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

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)

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 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

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

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: 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+ TAM TAM alone HR ratio 95% CI HR ratio 95% CI 0.51 0.31 – 0.84 0.37 0.17 –0.80 0.19 0.09 – 0.39 p= 0.08 P=0.01 P<0.01

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

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

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+ 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

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

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

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

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 2 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

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

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 tangent fields In periclaviculair field Breast fibrosis and retraction

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

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%)

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.