Late Effects of Treatment in Lymphoma Survivors
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Transcript of Late Effects of Treatment in Lymphoma Survivors
Late Effects of Treatment in Lymphoma Survivors
Adam Gibb
Clinical Research Fellow
The Christie
2010
Importance, Nature and Incidence
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:
Why are Late Effects Important? NHSI Cancer Survivorship Initiative Cancer Reform Strategy 2007 Patient Groups-
Lymphoma Association Other Charities-
British Heart FoundationCancer Research UK
Patients themselves
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
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
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%)
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
Background: Curative Therapies
R-CHOP:Rituximab/cyclofosfamide/
doxorubicin/vincristine/ prednisolone
ABVD:doxorubicin/bleomycin/
vinblastinedacarbazine
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
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’
Categories
PsychosocialCardiacPulmonaryEndocrineSecond CancersBone Marrow
Psychosocial
Difficulty obtaining jobs, mortgages, life insurance
DepressionFear for/of the futureRelationship problems
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:
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.
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
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
Pulmonary
Lance Armstrong (7 times Tour De France winner) famously declined bleomycin (in BEP) when treated curatively for stage 4 testicular Ca!
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
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
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)
Ca Breast
Lifetime risk in untreated female population:10%
Lifetime risk in female population treated with supradiaphragmatic radiotherapy:14-30% according to XRT fieldCommences ~ 10 years out from XRT
Bone Marrow Failure
Treatment related myelodysplasia (tMDS) risks:~1% with chemo1.5-2% with radioimmunotherapy
(Zevalintm) 5-10% post autograft
Similar rates for Acute Myeloid Leukaemia
So What Should Be Done?
Follow-up
Follow up is of course important
The big question is how this should be done!
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!
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
What are we doing?
Appropriate referrals to endocrine/fertility/cardiology etc
Psycho-oncologyInformal support/adviceFormal referral
Referral for Breast Screening
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
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
What are we not doing?
Lots of things!
Clear area of unmet need for this population
Lots of work to do!
The Future of Late Effects
Detect
Treat
Prevent
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!
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
Detection
Different age/disease groups may need different approaches
Personalised treatment summaries may helpAnyone can offer follow up according
to its recommendations‘Dip-in/dip-out’ may appeal to teenage
or busy working adults
Treat
Should we be treating late effects the same as de novo diseases e.g. should XRT induced Ca Breast be treated the same as sporadic?
Do the various specialists need knowledge of the original oncology diagnosis/treatments?
Prevention
Better never than late?
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
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
Summary
Late effects are under-detected and under-treated
Huge area of unmet need:Basic researchService gapsPatients and families
There are some basic things that we can be doing now
Thank youAny Questions?
There are NO silly ones!
Thanks to: All my colleagues at The Christie Especially Val Goode
Copies of the presentation available upon request