related HL is often characterized by a predominance of CD8-positive T lymphocytes over CD4-positive lymphocytes, by contrast with the background in HL without HIV infection

35 Epidermiology of HIV-related HL and the effect of HARRT
HAART-related improvement in CD4 counts likely explain the increasing HIV related HL incidence since 1996 Biggar et al. Blood. 2006; 108: 3786

36 Characteristic of HIV related HL
Connors J. ASH Educational session. 2008

37 HIV related HL in HAART era
Patients treated in the pre- HAART era (1984–1996) were compared with those belonging to the HAART era ( ) By multivariate analysis patients without HAART had a 5.6-fold higher risk for 3- year mortality; HR 5.6, (95% CI 2.20–14.26) 2-year OS 74% vs 34%, p <.0001 Biggar, et al. Blood. 2006; 108: 3786

38 Response of HAART and survival outcomes
Kaplan Meier cumulative survival plot Multivariate analysis HR P-value Response to HAART .19 .0045 Age < 45 .23 .003 CR .30 .007 2-year OS 89% vs 44%, p <.0001 Hoffman C, et al. Br J Haematol. 2004; 125: 445

39 Chemotherapy regimens for HIV-related HL
Standford V1 BEACOPP2 VEBEP3 ABVD4 No. 56 12 28 62 Stage III-IV (%) 71 92 100 CD4 (/uL) 238 205 257 129 HARRT Yes Yes (25%) G-CSF NS 20% CR (%) 81 75 87 Survival, % (year) 51 (3) NA 86 (2) 76 (5) Spina, et al. Blood. 2002; 100: 19871; Hartman P, et al. Ann Oncol : 15622 Spina M, et al. Blood. 2005; 106: 100a3; Xicoy B, et al. Haematologica. 2007; 92: 191 4

40 Additional therapy in HIV related HL
HAART Opportunistic infection prevention Hematopoietic growth factor Psychological support

41 HL during Pregnancy

42 HL during pregnancy Two patients need to be managed
Mother : optimally controlling lymphoma Fetus : avoiding toxicity and allowing the normal term delivery Information about the best approach to management of coincident HL and pregnancy is limited

43 HL and birth outcomes : a Danish nation wide cohort study
Dx within 2 yr prior to pregnancy Dx during Preg Langagergaard V, et al. Br J Cancer. 2008; 98: 183

44 Staging in HL during pregnancy
Avoiding the use of imaging that requires radiation CXR with proper shielding and abdominal ultrasonography MRI Abdominal and pelvic CT should be avoided FDG-PET can cross the placenta and reach the fetus, it may involve higher radiation exposure than regular CT and its use cannot be recommended during pregnancy

45 HL during pregnancy As a general rule any treatment, radiation or chemotherapy should be avoided during the first trimester unless severely threatening symptoms are present More than 50% of patients can continue the pregnancy to term without any treatment for the lymphoma

46 Management HL during pregnancy
If treatment are required Radiation Single agent chemotherapy Combined chemotherapy

47 RT during pregnancy From 2 case series : 11 patients with limited-stage received supradiaphargmatic RT with special shielding 10 patients achieved CR without evident fetal injury When conventional doses of radiotherapy are administered, a distance of over 30 cm from the field edges will limit the total exposure of the fetus to only 4-20 cGy Therefore, radiotherapy may be considered in specific circumstances such as lymphoma confined to the neck or axillary lymph nodes Exposure to cGy of radiation is considered as the threshold dose for severe congenital malformation when given during organogenesis Gelb AB, et al. Cancer1996; 78: 304; Nisce LZ, et al. J Clin Oncol. 1986; 9: 146; Kal HB, et al. Lancet Oncol 2005; 6: 328

48 RT during pregnancy Radiation exposure during the second and third trimesters is associated with a carcinogenic effect that may include an increased risk for the development of leukemia and solid tumors within the first decade of life Another concern is the increased risk of neurodevelopmental impairment, including a decrease in the IQ and even severe mental retardation Kal HB, et al. Lancet Oncol 2005; 6: 328

49 Chemotherapy during pregnancy
Chemotherapy during the first trimester may increase the risk of spontaneous abortions, fetal death and major malformations The fetus is extremely vulnerable from the 2nd -8th week of gestation, during which organogenesis occurs Between the 14th to 16th weeks of gestation the risk of severe malformations or mental retardation is reduced significantly Cardonick E, et al. Lancet Oncol 2004; 5: 283; Leslie KK, et al. Obstet Gynecol Clin North Am 2005; 32: 627

50 Chemotherapy during pregnancy
Second and third trimester exposure is not associated with malformations but increases the risk of Fetal or neonatal death IUGR Pre-term delivery Low birth weight These complications may be associated with adverse long-term effects such as neurodevelopmental impairment, increased rate of cardiovascular risk factors Cardonick E, et al. Lancet Oncol 2004; 5: 283; Leslie KK, et al. Obstet Gynecol Clin North Am 2005; 32: 627

51 Case series: HL during pregnancy
24 cases of HL during pregnancy 12 cases received MOPP, MOP or cyclophosphamide during 1st trimester Spontaneous abortion : 2 Fetal malformation : 5 10 cases receiving combined chemotherapy after 1st trimester delivered normal infants Based on this observation and the known carcinogenicity of alkylating agent such as mechlorethamine, cyclophosphamide, procarbazine and chlorambucil should be avoided Ebert U, et al. Pharmacol Ther. 1997; 74: 207

52 ABVD regimen in pregnancy
2 case series involving 13 cases No fetal adverse outcomes after receiving ABVD during first, second and third trimesters Anselmo AP, aet al. Fetal Diagn Ther. 1999; 14: 102; Cardonick E, et al. Lancet Oncol. 2004; 5: 283

53 Single agent : Vinblastine
> 75% response rate in treatment naïve HL patients and modest toxicity Reported to be teratogenicity in mice No similar effect reported in human at doses therapeutic for lymphoma The combination of high level of effectiveness, minimal acute toxicity and low likelihood of negative effect on the fetus make vinblastine a useful agent to suppress HL during pregnancy Armstrong JG, et al. Science. 1964; 143: 703 Lacher MJ, et al. Ann Intern Med. 1964; 61: 113 Rosenzweig AI, et al. Ann Intern Med. 1964; 61: 108 Connors J, et al. ASH Educational session. 2008

54 Management after delivery
Patients who have been able to complete the pregnancy without treatment Repeat full staging Consider appropriate therapy according to stage of lymphoma Patients who have been treated with vinblastine Multi-agent chemotherapy 6-8 cycles as accurate staging cannot be performed Connors J, et al. ASH Educational session. 2008

55 Suggesting algorithm for the treatment of HL during pregnancy
Perek D, et al. Hematologica. 2007; 92: 1230

56 HL in elderly

57 GHSG: HL in elderly Age < 60, n = 3879 Age > 60, n = 372
Median Age (years) 31 65 Stage III-IV (%) 40 48 B-symptom (%) 43 50 Bulky disease (%) 60 49 PS < 70 (%) 3 11 IPS > 4 (%) 13 Histology (%) NS MC 66 19 41 35 Engert, et al. J Clin Oncol. 2005; 23: 5052

58 GHSG: HL in elderly Engert, et al. J Clin Oncol. 2005; 23: 5052

59 Poorer outcomes in limited-stage unfavorable elderly patients treated with EFRT compared with IFRT after chemotherapy Kaplan-Meier plot of FFTF according to treatment (EFRT vs IFRT) Kaplan-Meier plot of OS according to treatment (EFRT vs IFRT) CTx4 & IFRT CTx4 & IFRT CTx4 & EFRT CTx4 & EFRT Klimm B, et al. Ann Oncol. 2007; 18: 357

60 Dose intensity and the outcomes in elderly patients
Langren O, et al. Haematologica. 2007; 88: 438

61 Factors contributing to poorer outcomes in elderly
Less favorable histologic subtypes Co-morbidity Delayed diagnosis Inadequate adherence to treatment protocols Failure to maintain dose intensity

62 Chemotherapy regimen for HL in elderly
2 4 5 6 3 1 Engert A, et al. J Clin Oncol. 2005; 23: 50521; Feltl D, et al. Leuk Lymphoma. 2006: 47: 15182 Kolstad A, et al. Leuk Lymphoma ; 2007; 48: 5703; Ballova V, et al. Ann Oncol Levis A, et al. Ann Oncol. 2004; 16:1245; Mcpherson N, et al. LeuK Lymphoma. 2002: 43: 13956

63 ABVD compared with other chemotherapy regimens in elderly
Connors J. ASH Educational session. 2008

64 Management for HL in elderly
Chemotherapy regimens No special regimen superior ABVD remains the goal standard Anticipate increase toxicity Hematologic Pulmonary Cardiac Neurologic Hemopoietic growth factors

65 Can bleomicin be omitted in patients with compromised pulmonary function?
Canellos G, et al. J Clin Oncol. 2004; 22: 1533

66 Overall treatment plan for HL in elderly
Favorable non-bulky limited stage ABVD x 2 + IFRT Unfavorable limited stage or advanced stage HL ABVD until 2 cycles past CR (minimum 6) Patients with quite advanced age and too frail to receive chemotherapy Radiation Connors J. ASH Educational session. 2008

67 THE END


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