Long-term Results of a Randomized Trial of Accelerated Hypofractionated Whole Breast Irradiation Following Breast Conserving Surgery in Women with Node-Negative Breast Cancer

Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 22 de septiembre del 2008

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Presenter: T.J. Whelan
Presenter's Affiliation: Juravinski Cancer Centre and McMaster University, Hamilton, ON, Canada
Type of Session: Plenary

Background

  • Large, well-designed trials have demonstrated that lumpectomy followed by whole breast radiotherapy is equivalent to mastectomy as treatment for early-stage breast cancer (Fisher B, NEJM, 2002). 
  • Commonly, radiotherapy following lumpectomy is delivered to the whole breast using tangent fields, to a total dose of approximately 50 Gray (Gy). This dose is generally delivered using daily fractions of 1.8 – 2.0 Gy. Whole breast radiotherapy is usually followed by a boost to the tumor bed, which may be given via photons, electrons, or radioactive implant. 
  • This type of treatment requires patients to undergo between six and seven weeks of daily treatments, the burden of which has been demonstrated to negatively impact quality of life for cancer patients (Whelan T, Cancer, 2000). Reducing the number of required treatments may thus be beneficial for certain groups of patients. 
  • Radiobiologic studies have demonstrated that increasing fraction size while decreasing total dose may allow for more equivalent radiation to be delivered over a shorter time period.Calculations taking into account normal tissue tolerance demonstrate that 50 Gy delivered in 25 fractions of 2 Gy each may be radiobiologically equivalent to 42.5 Gy delivered in 16 fractions of 2.65 Gy each.
  • Several methods for delivering radiation after lumpectomy over reduced total time course have been described. Accelerated partial breast irradiation (APBI), consisting of delivery of larger fractions of radiation to the lumpectomy cavity alone, rather than the whole breast, is being examined in current clinical trials.
  • The current study was undertaken to evaluate outcomes for patients receiving accelerated, hypofractionated whole breast radiotherapy (AHWBI) versus those receiving standard whole breast radiotherapy (SWBI).
    • The results of this study were first published in 2002 with 5 years of follow-up, and demonstrated no difference in rates of local recurrence or distant failure between the two groups (Whelan T, JNCI, 2002).
    • Cosmetic outcomes also appeared to be equivalent.
  • The authors acknowledged the need for increased follow-up for further evaluation of AHWBI vs. SWBI, and their results, with 12 year follow-up, are presented here.

Materials and Methods

  • This trial was designed to compare AHWBI and SWBI in the setting of a randomized controlled trial. 
  • Women with early-stage, invasive breast cancer and breast width of 25 cm or less were eligible for this study. All patients underwent lumpectomy, and only those with negative surgical margins and negative axillary lymph nodes were included.
  • Patients were stratified according to age, tumor size, systemic treatment, and institution, and were then randomized to AHWBI or SWBI. 
    • Patients assigned to AHWBI received 42.5 Gy to the whole breast in 16 fractions over 22 days.
    • Those assigned to SWBI received 50 Gy to the whole breast in 25 fractions over 35 days.
    • Whole breast radiotherapy was delivered using tangent fields with wedges utilized as necessary.
    • No patient enrolled in this study received a boost to the tumor bed.
  • The primary outcome of this study was local invasive recurrence in the treated breast. Breast cosmesis and late radiation morbidity were secondary outcomes.

Results

  • Between April, 1993 and September, 1996, 1234 women were enrolled on this study. 
    • Of these, 622 received AHWBI and 612 received SWBI.
    • Patient characteristics were similar between the two groups, with approximately 25% of patients in each arm being under 50 years of age, 30% in each arm having tumors of 2 cm or greater, and 75% of patients in each arm having estrogen receptor positive tumors.
  • Median follow-up was 12 years (144 months).
  • Local recurrence risk at 10 years was 6.2% with AHWBI versus 6.7% for SWBI.
  • Overall survival was equivalent between the two arms.
  • Breast cosmesis was scored according to the European Organization for Research and Treatment of Cancer (EORTC) scale as excellent, good, fair, or poor.
  • Excellent or good cosmesis at 10 years was observed in 70% of patients having received AHWBI versus 71% of those having received SWBI. Although the proportion of patients with excellent or good cosmetic outcome declined from over 80% at 3 years to 70% at 10 years, this decline was similar between the two arms.
  • The incidence of moderate or severe late radiation-induced skin toxicity at 10 years was 6% with AHWBI, versus 3% with SWBI; incidence of subcutaneous tissue toxicity was 8% versus 4%, respectively. No grade 4 ulceration nor necrosis was observed in either arm.
  • Cause of death was evaluated in both arms as a surrogate for cardiac/ pulmonary toxicity. Cancer-related deaths occurred in 13.7% of patients receiving AHWBI and 13.2% of those receiving SWBI. No excess in non-cancer-related deaths were observed in either arm.

Author's Conclusions

  • The authors conclude that AHWBI was associated with excellent local control and limited late morbidity when compared to SWBI with 12 years of follow-up.
     
  • They note that no differences in cosmetic outcome, toxicity, or non-cancer death were observed in patients receiving AHWBI.
     
  • They comment that increased feasibility and decreased cost make AHWBI a reasonable and appealing treatment strategy for early-stage breast cancer patients.

Clinical/Scientific Implications

  • The results presented in this study are the product of a well-designed study with follow-up of 12 years. The authors demonstrate no difference in local recurrence, distant failure, or overall survival with accelerated hypofractionated whole breast radiotherapy compared to standard whole breast radiotherapy.
  • As they note, these findings support the use of AHWBI, particularly for patients for whom access to daily treatments over a 6-7 week period may be limited. In the current milieu of shrinking resources, their points regarding cost-saving are also well-taken.
  • Certain aspects of this trial are important to keep in mind during decision-making regarding treatment for early-stage breast cancer.
    • First, patients treated as part of this trial had both surgical margins and axillary nodes that were negative. Many patients treated for early-stage breast cancer do not fall into this category and may not be appropriate candidates for this type of treatment.
    • Along these same lines, patients treated as part of this trial did not receive a breast boost. Certain subsets of patients with early-stage breast cancer have recently been demonstrated in the EORTC Boost No-Boost Trial to benefit most from receiving breast boost – namely those with positive surgical margins and high-grade histology (Bartelink H, JCO, 2007). In the EORTC trial, reduction in local recurrence risk was reduced across all age groups, but this did not translate to a difference in overall survival. The trial presented here included only patients with negative surgical margins; however, information on histologic grade and/ or histology was not included during the abstract presentation. Certainly, the decision of whether or not to deliver boost must be based on individual patient and treatment characteristics, but the results of this trial do not answer the question of whether a subset of patients included in it would benefit from radiotherapy boost to the lumpectomy cavity.
    • Treatment delivered as part of this trial was not used for post-mastectomy chest wall treatment, nor for treatment of regional lymph nodes; further investigation is warranted before this treatment is extrapolated to apply to populations requiring these treatments.
    • Additionally, patients with breast width of greater than 25 cm were excluded from this study; further analysis of their eligibility would be interesting.
  • The authors make note that overall survival was not different between the two arms, and that non-cancer related deaths were not increased in the experimental arm. They use this point as a surrogate for measuring cardiac toxicity; however, cardiac effects following radiotherapy for breast cancer may develop many years out from treatment, and 12 years is likely not enough follow-up time for full assessment of cardiac risk (Harris EE, JCO, 2006).
  • Despite these limitations, the study presented here represents a well-designed trial. The accelerated, hypofractionated treatment strategy described appears to be feasible for a subset of patients with favorable risk factors following lumpectomy, and this approach should be considered a possible treatment option for these patients.

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