ABSTRACT: Over the past 30 years, lumpectomy and radiation therapy (breast-conservation therapy, or BCT) has been the preferred treatment for early-stage breast cancer. With accumulating follow-up, we have an ever-expanding pool of patients with history of an irradiated intact breast. Routine use of every-6-month or annual screening in this population has identified an emerging clinical dilemma with respect to managing a small recurrence or a second primary tumor in the treated breast. Most women diagnosed with a second cancer in a previously irradiated breast are advised to undergo mastectomy. More recently, with an improved understanding of the patterns of in-breast failure, and with advances in the delivery of conformal radiation dose there is an opportunity to reevaluate treatment alternatives for managing a small in-breast recurrence. A limited number of publications have reported on patient outcomes after a second lumpectomy and radiation therapy for this clinical scenario. In this report, we review the controversial subject of a second chance at breast conservation for women with a prior history of breast irradiation.
Breast cancer is the most common newly diagnosed malignancy among American women. In 2008, an estimated 182,460 new cases of invasive breast cancer, and an additional 67,770 cases of in situ cancer were diagnosed. Approximately 40,480 women will die from breast cancer each year.
Up to 10%–15% of patients treated with lumpectomy and whole-breast irradiation (breast-conservation therapy, or BCT) will have a subsequent in-breast local recurrence when followed long term. Salvage mastectomy is widely accepted as the standard of care for local recurrence after BCT.[1-4] Few data in the literature have described the clinical outcome from a second conservative surgery with or without additional radiation therapy among women who do not consent to mastectomy.[5-14]
Prognostic Factors of a Second Cancer Following BCT
Several factors may influence patient outcome after local recurrence following BCT.[15-20] The various prognostic factors include tumor size, histologic subtype of recurrent disease (invasive or noninvasive), involvement of the skin and lymph nodes at the time of recurrence, location of the tumor in the breast in relation to the initially treated breast cancer, and the time interval between the first and second in-breast cancer diagnosis. Patients who have experienced a longer time interval between the two cancers have a better outcome. Kurtz et al[14] reported that when mastectomy was used to treat the recurrence, the 5-year local control rate was 92% for recurrences occurring after 5 years and only 49% for time intervals of less than 5 years.
| • | Up to 10%–15% of breast cancer survivors with an intact breast will experience an in-breast local recurrence. In an era of personalized care, options for managing a true local recurrence or a second new primary in a previously irradiated breast need to be considered. |
| • | The clinical outcomes of a local recurrence or a second primary in a previously irradiated breast are influenced by a variety of prognostic and biologic characteristics of the second cancer event. |
| • | Although mastectomy is the standard of care for cancer in a previously irradiated breast, many women desire repeat breast conservation. Further, evolving radiotherapy techniques can deliver a conformal dose to target structures while limiting toxicity associated with a repeat course of whole-breast irradiation. |
Further, some investigators have studied clinical and pathologic criteria to help distinguish between a true recurrence and a new primary. Haffty et al[21] distinguished new primaries as lesions that were far removed from the original scar, were of a different histology than the original primary tumor or had diploid tumors in the face of an aneuploid primary tumor. They observed statistically significant differences in the 5-year survival—89% for new primary tumors and 36% for lesions classified as a true recurrence. A subsequent update on this work with a mean follow-up of over 10 years confirmed the differences in outcome between a new primary tumor and a recurrent lesion.[20]
Another study[22] that used clinical and pathologic criteria to differentiate a new primary from a true recurrence observed similar findings. The mean time to the second cancer event was longer for the new primary compared to true recurrence. Both the 10-year overall and distant disease-free survival was significantly better among patients categorized as having new primaries. Of note, the 77% survival rate reported among patients with tumors classified as a new primary is comparable to what we might expect for similar-stage disease at initial presentation. These observations suggest that the prognosis of all second cancer events is not uniformly associated with poor risk. The ability to recognize biologically favorable second events may have implications for the choice of local therapy when individualizing cancer care.
Mastectomy Following Local Recurrence
Salvage mastectomy is the accepted standard of care. Studies on salvage mastectomy have, on average, reported local failure rates of less than 10% with expected control rates of greater than 90%.[23-25]
Psychological issues related to mastectomy include emotional and physical distress. Ganz et al[26] have demonstrated a clear cause-and-effect relationship between mastectomy and the patient experiencing difficulty with clothing and body self-image. In a study by Rowland et al,[27] the impact of lumpectomy, modified radical mastectomy without reconstruction, and modified radical mastectomy with subsequent reconstructive surgery was evaluated. The findings revealed the highest incidence of negative impact on sex life (45.4%) among women who had undergone modified radical mastectomy with reconstruction, and the lowest (29.8 %) among women undergoing lumpectomy. The impact of patient age was evaluated by Maunsell et al,[28] who observed that women under age 40 experienced a significantly less negative effect from undergoing conservation surgery compared to modified radical mastectomy.
Second Lumpectomy Without Radiation Therapy
Outcome of Patients Treated With Conservative Surgery Alone After an In-Breast Failure
The outcome of a small number of patients managed with a second lumpectomy alone without radiation therapy has been reported. The local recurrence rates observed with this approach range from 19% to 50% (Table 1).[5-8,15,29] Salvadori et al[5] reported a local recurrence rate of 19% in patients treated by reexcision, compared to 4% in those undergoing salvage mastectomy. However, no difference in disease-free survival was seen between the two groups, with a mean follow-up time of 73 months (range = 1–192 months).
From a population of 979 patients, Komoike et al[8] evaluated 41 patients who developed a localized breast recurrence. The mean interval between initial treatment and recurrence was 37 months. Salvage mastectomy was performed in 11 patients, and repeat lumpectomy performed in 30. Of the 30 patients treated with repeat lumpectomy, 9 developed a second local recurrence within 3 years.
Chen et al[29] reported on 747 patients who developed an ipsilateral breast recurrence after breast-conservation surgery from the SEER database between 1998 and 2004. Almost one-quarter (24%) of the women underwent a second lumpectomy without radiation therapy, and this group of patients was found to have a survival rate inferior to that seen in women who had undergone salvage mastectomy. However, it was also noted that women in the lumpectomy group were significantly older than those in the mastectomy group (P = .03). Moreover, survival rates improved when radiation therapy followed the second lumpectomy. However, the authors did not elaborate on these results.
Remarkably, the average 33% risk for relapse after lumpectomy alone is in the same range of what has been reported in randomized trials among women with early-stage breast cancer initially managed with lumpectomy alone (Table 1). These observations signify the potential therapeutic benefit gained by adding radiation therapy. One could hypothesize that most late relapses in previously irradiated breasts may represent a new primary tumor, and similar therapeutic benefit from using targeted radiation therapy techniques for primary tumors may be achieved following second lumpectomy.
Second Lumpectomy With Radiation Therapy
| • | Salvage mastectomy, with or without immediate reconstruction |
| • | Second lumpectomy and partial-breast irradiation |
The application of radiation therapy as a treatment for recurrence is often cited as an absolute contraindication due to the risk of reirradiating the breast tissue and skin. Nevertheless, since the late 1990s, accumulating evidence has suggested that partial-breast brachytherapy is safe and effective following lumpectomy for selected early-stage breast cancer.[30-33] The option of partial-breast irradiation (PBI) for conservatively treating a localized second cancer in a previously irradiated breast results from techniques that administer a highly conformal radiation dose to the target volume while sparing adjacent critical structures, such as lung, heart, and chest wall, as well as breast tissue remote from the lumpectomy cavity.
The most commonly used PBI techniques include three-dimensional (3D) conformal external-beam radiotherapy, interstitial multicatheter brachytherapy, and intracavitary Mammosite brachytherapy. All three techniques have distinguishable variability in technique and dosimetric considerations. Given these factors, the safety and clinical outcomes of reirradiation are not directly transferable between PBI techniques. Hence, the feasibility of reirradiation using any given technique of PBI has to be individually evaluated. Protocols for the specific technique should define absolute dose prescription to target and dose constraints of adjoining normal structures.
