Managing a Small Recurrence in the Previously Irradiated Breast

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.

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

TABLE 1

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

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.

Brachytherapy

FIGURE 1

Interstitial Low–Dose-Rate Brachytherapy TechniqueFIGURE 2

Survival After Low–Dose-Rate Brachytherapy for Local Recurrence

• Low Dose Rate-The selection of low–dose-rate brachytherapy for retreatment is mostly based on the fact that practitioners have had the longest clinical experience with this technique. Moreover, the low–dose-rate approach may be radiobiologically safer in the retreatment setting, by limiting the risk of late effects while potentially delivering higher radiation doses in the tumor cavity. This technique, however, requires that the physician be experienced in brachytherapy.

The feasibility and safety of brachytherapy to reirradiate a recurrent tumor bed in the breast using a dose of 30 Gy was studied at Beth Israel Medical Center.[9] The target volume was identified as the lumpectomy cavity plus 1- to 2-cm margin, and the prescription isodose was defined as the dose encompassing the target volume. In cases where the skin proximity was of concern, the calculated skin dose was maintained at ≤ 20 Gy.

After administering a dose of 30 Gy, no major toxicity was observed over a follow-up period of 1 year, so the prescribed dose for all subsequent patients on the study was increased to 45 Gy.

The combined experience from Allegheny General Hospital[10] and Beth Israel Medical Center[9] includes 38 patients treated with second lumpectomy and partial-breast reirradiation with interstitial low–dose-rate brachytherapy to a dose of 45–55 Gy (Figure 1). The investigators reported the following median results: Time from initial primary to in-breast recurrence was 11.5 years; age at diagnosis of the in-breast cancer was 61 years; tumor size was 1 cm; and follow-up after salvage brachytherapy was 45.5 months. The 5-year actuarial overall survival rate after salvage brachytherapy was 87.9% (95% confidence interval [CI] = 77.4%–99.8%; Figure 2A). The 5-year mastectomy-free survival rate was 94.4% (95% CI = 95.5–100; Figure 2B).

Most patients had some degree of baseline asymmetry due to the deficit in breast volume from the second lumpectomy. With breast asymmetry as a given, the postbrachytherapy cosmetic result observed in 35 patients has been good to excellent. Three patients have grade 3 (or fair) cosmesis as per the Harvard scoring criteria. On further analysis, the negative contributing factor among all three of these patients was the minimal residual breast tissue at the implant site after the second lumpectomy. This observation illustrates that patient selection criteria should include focused evaluation of the anatomic site. Further, prescription dose constraints should be clearly defined when the dosimetry is less than ideal. In summary, among properly selected patients, we observed good cosmetic results, high levels of local control, and freedom from mastectomy.

TABLE 2

Brachytherapy Alone After Second Lumpectomy for Breast Cancer

Experience using low–dose-rate brachytherapy as a reirradiation modality has been reported in a combined experience from Hannoun-Levi at the Marseille and Nice Cancer Institute including 69 patients (Table 2).[12] In this study, patients treated with second lumpectomy and low–dose-rate interstitial brachytherapy represented only a select 14.6% of all local failures. Patients treated at Nice received 30 Gy, whereas 45 to 50 Gy was delivered to all patients treated at Marseille. The investigators observed an association between brachytherapy dose and toxicity. The incidence of grade 2/3 complications was 0%, 28%, and 32% with brachytherapy doses of 30 Gy, 45 to 46 Gy, and 50 Gy, respectively (P = .01). The 5-year overall survival rate was 91.8%, and the 5-year freedom from second local recurrence and disease-free-survival rates were 77.4% and 68.9%, respectively. On multivariate analysis, factors associated with a higher overall survival included absence of axillary lymph node metastases at initial presentation, time interval between initial and in-breast cancer, and the site of relapse in a quadrant other than that of the initial primary cancer. Also, patients treated with a fewer number of interstitial catheters and who received lower brachytherapy doses were at a higher risk for local failure.

The report by Maulard et al[34] included 38 patients with isolated local relapses who underwent salvage treatment with perioperative or split-course low–dose-rate interstitial brachytherapy. With a mean follow up of 40 months (range = 16–64 months), 21% (8 patients) experienced a local relapse after salvage treatment. The overall 5-year survival rate was 55%.

Severe complications requiring a mastectomy occurred in three patients (skin necrosis in one and severe breast pain in two). The lack of stringent selection criteria and inclusion of patients with large tumors that required higher radiation doses resulted in toxicity and inferior cosmetic outcomes.

Resch et al[13] reported that when using pulsed–dose-rate brachytherapy alone, prescribing a dose of 40.2 to 50 Gy limited the toxicity to moderate grade 1/2 fibrosis only.

FIGURE 3

External-Beam Radiotherapy for Local Recurrence

• High Dose Rate-Limited data are available for the use of high–dose-rate brachytherapy for retreatment. A preliminary experience in 10 patients was reported by Trombetta et al[10] using the intracavitary MammoSite balloon technique. With a reirradiation dose of 3.4 Gy × 10 fractions, these investigators’ observations suggest acceptable toxicity and good cosmesis. However, the authors suggest alternative intracavitary techniques might achieve better dosimetry when the tumor bed is in proximity to the skin of the breast or the rib. The authors caution that these preliminary observations warrant additional study, with specific attention to technique and dose fraction schedule.

Protocols using high–dose-rate brachytherapy will need to establish safe dose thresholds for breast, skin, and subcutaneous tissues. The established high–dose-rate brachytherapy dosimetric guidelines used when prescribing PBI as primary treatment for the initial diagnosis of breast cancer may not necessarily be the optimal dose for reirradiation.

External-Beam Radiotherapy

Recht et al[18] reported on a single case of in-breast recurrence treated with wide excision and postoperative external irradiation; the patient was disease free at 72 months postprocedure. Mullen et al[35] published an initial report describing a series of patients retreated with external-beam therapy at a dose of 5,000 cGy (200 cGy/fraction) to the involved quadrant only. All patients had a prior history of receiving 4,500 to 5,040 cGy at 180 to 200 cGy/fraction as part of initial BCT. Deutsch[11] later expanded the series reporting on 39 patients, with in-breast invasive ductal carcinoma in 31 and DCIS in 8 patients. Five patients had positive margins of resection at the time of reirradiation. The 5-year disease-free and overall survival rates were 68.5% and 77.9 %, respectively. The reported cosmetic results were good in 12 patients, fair in 15 patients, and poor in 9 patients (Figures 3A and 3B).

• RTOG Phase II Trial-A proposed Radiation Therapy Oncology Group (RTOG) phase II study will include patients experiencing an in-breast recurrence after lumpectomy and whole-breast irradiation for primary early-stage breast carcinoma (personal communication, D. Arthur, 2009). Patients with biopsy-proven recurrent tumors ≤ 3 cm in greatest dimension, and with mammographic or magnetic resonance imaging (MRI) documenting no evidence of multicentric disease are eligible. Patients with ≤ 1 year between whole-breast radiation therapy and recurrence will be ineligible.

Case Report: A Woman With a Local Breast Recurrence Who Refuses Mastectomy

A 54-year-old female diagnosed in 1988 with stage T1, cN0 infiltrating duct cell cancer at the 12 o’clock axis of the right breast was treated with lumpectomy and axillary dissection followed by external-beam radiation therapy, receiving a total dose of 60 Gy. She also received adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy followed by tamoxifen for a period of 3 years.

FIGURE

Cosmetic result at 36 months’ (left) and at 74 months’ (right) follow-up.In February 2003, on self-exam the woman palpated an approximately 1-cm freely mobile mass in the lower outer quadrant of the right breast. Pathology confirmed a 1.5-cm poorly differentiated infiltrating duct cell cancer. The workup included a bilateral MRI that reported no additional lesions.

The patient refused the recommended mastectomy and signed an informed consent to participate in an IRB-approved reirradiation protocol to have a second lumpectomy and partial breast brachytherapy. In April 2003, following lumpectomy and pathologically documented negative margins, a multicatheter interstitial implant was performed. The patient received 45 Gy at 9 Gy per day low–dose-rate brachytherapy using Ir-192 ribbons. With the exception of breast asymmetry secondary to volume loss from the second lumpectomy, the cosmetic result achieved was good and has remained stable. At last follow-up (6/17/09) the patient was alive and well with an intact breast and no evidence of disease (see Figure).

The retreatment will consist of a second lumpectomy followed by a hyperfractionated regimen of 1.5 Gy twice daily for a total dose of 45 Gy delivered in 30 treatments over 15 days using the 3D-conformal PBI technique. The protocol will include only one PBI technique, to gain meaningful and interpretable results without adding the confounding variable of varying dosimetry within the target. The 3D conformal technique was also selected because its reproducibility has been established in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/RTOG 0413 phase III trial, and it is the most common PBI technique used by the participating institutions. Concerns about clinical safety and toxicity of reirradiating normal tissues weighed on the choice of the dose fractionation schedule (personal communication, D. Arthur, 2009).

It is anticipated that approximately 69 patients are needed to answer the primary goal of the trial and, with the participation of multiple centers, that enrollment will be completed in a 2-year period. The endpoints of the study will include incidence of acute and late toxicity, cosmetic results, local control rate, and freedom-from-mastectomy rate. In addition, a translational study is incorporated in the protocol as a secondary endpoint to evaluate the rate of circulating tumor cells in this patient population as well as their significance and predictive ability with regard to outcome. With a prospective national study, we will gain additional clinical experience in this controversial treatment approach.

Conclusions

In an era of individualized care, the treatment options for second cancer events in a previously irradiated breast need to be redefined. Due to the accepted bias that a second lumpectomy and reirradiation is associated with unacceptable soft-tissue toxicity and cosmesis, the alternative to mastectomy has never been primarily studied in a large clinical trial. In light of recent advances on many fronts-including improved understanding of the biology of breast disease, imaging modalities, and advances in targeted radiation therapy techniques-there is a renewed interest in studying the alternative of breast conservation for patients presenting with a small recurrence in the previously irradiated breast.

Better selection using biologic markers may be forthcoming. Studies suggest that new primary tumors in a breast previously treated for cancer have a more favorable outcome than true local recurrences. Further research in the area of genetic fingerprinting will provide more accurate means of distinguishing between true recurrence and a new primary by identifying a true clonogenic recurrence from de novo cancer.

With careful selection criteria, there may be opportunities to individualize treatment options and to offer women a second chance at breast conservation. Early data on a second chance at breast conservation, as published in the literature, suggest that mastectomy may not be the only treatment option for women who have a small second cancer in a previously irradiated breast. Finally, as proposed by the RTOG, a prospective multi-institutional trial would be the appropriate means of addressing this controversial clinical issue.

Acknowledgements:The authors would like to thank Dr. Doug Arthur for his contribution on the details about the proposed RTOG trial mentioned in this paper.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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