1. Potential interactions and timing of radiotherapy and hormonal therapy
Nicola Russell
29 June 2005
Potential interactions and timing of radiotherapy and hormonal therapy

2. Potential interactions and timing of radiotherapy and hormonal therapy
Negative interaction: antagonistic effect or sub-additive effect
No interaction, additive effect
Synergistic of supra-additive effect

3. Sub-additive effect? (Albain, ASCO proc 2002)
Radiation could potentially be less effective with tamoxifen, in analogy with the results of chemotherapy and tamoxifen
(Albain, ASCO proc 2002)

4. 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)

5. 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 TGF-beta-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

6. 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

7. Survival of breast cancer
Survival of breast cancer. After lumpectomy (BCS) or lumpectomy with radiotherapy
Isolated local recurrences of breast cancer. After lumpectomy (BCS) or lumpectomy with radiotherapy
EBCTCG Overview Results, Oxford, UK: September 2000(not yet published)

8. Omission versus radiotherapy after breast-conserving surgery.
Survival
Local Control
Vincent Vinh-Hung, JNCI 2004

9. Is the relative effect of radiotherapy decreased if patients receive adjuvant hormonal therapy?

10. 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 , 1999)
Post-mastectomy radiotherapy:
Danish DBCG 82c Overgaard 1999

11. 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

12. Cumulative incidence of IBTR after treatment with TAM, XRT and placebo, or XRT and TAM.
B. Fisher: JCO 2002

13. NSABP-21 Fisher 2002 5 year rates of IBTR
XRT + placebo
vs.
TAM
XRT + TAM
Vs.
XRT+ TAM
TAM alone
HR ratio % CI
HR ratio % CI
– 0.84
–0.80
– 0.39
p= 0.08
P=0.01
P<0.01

14. 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

15. Cumulative Incidence of Local Relapse
Radiotherapy reduces the local recurrence rate in patients treated with lumpectomy and tamoxifen
Cumulative Incidence of Local Relapse
Similar impact of RT seen in all age groups above 50
Average follow up is limited
Large part of patients still receive tamoxifen
Fyles_NEJM Sept. 2004

16. 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)

17. 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

18. 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

19. Clinical trials of tamoxifen with a radiotherapy comparison
Breast conserving:
German trial: Winzer 2004
347 women years pT1N0M0 tumors, ER+
Randomisation 2x2 design
BCS alone (n= 79) BCS+ XRT (n=94)
BCS + TAM (n=80) 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

20.                                                
Event-free survival rate (EFS) by treatment group. BCS, breast-conserving surgery; RT, radiotherapy; TAM, tamoxifen.
Winzer et al., 2004

21. Effect of therapy and prognostic factors on event-free survival
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

22. Effect of therapy and prognostic factors on event-free survival
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

23. Clinical trials of tamoxifen with a radiotherapy comparison
Breast conserving:
DICSTrials:
NSABP-B BSO with or without RT
NSABP BSO, RT with or without tamoxifen
UK/ANZ DCIS trial 2004

24. 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

25. 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

26. 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

27. 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

28. DBCG 82 c EFFECT OF RADIOTHERAPY ON OVERALL SURVIVAL2 4 6 8 10 12 14 16 18
Years after mastectomy 20 40 60 80
100
Overall survival (%)
RT+TAM
(686 pts)
TAM alone
(689 pts)
26%
18%
P=0.018
POSTMENOPAUSAL PATIENTS
Marie Overgaard

29. Site of first recurrence by treatment DBCG 82c trial
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

30. 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 to 0.12
HR for local control varies from 2.6 to 8.3
(with wide CI’s)

31. 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)

32. Late radiation effects: lung and breast/ subcutaneous fibrosis
In tangent fields
In periclaviculair field
Breast fibrosis and retraction

33. Effect of irradiation on fibroblasts in culture
Mitotic fibroblasts, low collagen production
Post-mitotic fibrocytes, high collagen production
Effect of radiation and / or TGF-beta:
Differentiation: 2 –3 divisions possible
Russell, 2000

34. 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
No difference in clinical symptoms of radiation pneumonitis
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%)

35. 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)

36. 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.

37. 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

38. 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.