Transcript 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 CharitiesBritish Heart Foundation
 Cancer 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%)
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Rarer aggressive sub-types (some Tcells, rarely mantle cell, <30%)
Background: Some
Numbers

NHL
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Approx 9500 new cases of NHL/year
Approx 3000 are aggressive/curable
Therefore ~1500 long-term survivors
Median age ~60
Hodgkin Lymphoma
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Approx 1500 cases/year
>1000 survivors generated
Median age 29
Background: Curative
Therapies

R-CHOP:
 Rituximab/cyclofosfamide/
doxorubicin/vincristine/
prednisolone

ABVD:
 doxorubicin/bleomycin/vinblastine
dacarbazine
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
 Psychosocial
 Cardiac
 Pulmonary
 Endocrine
 Second
Cancers
 Bone Marrow
Psychosocial
 Difficulty
obtaining jobs,
mortgages, life insurance
 Depression
 Fear for/of the future
 Relationship 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:
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Cardiac
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
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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 agematched 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
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Major effect is increased risk of Ca Lung
Risk increased by:

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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)
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Ca Breast
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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

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
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
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What are we doing?
Appropriate referrals to
endocrine/fertility/cardiology etc
 Psycho-oncology
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Informal support/advice
 Formal referral
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Referral for Breast Screening
Breast Screening
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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
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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!
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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:

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Correct tests at the right times
National Screening Programmes:
•
•
•
•
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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 help

Anyone 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

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
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 research
 Service gaps
 Patients and families

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There are some basic things that we
can be doing now
Thank you
Any Questions?
 There are NO silly ones!

Thanks to:



All my colleagues at The Christie
Especially Val Goode
Copies of the presentation available upon
request