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

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 sub-additive 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 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. After lumpectomy (BCS) or

lumpectomy with radiotherapy

EBCTCG Overview Results, Oxford, UK: 21-23 September 2000(not yet published)

Isolated local recurrences of breast cancer. After lumpectomy (BCS) or

lumpectomy with radiotherapy

Omission versus radiotherapy after breast-conserving surgery.

Vincent Vinh-Hung, JNCI 2004

Survival Local Control

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


•Breast conserving:NSABP-B21 Fisher 20021009 women following lumpectomy and ANDTumor < 1 cm, N0Randomisation:

XRT + placebo (n=336)XRT + TAM (n=337)Only TAM (n=336)

Tamoxifen = 10 mg bid for 5 yearsXRT = 50 GyTiming: XRT after 14 days post operative, Tamoxifen within 35 daysMedian FU = 87 months

B. Fisher: JCO 2002

Cumulative incidence of IBTR after treatment with TAM, XRT and placebo, or

XRT and TAM.

NSABP-21 Fisher 2002 5 year rates of IBTR

XRT + placebovs.TAM

XRT + TAMVs.XRT + placebo

XRT+ TAM Vs.TAM alone

HR ratio 95% CI

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


•Breast conserving:Canadian trial, Fyles 2004769 women, age > 50 years, T1 or T2 N0 tumorsRandomisation 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 frTAM = 20 mg for 5 years (early discontinuation in 159 pts)

Timing: not specified

Similar impact of RT seen in all age groups above 50 Average follow up is limited

Large part of patients still receive tamoxifenFyles_NEJM Sept. 2004

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Radiotherapy reduces the local recurrence rate in patients treated with lumpectomy and 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)


•Breast conserving:CALB / RTOG / ECOG trial Hughes 2004636 women >70 years T1N0M0 tumors, ER+Randomisation – TAM alone (n= 319) TAM + XRT (n=317)

TAM = 20 mg for 5 yearsXRT = 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

Hughes_NEJM Sept. 2004

Very strict criteria: patients above 70, tumors less than 2 cm with clear margins and ER pos tumors


•Breast conserving:German trial: Winzer 2004347 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 yearsXRT = 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

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)).


•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


UK/ANZ DCIS trial 20041694 patients 2x2 factorial designFollowing 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 monthsRT 50 Gy in 25 frTAM = 20 mg 5 yearsTiming: 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


•Post mastectomy:Danish PMRT trial Overgaard 1460 patients with St II-III post mastectomyRandomisation to: Tam alone (n=689) or Tam + locoregional RT (n=686)

RT 50 Gy in 25 fr / 48 Gy in 22 frAll 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

0 2 4 6 8 10 12 14 16 18

Years after mastectomy

0

20

40

60

80

100

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%)

RT+TAM (686 pts)

TAM alone (689 pts)

26%

18%

P=0.018

POSTMENOPAUSAL PATIENTS

DBCG 82 c EFFECT OF RADIOTHERAPY ON OVERALL SURVIVAL

Marie Overgaard

Site of first recurrenceRadiotherapy 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%)

Site of first recurrence by treatment DBCG 82c trial

Overgaard 1999

HR for LRR Tam vs. RT + TAM = 7.25

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 0.12HR 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

In tangent fields

Breast fibrosis and retraction

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 toxicityBentzen et al 1996:Patients from DBCG-77 study, 84 patientsCochran- 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 + TAMNo 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.

Documents

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