Transcript No Slide Title

Potential interactions and timing of
radiotherapy and hormonal therapy
Nicola Russell
29 June 2005
Potential interactions and timing of
radiotherapy and hormonal therapy
Potential interactions:
• Negative interaction: antagonistic effect or subadditive effect
• No interaction, additive effect
• Synergistic of supra-additive effect
Sub-additive effect?
Radiation could potentially be less effective with
tamoxifen, in analogy with the results of
chemotherapy and tamoxifen
(Albain, ASCO proc 2002)
Pre-clinical (in vitro) experiments with
tamoxifen and radiation:
Tamoxifen causes cell cycle arrest of breast cancer cell lines in
vitro in G0/ G1, a relatively radio-resistant phase of the cell cycle
(Osbourne 1983)
MCF-7 cells more radio-resistant in culture with tamoxifen
(Wazer et al 1989, Paulsen et al 1996)
No effect on radiation sensitivity (Sarkia 1994)
Pre-clinical (in vitro) experiments with
tamoxifen and radiation:
Activation of Smad 3 and 4 phosphorylation by tamoxifen -cross talk
with TGF-beta signalling pathways in MCF-7 cells– increase in
apotosis (Wu 2003, Danforth 2004, Buck 2004)
MCF-7 cells have TGF- beta RII on cell surface and produce TGFbeta-1 on stimulation with tamoxifen, may or may not be
related to tamoxifen mediated apoptosis / tamoxifen resistance
(Perry 1995, Chen 1996, Koli 1997, Arteaga 1999)
Increase in radiation sensitivity due to apotosis (Ellis 1997)
Conclusion: inconsistent findings in vitro
Is there evidence of an interaction from clinical
trials of radiotherapy and tamoxifen?
Effect of radiotherapy on local control and survival:
Based on overview of trials, including those with
adjuvant systemic treatment:
3 to 4 -fold decrease in local recurrence rate with
radiation aplied after mastectomy or breast
conserving therapy
Isolated local recurrences of breast
cancer. After lumpectomy (BCS) or
lumpectomy with radiotherapy
Survival of breast cancer.
After lumpectomy (BCS) or lumpectomy
with radiotherapy
EBCTCG Overview Results, Oxford, UK: 21-23 September 2000(not yet published)
Omission versus radiotherapy after
breast-conserving surgery.
Survival
Local Control
Vincent Vinh-Hung, JNCI 2004
Is the relative effect of radiotherapy
decreased if patients receive
adjuvant hormonal therapy?
Clinical trials of tamoxifen with a radiotherapy
comparison
•Breast conserving:
–NSABP-B21 Fisher 2002
–Canadian trial Fyles 2004
–CALB / RTOG / ECOG trial Hughes 2004
–German trial Winzer 2004
•DICS Trials:
•UK/ANZ DCIS trial 2004
•(NSABP B-17 and B-24 1993, 1999)
•Post-mastectomy radiotherapy:
–Danish DBCG 82c Overgaard 1999
Clinical trials of tamoxifen with a radiotherapy
comparison
•Breast conserving:
NSABP-B21 Fisher 2002
1009 women following lumpectomy and AND
Tumor < 1 cm, N0
Randomisation:
XRT + placebo (n=336)
XRT + TAM (n=337)
Only TAM (n=336)
Tamoxifen = 10 mg bid for 5 years
XRT = 50 Gy
Timing:
XRT after 14 days post operative,
Tamoxifen within 35 days
Median FU = 87 months
Cumulative incidence of IBTR after treatment with
TAM, XRT and placebo, or XRT and TAM.
B. Fisher: JCO 2002
NSABP-21 Fisher 2002
5 year rates of IBTR
XRT + placebo
vs.
TAM
XRT + TAM
Vs.
XRT + placebo
XRT+ TAM
Vs.
TAM alone
HR ratio
HR ratio
HR ratio
0.51
p= 0.08
95% CI
0.31 – 0.84
0.37
P=0.01
95% CI
0.17 –0.80
0.19
P<0.01
95% CI
0.09 – 0.39
Clinical trials of tamoxifen with a radiotherapy
comparison
•Breast conserving:
Canadian trial, Fyles 2004
769 women, age > 50 years, T1 or T2 N0 tumors
Randomisation
TAM + XRT (n=386)
TAM alone (n=383)
Median FU= 5.6 years
XRT = 40 Gy in 16 fr + boost 12.5 Gy in 5 fr
TAM = 20 mg for 5 years (early discontinuation in
159 pts)
Timing: not specified
Radiotherapy reduces the local recurrence rate in patients
treated with lumpectomy and tamoxifen
Similar impact of RT seen in all age groups above 50
Average follow up is limited
Fyles_NEJM Sept. 2004
Large part of patients still receive tamoxifen
Canadian trial: Fyles, 2004
• Ipsilateral breast relapse 5 years
– 7.7% in Tam alone group
– 0.6% in Tam + RT group
• HR: 8.3 (95% CI= 3.3 –21.2, P<0.001)
Clinical trials of tamoxifen with a radiotherapy
comparison
•Breast conserving:
CALB / RTOG / ECOG trial Hughes 2004
636 women >70 years T1N0M0 tumors, ER+
Randomisation –
TAM alone (n= 319)
TAM + XRT (n=317)
TAM = 20 mg for 5 years
XRT = 45 Gy in 25 fr + boost of 14 Gy in 7 fr
Median FU = 5 years
Timing: TAM during or after XRT, depending on
treating physician
Radiotherapy reduces the local recurrence rate but has until
so far no impact on survival in patients treated with
lumpectomy and tamoxifen
Very strict criteria: patients above 70, tumors less than 2 cm with
clear margins and ER pos tumors
Hughes_NEJM Sept. 2004
Clinical trials of tamoxifen with a radiotherapy
comparison
•Breast conserving:
German trial: Winzer 2004
347 women 45-75 years pT1N0M0 tumors, ER+
Randomisation 2x2 design
BCS alone (n= 79)
BCS + TAM (n=80)
BCS+ XRT (n=94)
BCS+RT+TAM (n=94)
TAM = 30 mg for 2 years
XRT = 50 Gy in 25 fr + boost of 12 Gy in 6 fr
Median FU = 6 years
Timing: not specified
Event-free survival rate (EFS) by treatment group. BCS, breastconserving surgery; RT, radiotherapy; TAM, tamoxifen.
Winzer et al., 2004
Effect of therapy and prognostic factors on event-free survival*: multivariate
analysis on complete case population with 311 patients and 76 events
BCS, breast-conserving surgery; RT, radiotherapy; TAM, tamoxifen: RR, relative
risk; CI, confidence interval. *All analyses are stratified according to mode of
randomisation (all four treatments (n=223); BCS versus BCS+RT (n=40);
BCS+TAM versus BCS+RT+TAM (n=48)).
Winzer et al 2004
Effect of therapy and prognostic factors on event-free survival*: multivariate
analysis on complete case population with 311 patients and 76 events
BCS, breast-conserving surgery; RT, radiotherapy; TAM, tamoxifen: RR, relative
risk; CI, confidence interval. *All analyses are stratified according to mode of
randomisation (all four treatments (n=223); BCS versus BCS+RT (n=40);
BCS+TAM versus BCS+RT+TAM (n=48)).
Winzer et al 2004
Clinical trials of tamoxifen with a radiotherapy
comparison
•Breast conserving:
•DICSTrials:
•NSABP-B-17 1993 BSO with or without RT
•NSABP-24 1999 BSO, RT with or without tamoxifen
•UK/ANZ DCIS trial 2004
Clinical trials of tamoxifen with a radiotherapy
comparison
UK/ANZ DCIS trial 2004
1694 patients 2x2 factorial design
Following complete excision of DCIS
Randomisation:
No further treatment: n= 544
RT alone: n = 267
TAM alone: n = 567
RT +TAM: n = 316
Median FU = 52 months
RT 50 Gy in 25 fr
TAM = 20 mg 5 years
Timing: not specified
UKANZ DCIS trial:
Kaplan-Meier curves for cumulative
incidence of all breast events,
invasive recurrence, and recurrence
of ductal carcinoma in situ
in patients in the
tamoxifen comparison
In patients in the
radiotherapy comparison
UKANZ DCIS trial
• HR RT vs. no RT = 0.38, p < 0.0001
• No interaction between tamoxifen and
radiation
• No effect of tamoxifen on breast events
• Possibly due to 91% of patients > 50 years
Clinical trials of tamoxifen with a radiotherapy
comparison
•Post mastectomy:
Danish PMRT trial Overgaard
1460 patients with St II-III post mastectomy
Randomisation to:
Tam alone (n=689) or Tam + locoregional RT (n=686)
RT 50 Gy in 25 fr / 48 Gy in 22 fr
All patients received tamoxifen 30 mg for 1 year
Median FU if alive 110 months
Timing: Tamoxifen within 2-4 weeks of operation and
concomitantly with RT if given
DBCG 82 c
EFFECT OF RADIOTHERAPY ON OVERALL SURVIVAL
POSTMENOPAUSAL PATIENTS
100
Overall survival (%)
80
RT+TAM(686 pts)
60
40
P=0.018
20
26%
18%
TAM alone (689 pts)
0
0
2
4
6
8
10 12 14 16 18
Years after mastectomy
Marie Overgaard
Site of first recurrence by treatment
DBCG 82c trial
Site of first recurrence
Radiotherapy plus
tamoxifen (n=686)
Tamoxifen only
(n=689)
All patients
(n=1375)
Distant metastases only
269 (39%)
169 (25%)
438 (32%)
Locoregional only
30 (4%)
203 (29%)
233 (17%)
Distant metastases and
locoregional
22 (3%)
39 (6%)
61 (4%)
All recurrences
321 (47%)
411 (60%)
732 (53%)
HR for LRR Tam vs. RT + TAM = 7.25
Overgaard 1999
Is there an interaction between tamoxifen
and radiation?
For local / loco-regional control no clinical evidence
that the relative effect of radiation is decreased
In the studies discussed with tamoxifen +/- radiotherapy the
HR voor recurrence varies from 0.38 to 0.12
HR for local control varies from 2.6 to 8.3
(with wide CI’s)
Supra-additive effect?
Possible increase in normal tissue damage:
Lung fibrosis / soft tissue fibrosis
Radiation-induced fibrosis mediated through
the cytokine TGF-β (Rodemann)
Tamoxifen stimulates an increase in TGF-β 1
and 2 synthesis in fibroblasts independent of
ER status (Benson)
Late radiation effects: lung and breast/
subcutaneous fibrosis
In periclaviculair
field
Breast fibrosis
and retraction
In tangent fields
Effect of irradiation on fibroblasts in culture
Mitotic fibroblasts,
low collagen
production
Effect of radiation
and / or TGF-beta:
Differentiation: 2 –3
divisions possible
Post-mitotic
fibrocytes, high
collagen
production
Russell, 2000
Clinical studies of lung toxicity
Bentzen et al 1996:
Patients from DBCG-77 study, 84 patients
Cochran- Mantel – Haenszel test for association between ling fibrosis and adjuvant tamoxifen
stratified for number of fractions; p= 0.01
RT + TAM
No with fibrosis / total
(% of total)
RT alone,
No with fibrosis / total
(% of total
12 fractions
15/24 (63%)
10/30 (33%)
22 fractions
5/14 (36%)
2/16 (13%)
No difference in clinical symptoms of radiation pneumonitis
Clinical studies of lung toxicity
Other studies of lung fibrosis assessed by CT scan or
radiographs:
All retrospective
Increase in non-sympotmatic fibrosis with tamoxifen
(Huang 2000, Kok et al 2002, Wennenburg 2002)
Clinical studies of lung damage
Conclusion:
Radiological increase in lung fibrosis with the
combination RT and tamoxifen, but no significant
increase in symptomatic radiation pneumonitis.
No conclusion possible regarding the timing, sequential
or concomitant
No literature about the interaction RT and aromatase
inhibitors regarding side effects.
Timing of radiotherapy and tamoxifen
3 retrospective studies published in JCO 2005
Ahn et al., n = 495 patients
Harris et al., n = 278 patients
Pierce et al. n = 309 patients
Retrospective cohort designs
Variation within and between studies in the concomitant and sequential groups
regarding age, ER status, chemotherapy etc
General conclusion: no evidence for detrimental effect of concomitant
treatment compared to sequential regarding local control
Harris: data on breast and arm oedema, cosmesis and pneumonitis: no
significant differences
Conclusions
• Most preclinical data and all clinical data pertains to the
combination of tamoxifen with radiation.
• No evidence for a decreased relative effect of radiation on local
control if combined with tamoxifen treatment.
• Possible increase in radiation-induced fibrosis, no data on
sequencing regarding side effects. Effects on TGF-beta
particular aspect of tamoxifen.
• No evidence base for delaying start of endocrine treatment until
after radiotherapy.