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