Controversies in early stage Hodgkin lymphoma. Marc ANDRE

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1 Controversies in early stage Hodgkin lymphoma Marc ANDRE

2 1L Therapy 2L Therapy 2L 2 Therapy 3L+ Therapy ASCT +/- BV Cure Cure! Cure? Courtesy P. Armand

3 Survival of Hodgkin lymphoma Causes of death 51% HL 10% treatment 18% second cancer 5% cardiovascular 2% infections 14% others. Favier, Cancer 2009

4 Our need Maintain high cure rate Reduce toxicities

5 Results are excellent Main messages ABVD + RT remains the standart of care FDG-PET is not the perfect tool to define a no radiotherapy group Patient adapted strategy is warranted in PET2+

6 Preview Late effects of radiotherapy Historical perspective PET directed trials New drugs

7 There can be little doubt by now that if radiation therapy use in Hodgkin s disease were a drug regulated by the US Food and Drug Administration (FDA), it would have been taken off the market. Dan Longo, J Natl Cancer Inst; 2009.

8 Vera Peters In Radiotherapy the domain of HD-Treatment Cure of localized stages Henry Kaplan Carl Musshoff Maurice Tubiana

9 The «star light» effect The late effects observed today are those produced by treatments given years ago. These observations may not be appropriate for treatment given today.

10 Patient immobilization «Head and Neck» thermoplastic mask

11 Méthode : design de l étude Pays-bas, 7 centres universitaires ou hôpitaux non-universitaires. Inclusion de 3905 patients traités pour un LH entre 1965 et 2000, âgés de 15 à 50 ans, ayant survécu min 5 ans après le R/ du LH. Informations concernant champs d irradiation, schémas de chimiothérapie, nombre de cycles, R/ de rechute : collectées dans dossiers médicaux. Dose de chimiothérapie alkylante dose cumulée estimée de Procarbazine. Schaapveld M, NEJM, 2015* *editorial: D. Longo

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13 Résultats : risque observé de second cancer Pdt le suivi : ème cancers diagnostiqués chez 908 patients, 3ème cancer développé chez 130 patients, 4ème cancer développé chez 17 patients. Risque de second cancer chez Px traités pour LH > la population générale SIR (O/E): 4.6 ; intervalle de confiance [CI] 95%, 4.3 to 4.9) AER: cancers en excès par 10,000 personnes-années.

14 Résultats : risque observé de second cancer (étude vs population générale) Cancer du sein contribue le + à l excès de risque absolu global Le risque absolu de cancer du sein parmi les femmes = 54,3 cas par personnes-années, représentant 40,5% d excès de risque de tout type de second cancer. Cancer du poumon : le 2ème cancer le plus fréquent (excès de risque absolu, 24.6 cas par 10,000 personnes-années, représentant 20.2% d excès de risque dans la cohorte).

15 Excès de risque absolu et relatif selon sexe, âge et suivi SIR de second cancer (tt type de cancer) reste élevé au moins 35 ans après l initiation du R/ du LH ) (Fig. 1A). SIR : pas de différence notable entre hommes et femmes. Excès de risque absolu régulièrement au fil du temps (P<0.001) (Fig. 1B). Après 35 ans de suivi des survivants d un LH : 364 excès de cancers par personnes-années.

16 Incidence cumulée selon période de traitement Incidence cumulée de second cancer solide : pas de significative selon les périodes de traitement (P = 0.71, hétérogénéité), Idem cancer du sein (P = 0.17)

17 Résultat : Association de traitement et risque de second cancer dans la cohorte Cancer du sein : Risque significativement moindre de cancer du sein chez px ayant reçu un champ de RT supra-diaphragmatique n incluant pas les creux axillaires, vs ceux ayant reçu un champ de RT de type mantelet (hazard ratio, 0.37; 95% CI, 0.19 to 0.72). Risque de cancer du sein = + faible avec hautes doses cumulatives de Procarbazine (hazard ratio pr dose cumulative de Procarbazine de 4.3 g/m2 BSA vs pas de CT, 0.57; 95% CI, 0.39 to 0.84; P = 0.002).

18 Incidence cumulée selon période de traitement Incidence cumulée de cancer pulmonaire, selon la période de R/, diffère entre hommes et femmes (P = 0.02) Incidence cumulée + faible chez les hommes traités pdt la période , versus périodes antérieures (P = 0.001) (Fig S1A) Figure S1 Cumulative incidence of subsequent malignant neoplasms (SMN) according to period of diagnosis with death as competing ris males, B:any SMN of stomach, pancreas, colon or rectum, C:NHL, D: leukemia, excluding MDS). Solid lines represent the observed incid Incidence parmi les femmes en fct du temps (P = 0.14) (Fig. 2C). the expected incidence. A

19 Résultat : Association de traitement et risque de second cancer dans la cohorte Cancer pulmonaire : Risque de cancer pulmonaire chez patients traités par champ de RT de type mantelet = similaire à celui chez les px traités avec un champ de type IF (hazard ratio, 1.04; P = 0.84). Risque associé au tabagisme multiplie le risque de cancer pulmonaire associé à l irradiation supra-diaphragmatique. Risque + élevé si fumeur ancien ou actif et RT supra-diaphragmatique (vs non-fumeurs et pas de RT supra-diaphragmatique) (hazard ratio, 14.38; 95% CI, 6.99 to 29.58).

20 Discussion : généralités Points forts de l étude : basée sur une large cohorte, suivi à long-terme et complet, détails des données de R/. Risque de second cancer solide : pas de changement sensible entre les Px traités pour un LH durant les années 1990 (période d étude de ), vs ceux R/ durant les décénies antérieures. Durant le suivi, SIR de second cancer solide = stable taux de second cancer qd les survivants de LH atteignent l âge où les taux de base de cancer sont importants. Même 40 ans après le R/ d un LH, les survivants ont un risque de second cancer, avec une incidence cumulée atteignant 48.5%.

21 Preview Late effects of radiotherapy Historical perspective PET directed trials New drugs

22 RISK FACTORS ACCORDING TO COOPERATIVE TREATMENT GROUPS EORTC-LYSA GHSG CANADA Risk factors (RF) A - mediastinal mass A - mediastinal mass B - Age 50yr B - Extra nodal site E B- Age>40 C - ESR 50 C - ESR 50 C- ESR > 50 D - 4 nod.areas D - 3 nod.areas D- 3 sites E - B + ESR > 30 Stage: Favorable (F) I II without RF I II without RF I-II without RF Unfavorable (UF) I II with 1 or + RF I IIA with 1 or + RF I-II with RF Or intermediate II B with C/D without A/B

23 Event-free Survival (%) Overall Survival (%) H8 Trial F group MOPP/ABV, involved-field radiotherapy (n=270) MOPP/ABV, involved-field radiotherapy (n=270) Extended-field radiotherapy (n=272) Extended-field radiotherapy (n=272) P< Time since Randomization (yr) No. at Risk 3 MOPP/ABV+IFRT Extended-field radiotherapy years EFS : STNI : 72% CMT : 99% 20 P= Time since Randomization (yr) No. at Risk 3 MOPP/ABV+IFRT Extended-field radiotherapy years OS : STNI : 93% CMT : 99% C. Fermé, NEJM, 2007

24 HD10 Trial Design CS IA, IB, IIA, IIB without RF Randomisation Arm A Arm B Arm C Arm D 4 x ABVD 4 x ABVD 2 x ABVD 2 x ABVD 30 Gy (IFRT) 20 Gy (IFRT) 30 Gy (IFRT) 20 Gy (IFRT)

25 Freedom from Treatment Failure HD10, RT-comparison p= 0,90 Arm difference in 5y-FFTF = -0,5% 95% CI [-3,6%; 2,6%] 30 Gy RT 20 Gy RT Pts. at Risk Time [months] 30 Gy RT Gy RT Median observation time = 79 months Engert, NEJM, 2010

26 Meyer R. et al, Feb 8, 2012

27 Kaplan Meier Estimates of Overall Survival and Freedom from Disease Progression. Meyer RM et al. N Engl J Med 2012;366:

28 Causes of Death, According to Treatment Strategy and Risk Profile. Meyer RM et al. N Engl J Med 2012;366:

29 Second Cancers and Cardiac Events, According to Treatment Strategy. Meyer RM et al. N Engl J Med 2012;366:

30 Some criticisms 1. Primary endpoint: survival (450 pts, 56 events at 12 yrs) 1. Stop at 405 pts 2. Analysis on 31 events 2. STNI vs IN-RT 3. Take care of a study with few events (incidental events may alter the results)

31 H9 J. Thomas, IJROT, 2018

32 Early favorable stages GHSG: HD13 (1730 pts randomised) CS I/II without RF ABVD ABV AVD AV ABVD ABV AVD AV 30 Gy IF 30 Gy IF 30 Gy IF 30 Gy IF Randomisation until 09/2009 Randomisation stop 02/2006 Randomisation until 09/2009 Randomisation stop 09/ pts 198 pts 648 pts 167 pts

33 Early favorable stages GHSG: HD13 ABVD (n= 586) AVD (n=571) Median obs. time 52 months 55 months Progression 3 0,5% 2 0,4% Early relapses 4 0,7% 6 1,0% Late relapses 20 3,5% 37 6,4% Number events ,9% 42 7,4% 2 5 0,9% 3 0,5% Total 27 4,8% 45 7,9% P= 0,04 Behringer, Lancet, 2015

34 Preview Late effects of radiotherapy Historical perspective PET directed trials New drugs

35 Principles of non inferiority trial PFS standart arm Non inferiority margin A B PFS experimental arm Result A is non inferior : A and the full 95% IC is into the non inferiority margin Result B is NOT non inferior : 95% IC is NOT COMPLETELY into the non inferiority margin

36 UK NCRI RAPID trial in early favorable HL Initial treatment: ABVD x 3 Re-assessment: if response, PET scan performed PET +ve PET -ve 4 th cycle ABVD then IFRT Randomisation 30 Gy IFRT No further treatment

37 Radford J et al. N Engl J Med 2015;372:

38 Events of Disease Progression or Death. Radford J et al. N Engl J Med 2015;372:

39 Progression-free Survival. It is important to note that the lower limit of the 95% confidence interval for the absolute risk difference ( 3.8 percentage points; 95% CI, 8.8 to 1.3) exceeds the designated noninferiority margin of 7 percentage points.. On the basis of a maximum allowable difference of 7 percentage points, this study did not show noninferiority of the strategy of no further treatment PFS standart arm Non inferiority margin Radford J et al. N Engl J Med 2015;372: B PFS experimental arm Result B is NOT non inferior : 95% IC is NOT COMPLETELY into the non inferiority margin

40 H10 H10F 2 ABVD PET 1 ABVD+IN-RT 30 Gy R 2 ABVD P E T ABVD 2 BEACOPPesc+IN-RT 30 H10U 2 ABVD PET 2 ABVD+IN-RT 30 Gy R 2 ABVD P E T ABVD 2 BEACOPPesc+IN-RT 30

41 favorable group unfavorable group Non-inferiority is concluded if the upper bound of the 95% confidence interval for the estimated hazard ratio does not exceed the non-inferiority margin. F group: HR < 3.20 U group: HR < 2.10 (upper bound is 2.50) M. André, JCO, 2017

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46 H10 RAPID HD16 PET Baseline 95% 0% 0% Conclusions Early PET 2 ABVD 3 ABVD 2 ABVD PET review 75% 100% 100% Non inferiority margin 10% 7% Stage I-IIB (bulky) I-IIA I-IIA Radiotherapy IN-RT 30 IF RT 30 IF RT 20 PET interpretation IHC 5PS DS RAPID, H10 and HD16 did not show the noninferiority of the strategy of radiotherapy omission after chemotherapy with regard to progression-free survival. Nevertheless, patients in these studies with early-stage Hodgkin s lymphoma and negative PET findings after two or three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy.

47 H10 H10F 2 ABVD PET 1 ABVD+IN-RT 30 Gy R 2 ABVD P E T ABVD 2 BEACOPPesc+IN-RT 30 H10U 2 ABVD PET 2 ABVD+IN-RT 30 Gy R 2 ABVD P E T ABVD 2 BEACOPPesc+IN-RT 30

48 PET2 positive M. André, JCO, 2017

49 Preview Late effects of radiotherapy Historical perspective PET directed trials New drugs

50 Study schema Experimental arm : BV 1.2 mg/kg every 2 weeks G-CSF mandatory 50

51 PET-based response after 2 cycles (IRC assessment) PET-response after 2 cycles, n (%) BV-AVD n=113 ABVD n=57 Negative 93 (82.3) 43 (75.4) 90% confidence interval (75.3% ; 88.0%) (64.3% ; 84.5%) The primary objective was met with a lower boundary of the 90% CI greater than 75% in the experimental arm. BREACH 51

52 Treatment administration Patients who actually received 4 cycles of treatment BV-AVD: 105/113 (92.9%) ABVD : 52/55 (94.5%) In the experimental arm, 90/113 (80%) patients received the 8 planned infusions of BV. In 16/23 cases, patients did not receive only the last dose of BV (D15C4), i.e 106/113 (94%) patients received 7 infusions of BV Patients who actually received radiotherapy BV-AVD: 102/113 (90.3%) ABVD: 49/55 (89.1%) Median treatment duration BV-AVD: 4.9 mo ABVD: 4.9 mo BREACH ISHL 11, Köln 28/10/

53 Response (EoT, Cheson 2007) Response, n (%) BV-AVD n=113 ABVD n=57 ORR 103 (91) 46 (81) CR 98 (87) 90% CI: 80% ; 92% 45 (79) 90% CI: 68% ; 87% PR 5 (4) 1 (2) SD 1 (1) 1 (2) PD 1 (1) 2 (3) Not done 8 (7) 8 (14) BREACH ISHL 11, Köln 53

54 Progression-Free Survival Median follow-up: 25.3 mo ( ) 24-month estimated PFS: BV-AVD: 97.2% (95% CI: ) ABVD: 91.3% (95% CI: ) BREACH ISHL 11, Köln

55 Overall Survival Median follow-up: 25.3 mo ( ) BREACH ISHL 11, Köln 55

56 Adverse events n(%) of pts reporting 1 event BV-AVD n=113 ABVD n=55* Any AE 113 (100) 55 (100) Grade 3-4 AE 97 (86) 38 (69) SAE 29 (26) 7 (13) Grade 3-4 SAE 25 (22) 6 (11) Treatment-related SAE 20 (18) 1 (2) SAE leading to permanent BV treatment discontinuation 8 - *2 patients with no study drug administration due to consent withdrawal Reasons for permanent BV discontinuation were loss of weight, hyponatremia, febrile neutropenia, epileptic seizure, peripheral neuropathy, hepatitis and cutaneous rash. BREACH 56

57 Common grade 3-4 AEs n(%) of pts reporting 1 event BV-AVD n=113 ABVD n=55 Neutropenia 85 (75) 34 (62) Leukopenia 40 (35) 15 (27) Febrile neutropenia 9 (8) 3 (6) Gastro-intestinal disorders 14 (12) 0 (0) ALT and/or AST increase 7 (6) 1 (2) Peripheral neuropathy 3 (3) 1 (2) Infections and infestations 9 (8) 2 (4) Skin and subcutaneous tissue disorders 5 (4) 0 (0) BREACH ISHL 11, Köln 57

58 Peripheral neuropathy BV-AVD (n=113): Grade 1: 45 (40%) Grade 2: 22 (20%) Grade 3: 3(2.7%) ABVD (n=55): Grade 1: 8 (15%) Grade 2: 1 (2%) Grade 3: 1 (2%) BREACH 58

59 Intention to give RT for selected PET neg patients declared before randomisation (see slide 8)

60 Review Radiotherapy 20 G for favorable patients Omitting radiotherapy Decrease survival in registry based studies PET negative: not able to show non inferiority, unfavorable difference is small. PET2 + : BEACOPPesc New approaches (BV and anti-pd1)?

61 Conclusion ABVD + radiotherapy remains a standard of care Individualized patients based approaches are warranted Reduction of late toxicities remains a major concern.

62 The balance between efficacy and toxicity