Late Effects of Treatment in Lymphoma Survivors

1. Late Effects of Treatment in Lymphoma Survivors Adam Gibb Clinical Research Fellow The Christie 25.3.10

2. Importance, Nature and Incidence

3. Why are Late Effects Important? • Because there are more survivors! • Increasing cure rates with modern therapies • Increasing incidence of HL/NHL as the demographic shift occurs in an ageing population • Increasing interest in this group:

4. Why are Late Effects Important? • NHSI Cancer Survivorship Initiative • Cancer Reform Strategy 2007 • Patient Groups- • Lymphoma Association • Other Charities- • British Heart Foundation • Cancer Research UK • Patients themselves

5. Survivors… • Are not as well as age-matched controls • Want more information about life after cancer • Need to know how to seek help and advice • The experience of cancer and the treatment needed will have some impact on quality of life for 25-50% of patients • Between 5-20% of people say this has had a major impact on their quality of life

6. Who Gets Them? • Long term survivors of aggressive lymphomas • They will have been cured with a variety of different treatments • All of these carry risks for the future

7. Background: Curable Lymphomas • Diffuse Large B-Cell NHL (~50%) • Hodgkin Lymphoma (50-95%) • Burkitt’s Lymphoma (70%) • Rarer aggressive sub-types (some T-cells, rarely mantle cell, <30%)

8. Background: Some Numbers • NHL • Approx 9500 new cases of NHL/year • Approx 3000 are aggressive/curable • Therefore ~1500 long-term survivors • Median age ~60 • Hodgkin Lymphoma • Approx 1500 cases/year • >1000 survivors generated • Median age 29

9. Background: Curative Therapies • R-CHOP: • Rituximab/cyclofosfamide/ doxorubicin/vincristine/ prednisolone • ABVD: • doxorubicin/bleomycin/vinblastine/dacarbazine

10. Background: Curative Therapies • Radiotherapy: • curative in Stage 1a disease, used as consolidation in HL, bulky disease, v.aggressive tumours • Stem Cell Transplantation: • high doses of chemo (BEAM, fludarabine), graft-versus-host disease, total body irradiation

11. What are the Late effects? • Many and varied! • Definitions a bit controversial: • When is a treatment-related problem ‘late’ as opposed to ‘early’ • Sterility/fertility is a good example • Most would call problems >5 years out as ‘late’

12. Categories • Psychosocial • Cardiac • Pulmonary • Endocrine • Second Cancers • Bone Marrow

13. Psychosocial • Difficulty obtaining jobs, mortgages, life insurance, • Depression • Fear for/of the future • Relationship problems

14. Cardiac • Anthracyclines (doxorubicin, epirubicin) known to be cardiotoxic • As is supradiaphragmatic radiotherapy • More recently, vinca alkaloids (vincristine, vinblastine) also found to be associated with cardiotoxicity • This has been confirmed in a recent study:

15. Cardiac • 7033 Hodgkin disease patients who were treated in Britain from 1967 through 2000 were studied • A total of 166 deaths from myocardial infarction • Standardized mortality ratio (SMR)= 2.5 x age-matched controls • Risk was particularly high for patients treated with the ABVD regimen (SMR = 9.5) • Swerdlow et al. J Natl Cancer Inst. 2007 Feb 7;99(3):206-14.

16. Pulmonary • Major effect is increased risk of Ca Lung • Risk increased by: • MOPP chemo (now not used) • Radiotherapy to the thorax, esp. ‘Mantle Field’ • Tobacco smoking multiplies the risk • Relative risk (RR) varies from 2x to 15x according to a variety of factors • Lancet Oncol 2005;6:773-79

17. Pulmonary • Bleomycin (ABVD, BEACOPP, VAPEC-B) can cause pulmonary fibrosis both acutely and in the long term • Can lead to late onset asthma/COPD • Again, risk is synergistic with smoking

18. Pulmonary • Lance Armstrong (7 times Tour De France winner) famously declined bleomycin (in BEP) when treated curatively for stage 4 testicular Ca!

19. Endocrine • Wide variety of hormone deficiency syndromes reported in survivors • RR of hypothyroidism up to 9x in patients who receive mantle/upper thoracic/neck XRT • Hypogonadism seen in patients treated with intensive chemo regimens, and esp. transplants

20. Endocrine • Manifests as reduced testosterone and libido in males • Oligo/amenorrhoea in females due to premature ovarian failure • This has secondary effects on bone density, leading to osteopaenia/porosis

21. Second Cancers • Increased risk in all cancer survivors • Most if not all cancer treatments are in themselves carcinogenic • Radiotherapy and alkylating chemo (cyclofosfamaide/dacarbazine etc) esp. risky • RR varies from 9.9x (leukaemias) to 1.6x (Ca Bowel) in a series of 32,591 HL survivors (Dores et al, 2002)

22. Ca Breast • Lifetime risk in untreated female population: • 10% • Lifetime risk in female population treated with supradiaphragmatic radiotherapy: • 14-30% according to XRT field • Commences ~ 10 years out from XRT

23. Bone Marrow Failure • Treatment related myelodysplasia (tMDS) risks: • ~1% with chemo • 1.5-2% with radioimmunotherapy (Zevalintm) • 5-10% post autograft • Similar rates for Acute Myeloid Leukaemia

24. So What Should Be Done?

25. Follow-up • Follow up is of course important • The big question is how this should be done!

26. Practice at The Christie • Val Goode set up this service in the 1990s for lymphoma patients • Ad-hoc service since the 1980s • Patients seen 3-6 monthly in years 0-5, mainly for relapse • Annually years 5-10 • Bi-annually thereafter • Offered discharge at year 20!

27. What are we doing? • Focused history/exam every visit • FBC/biochemistry up to year 3 • TFTs annually in those at risk of hypothyroidism • Chest X-rays for those with previous mediastinal bulk/thoracic XRT/pulmonary lesions

28. What are we doing? • Appropriate referrals to endocrine/fertility/cardiology etc • Psycho-oncology • Informal support/advice • Formal referral • Referral for Breast Screening

29. Breast Screening • A national notification risk assessment and screening programme (NRASP) was set up in 2003 • Offered to females who • Have received XRT to the thorax/mediastinum/breasts • under the age of 36 at the time • Commences 8 years following completion of treatment • Annual screening until the age of 50 • May require USS or MRI mammography • Then have 3-yearly screening in the national breast screening programme

30. Breast Screening • This has been looked at in a pilot study (BJC (2009) 101, 582 – 588): • NRASP database searched • 417 women invited for clinical review • 243 (58%) attended • 23 (5.5%) have been diagnosed with Ca Breast by the NRASP • Standardised incidence ratio of 2.9 compared with the age-matched general population

31. What are we not doing? • Lots of things! • Clear area of unmet need for this population • Lots of work to do!

32. The Future of Late Effects • Detect • Treat • Prevent

33. Detection • Ensure all patients are offered/ encouraged to attend follow-up for relapse initially, and later on for late effects: • Do we have the databases? • Resources: • Staff/space/money!

34. Detection • Picking up problems: • Correct tests at the right times • National Screening Programmes: • Breast- established 2003, improvements proposed • Lung- proposed • Cardiac- proposed • Endocrine- ad hoc? • Further research needed in this area: • Biomarkers of early disease • Preliminary work underway at The Christie

35. Detection • Different age/disease groups may need different approaches • Personalised treatment summaries may help • Anyone can offer follow up according to its recommendations • ‘Dip-in/dip-out’ may appeal to teenage or busy working adults

36. Treat • Should we be treating late effects the same as de novo diseasese.g. should XRT induced Ca Breast be treated the same as sporadic? • Do the various specialists need knowledge of the original oncology diagnosis/treatments?

37. Prevention • Better never than late?

38. Prevention • Can we minimise/eliminate some or all late effects? • Two main strategies to employ here: • De-escalate therapies based upon individualised treatment plans/biomarkers of good prognosis • Substitution of less-toxic therapies

39. Prevention: Some examples • RAPID Study • 1A/2A Hodgkin Lymphoma • Those who are PET –ve after chemo are randomly assigned to receive XRT or not • R-GCVP Study • Removing doxorubicin from CHOP and replacing it with gemcitabine in patients with DLBCL and poor cardiac risk

40. Summary • Late effects are under-detected and under-treated • Huge area of unmet need: • Basic research • Service gaps • Patients and families • There are some basic things that we can be doing now

41. Thank you • Any Questions? • There are NO silly ones! • Thanks to: • All my colleagues at The Christie • Especially Val Goode • All at the Lymphoma Association for inviting me! • Copies of the presentation available upon request