Radiation Oncology/Breast/Early breast/BCT/RT in BCT

Randomized trials of radiotherapy in breast-conserving surgery

BCS +/- RT

• Please note that eligibility criteria and adjuvant tamoxifen/chemo varied significantly

Trial	Follow-up	Surgery	Dose	LR RT(-)	LR RT(+)
NSABP (1976)	20 years	lumpectomy	50	39%	14%
Uppsala-Orebro (1981)	10 years	sector resection	54	24%	8%
St. George's (1981)	5 years	WLE		35%	13%
Ontario (1984)	8 years	lumpectomy	40/16 + 12.5/5	35%	11%
Scotland (1985)	6 years	WLE	50 + 10-30	24%	6%
Tokyo (1985)	8 years	sector resection		9%	7%
St. Petersburg (1985)	5 years	quadrantectomy		17%	4%
Milan 3 (1987)	10 years	quadrantectomy	50 + 10	23%	6%
NSABP B-21 (1989)	8 years	lumpectomy	50 +/- boost	16%	3%
Finland (1990)	12 years	lumpectomy	50	27%	12%
SweBCG (1991)	5 years	sector resection	48-54	14%	4%
German GBSG (1991)	10 years	BSC	50 + 10-12	34%	10%
Canada (1992)	5 years	BCS	40/16 + 12.5/5	8%	1%
CALGB (1994)	5 years	lumpectomy	45 + 14	4%	1%

• EBCTCG analysis of individual patient data from 10 trials (PMID 16360786) suggests 5-year outcome benefits:
  • Overall LR: 26% vs. 7% (SS)
    • If LN- LR: 23% vs. 7% (SS)
    • If LN+ LR: 41% vs. 11% (SS)
  • BCA mortality: 36% vs. 30% (SS)
  • This may translate into preventing 1 BCA death for every 4 local recurrences prevented, at 15 years
  • Risks of RT for breast cancer:
    • Excess risk of contralateral breast cancer (RR 1.18) associated with older RT regimens
    • Excess risk of non-breast cancer deaths (RR 1.12) associated with older RT regimens. Excess mortality from heart disease (RR 1.27) and lung cancer (RR 1.78).

• CALGB 9343 (RTOG 97-02, ECOG) (1994-99) -- 70 years or older, T1N0, ER+ -- TAM. vs RT + TAM
  • 636 pts. Randomized to tamoxifen +/- RT. 56% >75 y/o. ALND 37%. RT 45/25 + boost 14/7
  • 5-years, 2004 PMID 15342805 — "Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer." Hughes KS et al. N Engl J Med. 2004 Sep 2;351(10):971-7. Median F/U 5 years
    • 5-yr outcome: LR tamoxifen 4% vs TAM+RT 1% (SS). No difference in rate of mastectomy, distant mets, or 5-yr OS (87% vs 86%)
    • Side effects:
      • Physicians: cosmesis, breast pain, edema, hyperpigmentation worse at 1 year; no differences at 4 years
      • Patients: breast pain, fibrosis worse at 1 year; breast pain, arm/shoulder stiffness worse at 4 years
    • Conclusion: lumpectomy + tamoxifen alone is acceptable for women 70 years or older with T1N0 ER+ tumors
  • 10-years, 2010 ASCO 2010 Abstract -- "Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer." (Hughes KS, Abstract #507) -- Median f/u 10.5 yrs
    • First recurrence local in 9% (Tam) vs 2% (Tam+RT) -- IBTR 8% vs 2%, Axilla 1% vs 0%. RT prolonged the time to first recurrence. 10-year freedom from mastectomy 96% vs 98%, freedom from DM 95% vs 93%. Breast cancer specific survival 98% vs 96%, OS 63% vs 61%. Only 7% of deaths were due to breast cancer.
    • Conclusion: RT results in absolute reduction of 6% in IBTR. No impact on overall survival, cancer specific survival, breast conservation, or distant DFS.
  • 2013 PMID 23690420 -- "Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343." (Hughes KS, J Clin Oncol. 2013 Jul 1;31(19):2382-7.) -- Median f/u 12.6 yrs
    • 10-yr freedom from locoregional recurrence: 90% (Tam) vs 98% (TamRT). No significant differences in time to mastectomy, time to DM, BCSS, or OS. 10-yr OS was 66% and 67%.
    • Conclusion: "With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer."

• Canada multi-institutional (1992-2000) - 50 years or older, pT1-2N0
  • 769 pts. Randomized to tamoxifen +/- RT. Median age 68. BCS, pN staging 83%. Almost all had positive receptors (81%) or unknown receptor status (13%). RT 40/16 + boost 12.5/5
  • 2004 PMID 15342804 — "Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer." Fyles AW et al. N Engl J Med. 2004 Sep 2;351(10):963-70. Median F/U 5.6 years
    • 5-yr local: LR tamoxifen 7.7% vs TAM+RT 0.6% (SS); DFS 84% vs 91%. Planned subset outcome (T1 ER+): LR 5.9% vs 0.4% (SS).
    • 5-year regional: axillary relapse 2.5% vs. 0.5% (SS). No difference in DM or OS.
  • Conclusion: RT in addition to tamoxifen significantly reduces local and axillary recurrence

• German GBSG (1991-1998) -- 2x2 factorial BCS +/- RT +/- TAM
  • Randomized. Stopped prematurely due to slow accrual. 2x2 factorial. 347 out of target 700 patients with pT1N0, ER+, Grade I-II, EIC-, LVI-, SM-, ALND with minimum 10 LNs. Age 45-75 (>=60 in 54%). Randomized to +/- RT and to +/- TAM. RT 50/25 + boost 10-12 Gy. TAM 30 mg x2 years
  • 6-years; 2004 PMID 15093574 -- "Radiation therapy after breast-conserving surgery; first results of a randomised clinical trial in patients with low risk of recurrence." (Winzer KJ, Eur J Cancer. 2004 May;40(7):998-1005.) Median F/U 5.9 years
    • Outcome: 6-year ITBR BCS 29% vs. BCS+RT 4% vs. BCS+TAM 2% vs. BCS+RT+TAM 3% (SS); regional failure 0% vs 1% vs 0% vs 0%; EFS 64% vs. 86% vs. 92% vs. 84% (SS). Strong (p=0.005) interaction between RT and TAM, since majority of events in BCS only group
    • Conclusion: In patients with favorable prognosis, lack of RT and TAM increases local recurrences substantially
  • 10-years; 2009 PMID 19879131 -- "Radiation therapy and tamoxifen after breast-conserving surgery: Updated results of a 2x2 randomised clinical trial in patients with low risk of recurrence." (Winzer KJ, Eur J Cancer. 2009 Oct 28. [Epub ahead of print]). Median F/U 9.9 years
    • Outcome: 10-year ITBR BCS 34% vs. BCS+RT 10% vs. BCS+TAM 7% vs. BCS+RT+TAM 5% (SS); regional failure 0% vs 1% vs 0% vs 0%; 8-year EFS 48% vs. 78% (RR 0.36) vs. 78% (RR 0.33) vs. 78% (RR 0.32) (SS). No difference for DMFS
    • Conclusion: In patients with favorable prognosis, avoidance of RT and TAM increases local recurrence substantially. Not powered to distinguish between RT, TAM, and RT+TAM

• SweBCG (1991-1997)
  • 1187 women. Stage I-II, N0. Median tumor 12mm, 65% detected by mammography. Sector resection + ALND. +/- RT 48-54 Gy. Adjuvant chemo not regulated, given in 9%
  • 5-years, 2003 PMID 12888363 -- "Breast conservation surgery, with and without radiotherapy, in women with lymph node-negative breast cancer: a randomised clinical trial in a population with access to public mammography screening." (Malmstrom P, Eur J Cancer. 2003 Aug;39(12):1690-7.)
    • Local control: no RT 14% vs. RT 4% (SS). DFS 77% vs. 88%

• Finland (1990-1995)
  • Randomized. 152 women. Low risk BCA: <2cm, G1-2, no EIC, DNA diploid, S-phase <=7, SM >=1cm. Lumpectomy with ALND. +/- RT 50/25. No systemic therapy
  • 7-years, 2001 PMID 11161371 -- "Lumpectomy with or without postoperative radiotherapy for breast cancer with favourable prognostic features: results of a randomized study." (Holli K, Br J Cancer. 2001 Jan;84(2):164-9.). Median F/U 6.7 years
    • Local recurrence: no RT 18% vs. RT 7% (SS); no difference in DM or OS, or breast preservation
    • Conclusion: RT beneficial even in women with small tumors with favorable biology
  • 12-years; 2008 PMID 19114687 -- "Radiotherapy After Segmental Resection of Breast Cancer With Favorable Prognostic Features: 12-Year Follow-Up Results of a Randomized Trial." (Holli K, J Clin Oncol. 2008 Dec 29. [Epub ahead of print]) Median F/U 12.1 years
    • Local recurrence: no RT 27% vs. RT 12% (SS). Time to recurrence longer in RT arm (SS). No difference in OS or BCSS
    • Conclusion: RT after breast resection beneficial even in small-size, favorable feature tumors

• NSABP B-21 (1989-1998)
  • 1009 women. Tumors <=1cm. Lumpectomy + ALND. Randomized to RT, TAM, or RT + TAM. RT 50/25, boost at discretion
  • 8-years, 2002 PMID 12377957 -- "Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less." (Fisher B, J Clin Oncol. 2002 Oct 15;20(20):4141-9.)
    • Local recurrence: TAM 16% vs. RT 9% vs. RT+TAM 3%; no difference in DM or survival
    • Contralateral BCA: no TAM 5.4% vs. TAM 2.2%
  • Conclusion: Even in tumors <=1cm, should consider RT and TAM

• Milan 3 (1987-1989)
  • 579 pts. Size < 2.5 cm. 32% N+. Quadrantectomy, ALND +/- RT 50/25 + boost 10/5. Systemic in N+ (premenopausal, postmenopausal and ER- chemo, postmenopausal ER+ tamoxifen)
  • 3-years, 1993 PMID 8387637 — "Radiotherapy after breast-preserving surgery in women with localized cancer of the breast." Veronesi U et al. N Engl J Med. 1993 Jun 3;328(22):1587-91.
    • Median f/u 39 months. LR 8.8% (no RT) vs 0.3% (RT). Low rate of recurrence in pts older than 55 yrs. No difference in survival.
  • 10-years PMID 11521809 -- "Radiotherapy after breast-conserving surgery in small breast carcinoma: long-term results of a randomized trial." (Veronesi U, Ann Oncol. 2001 Jul;12(7):997-1003.)
    • Local recurrence: no RT 23% vs. RT 6% (SS); women <45 43% vs. 9%; women >65 4% vs. 4%
    • Node positive: death rate no RT 34/100 vs. RT 19/100 (SS); no difference in N0
  • Conclusion: RT indicated for <=55 years old, N+, or EIC, not indicated if >65

• St. Petersburg (1985-1996)
  • 360 patients. T1-2N0, <2.5cm. Quadrantectomy. +/- RT, systemic therapy
  • 5-years, 1998 PMID 9807204 -- "[Preliminary results of the randomized trial "The role of adjuvant radiotherapy in organ-preserving treatment of breast cancer"] - [Article in Russian]" (Semiglazov VF, Vopr Onkol. 1998;44(4):414-21.)
    • Local recurrence: no RT 17% vs. RT 4% (SS); no difference on OS

• Tokyo (1985-1993)
  • 113 patients. Stage I-II. Sector resection +/- RT, systemic therapy
  • 8-years, 1996 PMID 11091552 -- "Local Control and Cosmetic Outcome after Sector Resection with or without Radiation Therapy for Early Breast Cancer." (Inoue M, Breast Cancer. 1996 Mar 29;3(1):39-46.). Median F/U 4.6 years
    • Local recurrence: no RT 9.4% vs. RT 7.1
  • Conclusion: Sector resection without RT reasonable for some patients

• Scottish (1985-1991)
  • 585 patients. BCA <4cm, <70 y/o. Local excision + 1cm margin, ALND/SLN. Tamoxifen or CMF. Randomized to RT 50/20 or 50/25 + boost (20-30 IR implant or 10-15 e-boost) vs. observation. If no ALND, RT 45/20 to axilla given
  • 6-years, 1996 PMID 8806289 -- "Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial. Scottish Cancer Trials Breast Group." (Forrest AP, Lancet. 1996 Sep 14;348(9029):708-13.) Median F/U 5.7 years
    • Local recurrence: no RT 24% vs. RT 6%; no difference in survival
  • Conclusion: RT advisable, even if chemotherapy given

• Ontario (1984-89)
  • Randomized. 837 patients, <4cm, LN-. Lumpectomy and axillary dissection +/- RT. RT 40/16 + boost 12.5/5 No systemic therapy
  • Original, 1992 PMID 1314910 (1992)
  • 8-years, 1996 PMID 8931610 -- "Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update. Ontario Clinical Oncology Group." (Clark RM, J Natl Cancer Inst. 1996 Nov 20;88(22):1659-64.). Median F/U 7.6 years
    • Ipsilateral recurrence: No RT 35% vs. RT 11% (SS). OS: 24% vs. 21% (NS). Bigger tumors on average
    • Predictors for relapse: age <50, size >2cm, poor grade
  • Conclusion: Reduced recurrence, but no survival difference. No subgroups identified

• St. George's (1981-1990)
  • 418 patients treated with wide local excision, adjuvant chemo (tamoxifen if ER+ or CMF if ER-), +/- RT
  • 5-years, 1996 PMID 8846860 -- "The importance of the resection margin in conservative surgery for breast cancer." (Renton SC, Eur J Surg Oncol. 1996 Feb;22(1):17-22.)
    • Local recurrence: no RT 35% vs. RT 13%. LR strictly related to margin status; if SM+ LR 17% with RT
    • Conclusion: RT cannot compensate for inadequate surgery

• Uppsala-Orebro (1981-88)
  • 381 patients. Stage I (<2cm, N0). "Sector resection" and ALND, +/- RT 54/27 without boost. No systemic therapy
  • 5-years, 1994 PMID 8158702 -- "Sector resection with or without postoperative radiotherapy for stage I breast cancer: five-year results of a randomized trial. Uppsala-Orebro Breast Cancer Study Group." (Liljegren G, J Natl Cancer Inst. 1994 May 4;86(9):717-22.)
    • Local recurrence 18% vs 2%. No survival difference.
  • 10-years, 1999 PMID 10561294 -- "10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial." (Liljegren G, J Clin Oncol. 1999 Aug;17(8):2326-33.)
    • 10-year LR: no RT 24% vs. RT 8.5% (SS); no difference in OS at 77%
    • Low risk: >55 and no comedo/LCIS - no RT 11% vs. RT 6% (NS)

• NSABP B-06 (1976-84)
  • See here for more details. Total mastectomy vs lumpectomy vs lumpectomy + RT. Chemo in N+ melphalan + 5-FU
  • 20-year LR: No RT 39.2% vs RT 14.3%. No difference in survival
  • Node negative subgroup showed survival advantage (unpublished)