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

• Radiation therapy (RT) after breast-conserving surgery (BCS):
  • Decreases the risk of ipsilateral breast recurrence (IBTR)
• Several studies have suggested that there exists a favorable subgroup of patients:
  • In whom irradiation may not provide meaningful overall benefit, including but not limited to:
    • Older women with smaller estrogen receptor (ER)–positive cancers treated with anti-hormonal therapy
• To test this hypothesis, the Cancer and Leukemia Group B (CALGB) initiated CALGB 9343
  • A randomized trial comparing the efficacy of:
    • Tamoxifen alone (Tam) with tamoxifen plus RT (TamRT) in older women with ER-positive, clinical stage I breast cancer
• When reported in 2004 (median follow-up, 5 years):
  • The 5-year incidence of IBTR or regional nodal recurrence was:
    • 4% for patients receiving Tam
    • 1% for those receiving TamRT
  • There was no difference in:
    • Survival
    • Time to distant metastasis
    • Ultimate breast-preservation rate
  • Examining Medicare data through 2007, Soulis et al found:
    • That CALGB 9343 report:
      • Had little impact, with the use of irradiation:
        • Only slightly diminishing in this population:
          • Because it was possible that with longer-term follow-up the results of the CALGB 9343 trial might not persist:
            • The CALGB 9343 trial performed a longterm analysis to address these concerns
• The methods of the CALGB 9343 trial study have been previously described:
  • CALGB 9343 was designed in cooperation with the Eastern Cooperative Oncology Group (ECOG) and Radiation Therapy Oncology Group (RTOG)
  • Local institutional review boards reviewed and approved the study in compliance with the Declaration of Helsinki
  • Written informed consent was obtained from all patients.
  • An independent data and safety monitoring committee provided oversight
  • The CALGB Statistical Center managed data collection, and data quality was ensured by the study chairperson and statistical center review
  • CALGB statisticians performed the statistical analyses
  • The CALGB quality-assurance program has been previously described
  • Patient Selection:
    • Women age 70 years or older with clinical stage I, ER-positive breast cancer and no history of cancer other than in situ cervical or non melanoma skin cancer within 5 years were eligible
    • Initial eligibility criteria included breast cancers up to 4 cm regardless of estrogen receptor status, but this was reduced in August 1996 to equal or less 2 cm (T1) with ER-positive or indeterminate receptor status
    • Patients were required to have clinically negative axillae
  • Treatment:
    • At entry, patients were randomly assigned (1:1 ratio) to receive Tam or TamRT
    • Random assignment was stratified by age (less 75 years vs equal or greater than 75 years) and axillary dissection (yes vs no)
    • Patients were observed every 4 months for 5 years and yearly thereafter
    • This study did not rigorously capture tamoxifen discontinuation
    • Local therapy:
      • All women underwent lumpectomy with a clear margin (absence of tumor at the inked margin)
      • Axillary node dissection was allowed but not encouraged
      • RT included tangential fields to the entire breast followed by an electron boost to the lumpectomy site
    • Tamoxifen:
      • All women received 20 mg of tamoxifen per day for 5 years:
        • Initiated either during or after irradiation
      • Adjuvant hormonal treatment beyond 5 years was discretionary
  • Study End Points:
    • The primary study end points were time to locoregional recurrence, frequency of mastectomy for recurrence, breast cancer–specific survival, time to distant metastasis, and overall survival (OS)
    • IBTR was defined as any cancer in the ipsilateral breast
    • Regional recurrence was defined as any recurrence in the ipsilateral supraclavicular, infraclavicular, or axillary nodes
    • Secondary end points were:
      • Cosmetic results, as judged by physician and patient, and adverse effects such as breast pain and skin changes
  • Actuarial Survival:
    • The expected proportion of women in this study who would be alive at each year after random assignment was found assuming the women were randomly sampled from women of the same age in the general population
    • They used the 2001 period life table of the US Social Security Administration (approximate middle of follow-up for this study)
    • They compared actual survival proportion and its confidence limits over time after random assignment of women in the study with their actuarial survival distribution
• Results:
  • The study was initiated by the CALGB (July 1994) and by the RTOG and ECOG (December 1996)
  • Enrollment ended in February 1999 with 647 women:
    • CALGB, 307; ECOG, 112; and RTOG, 228 women
    • Eleven patients (2%) never began protocol treatment
    • Statistical analyses used a modified intent-to-treat approach that included all 636 patients who began protocol treatment:
      • 317 with TamRT and 319 with Tam
    • Before the eligibility change, 10 patients with ER-negative tumors and 13 patients with tumors greater than 2 cm were entered
    • Baseline characteristics of the women were similar in the two groups
    • As of January 2011, median follow-up was 12.6 years (maximum, 16.5 years)
    • Of the 636 treated patients:
      • 335 (53%) survived at least 10 years:
        • 227 of whom remain in active follow-up
    • Because the observed treatment effect was similar when assessed by both log-rank and multivariate methods, they quote the P values from only the log-rank test
    • Time to Locoregional Recurrence:
      • As compared with the Tam group:
        • The TamRT group experienced a significantly longer time to locoregional recurrence (observed HR, 0.18; 95% CI, 0.07 to 0.42; P < .001)
      • At 10 years:
        • 90% of patients in the Tam group (95% CI, 85% to 93%) compared with 98% in the TamRT group (95% CI, 96% to 99%):
          • Were free from locoregional recurrence
        • Thirty-two women in the Tam group experienced locoregional recurrence:
          • Of these, 20 had only IBTR
          • Six, IBTR with distant metastasis
          • Five, only axillary recurrence
          • One, both IBTR and axillary recurrence
        • Six women in the TamRT group experienced locoregional recurrence:
          • All six were IBTRs
      • At 10 years:
        • 91% in the Tam group (95% CI, 87% to 94%) compared with 98% in the TamRT group (95% CI, 96% to 99%) were free from local (IBTR) recurrence
        • There were no axillary recurrences among the 244 women who underwent initial axillary dissection
        • Among those who did not undergo axillary dissection:
          • There were no axillary recurrences in the TamRT group
          • There were six of 200 in the Tam group
    • Treatment of IBTR:
      • Six patients receiving TamRT and 27 receiving Tam had in-breast recurrences (IBTRs):
        • Of these, four (TamRT) and 10 (Tam) underwent mastectomy
        • One patient in the TamRT arm underwent lumpectomy without RT
        • 13 in the Tam arm underwent lumpectomy (four without RT, eight with RT, and one unknown RT)
    • Time to Mastectomy:
      • Time to mastectomy did not differ significantly between the two treatment groups (observed HR, 0.50; 95% CI, 0.17 to 1.48; P 􏰅 .17)
      • The 10-year probability of not undergoing mastectomy was 98% (95% CI, 96% to 99%) in the TamRT group and 96% (95% CI, 93% to 98%) in the Tam group
    • Time to Distant Metastasis:
      • Time to distant metastasis did not differ significantly between the two treatment groups (P < .50;); distant relapse occurred in 21 patients in the TamRT group (13 have died as a result of breast cancer) and 16 in the Tam group (eight have died as a result of breast cancer)
      • The 10-year probability of freedom from distant metastasis was 95%
    • Survival:
      • Of the 636 women in the trial, there were 334 deaths:
        • 166 in the TamRT arm and 168 in the Tam arm (HR, 0.95; 95% CI, 0.77 to 1.18)
        • The respective 10-year estimates of OS were:
          • 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%)
        • Only 21 of the deaths (6.3%) resulted from breast cancer:
          • 13 in the TamRT arm and eight in the Tam arm (HR, 1.55; 95% CI, 0.64 to 3.74)
        • The respective 10-year breast cancer–specific survival estimates were:
          • 97% (95% CI, 94% to 99%) and 98% (95% CI, 95% to 99%)
• Conclusion:
  • Long-term follow-up of CALGB 9343 confirms and extends the earlier report that in women age equal or greater than 70 years with clinical stage I, ER-positive breast cancer treated with lumpectomy followed by tamoxifen:
    • Irradiation adds no significant benefit in terms of survival, time to distant metastasis, or ultimate breast preservation, even though it provides a small decrease in IBTR

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