Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer

Reporter: Arpi Thukral, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 7, 2010

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Presenter: K. S. Hughes, CALBG, ECOG, RTOG, Massachusetts General Hospital, Boston, MA

Background

  • The Early Breast Cancer Trialists’ Collaborative Group Overview (Lancet, 2005), showed that radiation therapy (RT) after breast-conserving surgery (BCS) produced significant absolute improvements in 5-year LR (17-19% benefit) and 15-year breast cancer mortality (5.4% benefit). Furthermore, the addition of RT improved 15-year OS by 5.3% after breast-conservation surgery.
    • This meta-analysis demonstrated the need post-operative radiation for early-staged breast cancer patients undergoing lumpectomy.
  • Tamoxifen, with or without radiation therapy, has also been demonstrated to decrease the risk of recurrence in early-stage, estrogen-receptor positive (ER+), breast cancer patients. (NSABP-21, JCO 2002)
  • Older women (age > 70) tend to present with less aggressive and more indolent breast cancers than younger women. It is know that the rate of ipsilateral breast tumor recurrence decreases with age, likely due to the presence of coexisting conditions and the fact that these women have fewer years to live than younger women, which may shorten the time for recurrence.
  • Although toxicities of breast irradiation are minimal, undergoing radiation therapy may have a negative impact on quality of life and is a costly treatment. With the availability of targeted hormonal therapies, the need for radiation in certain populations, such as the elderly, is often questioned.
  • This randomized trial was designed to determine whether women 70 years of age or older who have early-stage, ER+ breast cancer can be safely treated with Tamoxifen alone instead of irradiation plus Tamoxifen.
  • The authors of this trial have previously published results of the CALGB C9343/INT Trial (Hughes, et. al. NEJM 2004).
    • They demonstrated that at 7.9 years median survival, in patients > 70 years of age with Stage I (T1N0M0), ER+ breast cancer s/p lumpectomy, the addition of RT to tamoxifen improved 5-yr LF (1% vs. 4%, p<0.001). No difference in breast cancer specific survival or OS was seen at that time point.
    • They concluded from this previous study that tamoxifen alone (Tam) is an effective alternative to tamoxifen plus radiation (TamRT).
  • The authors now provide longer-term results and present outcomes at a median FU of 12 years.

Methods

  • Eligibility criteria:
    • Histologic diagnosis of clinical Stage I (T1N0M0), ER+ breast cancer treated with lumpectomy with negative margins
    • Age > 70 years
    • Clinically node negative
    • Tumor < 2cm
    • ER + or indeterminate (However, 97% of patients in the study were ER+).
  • Trial Schema:
    • 631 women were prospectively enrolled from July 1994 to February 1999 and randomized to receive Tamoxifen (Tam; N=319) or Tamoxifen + radiation (TamRT; N=317).
    • All women underwent lumpectomy with negative surgical margins (absence of tumor at inked pathologic margins).
    • Radiation techniques have been previously described (Hughes, NEJM, 2004). Briefly, the entire ipsilateral breast was treated with tangential fields to a dose of 45 Gray (Gy). A 14 Gy electron boost the the tumor bed was then delivered.
    • Tamoxifen was delivered daily, 20 mg per day. For patients in the TamRT group, Tamoxifen was initiated either during or after radiotherapy.
  • Primary endpoints examined were rate of ipsilateral breast tumor recurrence (IBTR), rate of mastectomy for recurrence, distant metastases rate, and breast cancer-specific and all-cause survival

Results

  • Patient characteristics were well-balanced between the 2 arms of the study.
    • Age > 75: 56% of patients in TAMRT arm and 54% in TAM arm
    • No axillary dissection: 63% of patients (pts) in TAMRT arm and 64% in TAM arm
  • Median follow up: 12 years
  • At this time, 51% of women participating in this study have died.
  • The addition of RT to Tam prolonged the time to first recurrence (p = 0.015) due to improved local control by TamRT.
  • IBTR rate: 9% (27 pts) in Tam arm vs. 2% (6 pts) in TamRT arm (p=0.0001)
    • Specifically, for Tam vs. TamRT, first recurrence occurred in the ipsilateral breast in 8% vs. 2% and solely in the axilla in 1% vs. 0%.
  • The remaining endpoints did not differ by arm (p > 0.05).
    • Mastectomy rate for patients with IBTR: 2% (4 pts) in TamRT group vs. 4% (10 pts) in Tam group; p=NS.
    • Rate of distant metastases was 5% in both arms.
    • The 10-year breast-cancer-specific mortality rate was 3% vs. 2%, for TamRT vs. Tam groups respectively.
    • OS was not statistically significant between the 2 arms.

Author’s Conclusions

  • The authors concluded that even at longer, follow-up of 12 years, the data still demonstrate that TamRT results in an absolute reduction of 7% in ipsilateral breast tumor recurrence (IBTR) when compared to Tam alone in this selected population.
  • However, the addition of radiation did not show an impact on overall survival, distant disease free survival, breast cancer specific survival or breast conservation/rate of mastectomy.
  • Based on these results, the authors believe that lumpectomy with Tamoxifen, but without the addition of radiation, is an appropriate treatment option for the selected patient population in this study.
  • They also note that this data should not be extrapolated to other populations of breast cancer patients.

Clinical Implications

  • This randomized Phase III clinical trial has significant implications on treatment decisions for patients over the age of 70 with clinically node negative T1N0M0 ER+ breast cancers.
  • The authors of this trial have clearly shown a 7% absolute reduction of risk of local recurrence with the addition of radiation to tamoxifen in these highly selected, favorable patients.
  • Although the authors have concluded that radiation may be omitted in this group of patients, there was a local recurrence benefit seen with radiation. Local control is an important endpoint in breast cancer, as local failure not only predicts for survival, but also can lead to decreased QOL in these patients. Therefore, the authors' conclusions should be taken with caution.
  • Furthermore, although no survival differences were seen, this study is underpowered to necessarily show a survival difference. From the EBCTCG meta-analysis, we know that reduction in local recurrence does eventually lead to reduction in OS in early-stage breast cancer patients.
  • It is also important to remember that this study pertains only to a highly selected favorable group of patients. This data should not be extrapolated to other subgroups of breast cancer patients.
  • Decisions regarding the addition of XRT in these patients should likely be made on an individual basis.
    • Radiation for breast cancer actually has minimal toxicity with current techniques, and may be very tolerable in the majority of breast cancer patients.
    • If this data is applied in the clinic, patients need to be compliant with taking hormones for 5 years and need to be followed closely for recurrence.
  • Another important point to keep in mind is that life expectancy has been steadily increasing over the past decade. Patients > 70 may in fact live long enough to see a translation of benefit of local control to overall survival.
  • Although this data is intriguing, this hypothesis was tested in a small number of patients, and a larger study with longer follow up may show survival benefit with radiation. Therefore, radiation should not be omitted in ­all patients >70 with T1N0M0 node negative breast cancer.
  • Physicians should weigh the 7% absolute increased risk of local recurrence against the cost, inconvenience, and adverse effects of irradiation for each patient on an individual basis. Patients should part of decision-making for their care, and the choice of treatment should take into account the needs of the patient.
  • Future research questions:
    • Most elderly post-menopausal women are now receiving aromatase inhibitors (AI) rather than Tamoxifen. It is unclear whether this data could/should be extrapolated to patients receiving AIs. Should this hypothesis be tested in patients receiving AIs?
    • What is the role of using accelerated partial breast irradiation in these elderly patients to minimize inconvenience of standard radiation? Would this be an acceptable alternative?
    • Is biology of disease different in women over age 70?