Lymphoma Education Day
13th October 2010
The modern management of Hodgkin
lymphoma
John Radford
Manchester Academic Health Science Centre
Manchester, UK
CXR of 30 year old female before treatment
Before starting treatment
• Biopsy of enlarged lymph node and central review by
expert lymphoma pathologist
• Investigations to determine stage; bloods, CT scan of
thorax, abdomen, pelvis, PET scan, BM biopsy if not
stage IA or IIA
• Discussion with colleagues at MDT meeting
• Discussion with patient; treatment options, relevant
clinical trials, immediate and late side effects
Treatment for HL
• Treatment for limited stage (IA and IIA): 3 cycles chemotherapy
+/- RT; 90% cure
• Treatment for advanced stage (II plus B symptoms or bulk and/or
B symptoms, III and IV); 6 cycles chemotherapy +/- RT; 70%
cure
• Treatment for first recurrence; 2nd line chemotherapy followed by
autologous or allogeneic transplantation
• Treatment for subsequent recurrence; new drugs (panobinostat,
iodine131 basiliximab, brentuximab vedotin) in clinical trial
ABVD
(days 1 and 15 of a 28 day cycle)
• Adriamycin; hair loss, nausea and vomiting,
myelosuppression, cardiotoxicity
• Bleomycin; shivers and shakes, skin pigmentation,
pulmonary toxicity
• Vinblastine; nausea, myelosuppression, neuropathy
• Dacarbazine; nausea and vomiting,
myelosuppression, painful veins during drug infusion
The early days: RT alone
• Imaging limited to plain radiology of the thorax and
lymphangiography of the abdomen and pelvis
• These techniques had low sensitivity for upper
abdominal and splenic disease
• Staging laparotomy performed (splenectomy, liver
and lymph node biopsies) to enhance sensitivity
• If all tissues histologically negative, patient said to
have pathological stage (PS) I/II and treated with
“mantle field” RT
Extended field RT
Rosenberg and Kaplan, 1970
Cures resulted, but…
• Despite pathological staging, relapse occurred
in ~30% mainly outside the radiation field
• In addition, staging laparotomy associated with
• immediate mortality and morbidity
• delay to start of chemotherapy in
those requiring it
• greatly increased risk of fatal septic
shock (Donaldson et al, NEJM, 1972)
Adjuvant MOPP/MVPP
(Anderson et al, BJC)
• 114 pts with PS IA-IIB HL randomised to receive
either mantle RT alone or mantle RT followed by 6
cycles MVPP
• After median follow-up of 62 mo
• RFS was 69% for RT alone and 93% for
RT+MVPP (p=0.0003)
• Overall survival was 93% with no difference
between trial arms (p= 0.54) because of
successful salvage
Relapse free survival
Overall survival
Anderson et al, Br J Cancer 1984, 49, 695-702
The move towards smaller RT
fields
• GHSG HD8 trial involving 1204 pts with stages I-II and
risk factors
• Randomised between COPP/ABVD x 2 followed by
either EFRT plus boost or IFRT plus boost (Engert et al
2003)
• no difference in terms of CR, FFTF, OS
• more toxicity with EFRT
…and smaller RT doses
• GHSG HD1 trial (Diehl et al, 1995)
• stages I and II with unfavourable features
• COPP/ABVD x 2 (total of 4 cycles chemo)
followed by either 20Gy or 40Gy of EFRT to
non-bulky sites (40 Gy to bulk)
• GHSG HD5 trial (Loeffler et al, 1997)
• similar group of patients
• same chemo followed by 30Gy of EFRT to
non-bulky areas (40 Gy to bulk)
• concluded that no relevant RT dose effect
exists in the range 20-40 Gy and doses of 20
Gy sufficient for non-bulky sites (40 Gy to
bulk) after 4 cycles of modern chemo
Chemotherapy alone?
• NCI Canada and ECOG: 399 patients stratified as
unfavourable (any of age ≥40, ESR ≥50, MC or LD
histology, ≥4 sites of disease) or favourable (none of
the above) (Meyer et al, 2005)
• Randomised to a treatment that included RT (STLI for
favourable or ABVD x 2 plus STLI for unfavourable) or
no RT (ABVD x 4-6 depending on response)
• FFP at 5 years superior in RT group (93% vs
87%) due to reduced levels of disease control
in unfavourable group receiving ABVD alone
• no difference in OS due to better FFP offset
by deaths from causes other than HL
Results encouraging but caution
necessary
• EORTC/GELA H9-F trial (Eghbali et al, 2005) in
favourable patients in CR after EBVP x 6 (epirubicin,
bleomycin, vinblastine, prednisolone) randomised to
receive either:
• IFRT 36 Gy
• IFRT 20Gy
• No RT
• Trial halted in line with early stopping rules
EORTC/GELA H9-F trial
IFRT
Patients
4 yr OS
239
Progress 4 yr EFS
relapse or
death
20
88%
36 Gy
20 Gy
209
21
85%
100%
No RT
130
37
69%
p<0.001
98%
p=0.241
98%
Q: Can PET identify those patients
who need RT after CT and those
who do not?
Q: Can PET identify those patients
who need RT after CT and those
who do not?
A: It’s an attractive idea but
the case is not yet proven
Positron Emission Tomography (PET)
“Positive” PET scan before
treatment (widespread disease)
“Negative” PET scan after
treatment (no disease identified)
UK NCRI RAPID trial
Initial treatment:
ABVD x 3
Re-assessment:
if NR/PD, patient goes off study
if CR/PR, FDG-PET scan performed
PET +ve
4th cycle ABVD then IFRT
PET -ve
Randomisation
IFRT
No further
treatment
Status at 2nd interim analysis
(presented ASH 12/08)
• 369 patients registered; 190 male, 179 female, median
age 34.5 years
• 331 have had a PET scan after 3 cycles ABVD
• Score 1, 203 (61%)
• Score 2, 58 (18%)
• Score 3, 35 (11%)
• Score 4, 20 (6%)
• Score 5, 15 (4%)
• Score 1,2 -ve (261, 79%); score 3,4,5 +ve (70, 21%)
Status - 2
• 257 of 261 PET -ve pts have been randomised
• Involved field RT (n=125, 49%)
• No further treatment (n=130, 51%)
• Outcome of randomisation entered after
database locked for analysis (n=2)
• 4 pts not randomised
• Patient choice (n=2)
• Clinician choice (n=1)
• Error (n=1)
Status - 3
• Median follow-up of 13 mo from randomisation
• 245 of 255 (96%) pts are alive and
progression-free
• 6 (2%) have progressed
• 4 (1.5%) have died (HL 1, treatment
related 1, other 2)
CXR of 30 year old female before treatment
4 years following treatment
Causes of death in patients aged < 50
0.20
(P Mauch, Bellagio, July 2004)
0.10
0.05
0.0
Probability
0.15
Hodgkin lymphoma (60 deaths)
Second malignancy (59 deaths)
Cardiopulmonary (22 deaths)
Other (13 deaths)
Infection (7 deaths)
0
5
10
15
Years
20
25
30
Risk of second cancer in HL
Cancer
All
Oesophagus
Stomach
SI
Colon
Lung
Female breast
Leukaemia
RR
2.3
2.8
1.9
1.5
1.6
2.9
2.0
9.9
AER
47.2
0.7
1.5
0.1
2.0
9.7
10.5
8.8
Small invasive breast cancer
Breast cancer screening in the UK
• Recommended for women receiving RT to
the chest below age 36 and…
• Now aged ≥25 and ≥8 years since treatment
• Annual MRI/ultrasound ages 25-30
• Annual mammography ages 30 and over until
age 50 (then every 3 years)
Screening for lung cancer
• By the time symptoms have developed the prognosis
is often poor
• Long latency following treatment so opportunities for
screening in this very high risk population
• Exploratory screening study (HOLYSTIC) has been
proposed and this to be discussed at forthcoming
international meeting in Cologne
Cardiovascular disease
• Increased risk of heart failure, fatal infarction (2.5 x
background risk, Swerdlow et al, JNCI 2007) and
stroke following doxorubicin containing CT and RT
• Before treatment; assess heart function in the older
patient and those with a history
• After treatment; screen for high BP, lipids and diabetes
mellitus
Conclusions - 1
• Pathological staging in HL is unnecessary
• Smaller fields of RT are as effective as larger
fields and a dose of 20Gy is sufficient for nonbulky sites
• CT plus RT is superior to RT alone and in
terms of choice of CT regimen, ABVD is the
current standard of care
Conclusions - 2
• Risk adapted therapy making use of pre-treatment
factors is entirely valid
• Response adapted therapy using FDG-PET to
determine the need for consolidation RT after CT is
under investigation
• Allogeneic transplantation and new agents are under
investigation
Conclusions - 3
• In the long term the greatest threat to Hodgkin
survivors is from the late effects of treatment
• Breast cancer screening guidelines have existed in
the UK since 2004 but need to be better implemented
• Screening for lung cancer is under investigation
• Cardiovascular morbidity/mortality remains a major
challenge and requires a multi-disciplinary research
effort
Finally
• Evolution of treatment for Hodgkin lymphoma is a
success story spanning 5 decades
• Significant challenges remain
• So all patients should be offered the opportunity to
take part in relevant clinical trials at presentation and
at relapse
• Unless this happens, treatment gets stuck and
progress will grind to a halt