Management of Local Regional Recurrences after Primary Breast Cancer Treatment

Meena S. Moran

Anees B. Chagpar

Erica L. Mayer

INTRODUCTION

Contemporary treatments for early-stage breast cancer have minimized the risk of local-regional recurrence (LRR) to a cumulative frequency that is typically <1% per year (1, 2). While multimodality advances in surgical approaches, radiation, and systemic therapy (chemotherapy, targeted drug therapy) all contribute to these low recurrence rates, the management of LRR remains challenging with limited data to guide subsequent treatment. The confirmation of a recurrent diagnosis may have widespread psychological and social implications for the patient, in addition to leading to loss of the conserved breast after breast conservation therapy (BCT), or causing uncomfortable and potentially difficult to control chest-wall disease after mastectomy. The care of each patient with LRR must be tailored to that individual’s needs, using a multidisciplinary team approach. The treatment strategy delivered to each patient with LRR should include a combination of active therapy and symptom palliation, with the ultimate aim of ensuring that the patient’s quality of life is maintained at an optimum level for as long as possible.

Initial clinical-pathologic features that lead to increased risk of LRR include number of involved lymph nodes, primary tumor size, and ultimate stage of disease. Other prognostic factors that may affect a patient’s risk for LRR include margin status after definitive surgery, tumor grade, patient age, hormone receptor status, receipt of adjuvant radiation, receipt of systemic therapy, and possibly primary tumor oncogene expression. LRR is most often detected clinically after mastectomy, and radiographically after BCT. Signs and symptoms of LRR include palpable nodules or induration, skin ulceration or other suspicious skin changes, thickening of the breast/chest wall, and abnormally enlarged or hard lymph nodes (Fig. 69-1).

When a patient experiences a LRR, the disease can recur locally and/or regionally, with or without distant metastasis. A local recurrence is defined as recurrent cancer in the previously treated ipsilateral intact breast (BCT) or along the chest wall (postmastectomy). Regional recurrences, which generally occur in under 4% of patients (3), arise most often within the lymph nodes of the axilla or supraclavicular fossa and less frequently in the infraclavicular chain or internal mammary nodes. While distant metastasis from breast cancer can occur anywhere in the body, the most common sites include bone, liver, and lungs.

The overall prognosis after a LRR is related to the disease-free interval before recurrence, with early recurrences (<2 years) carrying a worse overall prognosis than LRRs that occur later (4). Other factors affecting overall prognosis after LRR include the extent of local-regional disease, presence of metastatic disease, hormone receptor status and HER-2 status at the time of recurrence, and patient age. A significant portion of patients with LRR will present with simultaneous distant metastasis, but for those with isolated local recurrence, aggressive treatment can offer patients long-term survival. While the hazard ratios for LRR are highest in the first few years after diagnosis of breast cancer, there is a persistent rate of relapse beyond 15 years (5).
Thus, long-term follow-up for breast cancer patients at risk of LRR is warranted.

FIGURE 69-1 (A) and (B) An advanced CWR in a patient who was not a candidate for surgical resection due to her elderly age and poor performance status. The CWR was ulcerated at presentation and continued to grow despite chemotherapy. Only superficial debridement was performed. Note the arrow highlighting the large, fixed palpable lymph node in the axilla.

Because new primaries should theoretically have a prognosis independent of the primary breast cancer, attempts have been made to distinguish LRR as ‘true recurrence’ versus ‘new primary’ based on location/quadrant of the recurrence (i.e., whether the recurrence is in or near the quadrant of primary disease, or is distant from the primary tumor) and histopathologic features (Fig. 69-2). Additionally, radiation oncologists have further classified ipsilateral breast tumor recurrence (IBTR) as a ‘marginal miss’ if the recurrence is adjacent to, but not within, a previously radiated area. Retrospective series suggest that true recurrences have an earlier median time to presentation, are located near the lumpectomy cavity or scar, have histology similar to the primary tumor, and are characterized by a more aggressive natural history and a higher association with concurrent metastasis, earlier metastasis, and shorter survival (6, 7). While earlier studies may have misclassified true recurrences versus new primaries, recent improvements in the classification of breast cancers and molecular analysis of clonal differences may help to distinguish patients with true recurrences who carry an overall worse prognosis (8). Nevertheless, given evidence suggesting the association of LRR with the development of distant failure and subsequent diminished overall survival (5), aggressive management of isolated LRR in a patient without documented distant metastasis is of paramount importance. Even for a patient with documented distant metastasis at the time of LRR, optimal local-regional therapy can significantly reduce the morbidity of uncontrolled LRR; however, the potential toxicity of local-regional treatment modalities needs to be weighed against possible benefits in quality of life.

FIGURE 69-2 Ipsilateral breast tumor recurrence in a patient previously treated with breast conservation. Despite the patient’s other skin lesions, the index of suspicion remained high, and a biopsy confirmed a local recurrence in the previously treated breast. The tumor recurrence was located in a separate quadrant remote from the primary tumor.

SCREENING AND EVALUATION FOR LRR

Routine surveillance for LRR after treatment for breast cancer should be conducted with regularly scheduled follow-up visits including a complete history/physical examination, yearly mammography (after BCT), and routine self-examination. Any additional work-up should generally be symptom-directed. To date, there are no data supporting the routine use of any diagnostic imaging (outside of breast imaging), laboratory testing, or tumor markers to detect recurrence in an asymptomatic breast cancer survivor.

Approximately one third of all IBTRs are found on surveillance mammography alone; the remainder are detected by physical examination with or without follow-up imaging (9). Most IBTR located close to the lumpectomy site tend to occur earlier than those remote from the primary tumor site (10), and tend to have the same mammographic appearance
as the primary tumor (11). Detection of IBTR by mammography alone can be challenging due to post-operative and post-radiation scar tissue development, but detection of IBTR is higher when recurrent tumors are associated with calcifications.

FIGURE 69-3 Imaging of an ipsilateral breast tumor recurrence in a patient previously treated with breast conserving surgery and radiation. Given the density of the breast and scar tissue, mammogram was unable to detect recurrence. MRI was more sensitive in discerning density and scar tissue from tumor.

Breast MRI can also be utilized to screen for LRR (Fig. 69-3), though the evidence to support the benefit of its use, particularly to detect LRR, needs to be established. Sensitivity of MRI for detection of recurrence ranged from 75% to 100%, while specificity ranged from 66.6% to 100% (12). Both sensitivity and specificity increase when MRI is performed after a longer time interval from the original surgery, although long-term follow-up data supporting this observation is limited to approximately 3 years (12). Other conditions (such as fat necrosis, foreign body cysts, bony nodules, or unrelated second primary tumors) may resemble a LRR; thus, the area of concern should always be pathologically confirmed with a biopsy.

At the time of biopsy, molecular subtype and variations in hormonal receptor and HER-2 status of the LRR should be reevaluated, as discordance between the primary tumor and recurrent tumor will be important for systemic treatmentrelated decisions. There should be a relatively high level of suspicion for simultaneous distant metastasis when LRR are detected, and thus, a full metastatic workup is warranted, which may include CTs, MRIs, PET/CT, and/or bone scan. This workup should be performed to determine the extent of recurrent disease prior to rendering decisions regarding aggressive local-regional management. For breast-conserved patients, in addition to routine diagnostic mammography and ultrasound, a breast MRI may help to elucidate multifocal or more extensive disease, and may be able to differentiate recurrence from scar tissue, as invasive recurrence often enhances on MRI whereas scar tissue does not (12). While a chest x-ray is typically not beneficial, a CT scan may be particularly useful in the postmastectomy recurrence setting to determine the extent of disease in superficial tissue versus more extensive pectoralis muscle or transmural involvement, in differentiating between radiation-induced versus tumor-induced brachial plexopathy, and in determining presence of visceral metastasis or enlarged lymph nodes. For any patient with suspicion of metastatic disease, efforts should be made to confirm the metastasis histopathologically when technically feasible.

MANAGEMENT RESULTS

IBTR after BCT

A standard treatment for optimizing local control in the definitive setting for early stage breast cancer is breast conservation therapy, which typically includes breast conserving surgery followed by adjuvant radiation therapy (5). Definitive adjuvant radiation therapy generally entails a course of whole breast radiation therapy, typically 44 to 50 Gy in 1.8 to 2.0 Gy per fraction (standard fractionation), often followed by a 10-16 Gy boost dose to the lumpectomy cavity, which is delivered over 5 to 6.5 weeks. Alternatively, patients may receive hypofractionated radiation, which delivers biologically equivalent doses of radiation in 3 to 4 weeks and has been demonstrated to be as safe and efficacious as standard fractionation (13). Over the last several years, increasing numbers of women have been treated with partial breast radiation (typically
delivered twice daily over 1 week) as a faster alternative to conventionally fractionated whole breast radiation. While the existing data on definitive partial breast irradiation cohesively suggest excellent local-regional control comparable to that of whole breast radiation, prospective data with longterm outcomes and safety are lacking (14). Irrespectively, given the limited tolerance of normal tissue after these definitive doses of radiation to the breast, IBTRs occurring in previously radiated BCT patients are often treated with mastectomy, which is generally felt to be the standard management approach. For patients who have not been treated with radiation therapy as a component of their initial treatment, a repeat breast conservation procedure with excision of the recurrence followed by a course of radiation therapy can be considered. It remains uncertain whether mastectomy after IBTR improves outcomes compared with lesser surgery. A number of studies comparing mastectomy and breast conservation as treatment for IBTR are detailed in Table 69-1. Together, these studies suggest that the rates of recurrence are greater after a second local excision compared with mastectomy, but whether this ultimately translates to improved survival outcomes remains unclear (15).

Second attempts of breast conservation in previously radiated patients with small, histologically favorable local relapses have been reported. The initial experiences of salvaging an IBTR with a breast conserving approach utilized a wide local excision alone. In carefully selected patients with mobile tumors measuring less than 2 cm in size and favorable pathologic features, 5-year local control approaches nearly 80%, and is significantly better for patients in whom a negative margin was attained on the second local excision surgery (20). The published data cohesively suggests that with a second local excision without additional radiation therapy, local relapse rates range from approximately 20% to 50% as shown in Table 69-1.

Based on the observation that the risks of local relapse reported after a second breast conserving surgery approximates the risk of local relapse experienced after primary breast conserving surgery (˜35%), there have been efforts in evaluating re-irradiation after second local excision for IBTR, with the hopes of decreasing the local relapse rates with a similar magnitude of benefit as seen in definitive settings (approximately two-thirds risk reduction). In previously radiated BCT patients, a repeat breast conserving approach should only be attempted if the patient is refusing salvage mastectomy, and re-irradiation should only be utilized on protocol where toxicity and efficacy can be monitored, documented, and reported.

TABLE 69-1 Surgical Treatment of IBTR

Study	Med FU (months)	Mastectomy			Breast conservation
Study	Med FU (months)	N	2nd LR (%)	5 yr OS (%)	N	2nd LR (%)	5 yr OS (%)
Abner (15)	39	106	7	79	16	31	81
Alpert (16)	146	116	7	66	30	7	58
Dalberg (17)	156	65	19	59	14	50	NR
Gentilini (18)	44	127	NR	NR	161	24	82.2
Ishitobi (19)	40	46	NR	NR	78	22	72.4
Kurtz (20)	53	43	12	53	55	32	NR
Salvadori (21)	73	134	4	70	57	19	85
Med FU, median follow-up; 2nd LR, second ipsilateral local tumor recurrence; OS, overall survival; NR, not reported.

With existing knowledge and expertise using partialbreast irradiation in the primary setting, various techniques to deliver a second repeated course of radiation for LRR have been investigated. Low-dose rate interstitial brachytherapy, which has the longest clinical experience for partial breast irradiation in the definitive setting (14), has been utilized in the hands of experienced clinicians to deliver a re-irradiation dose to the tissue surrounding the lumpectomy cavity. The rationale for re-irradiation with a partial breast technique is based on the hypothesis that focal treatment can eradicate microscopic disease while maintaining normal tissue tolerance, and thus have acceptable side effects. Various methods of re-irradiation of IBTR have been described; these include interstitial brachytherapy, where multiple interstitial catheters are inserted into the high-risk area (typically 1-2 cm surrounding the lumpectomy cavity). The catheters are after-loaded with low-dose-rate sources to deliver 30 to 55 Gy to the previously radiated breast (22). Furthermore, intra-operative radiation has been described to deliver a targeted x-ray to the IBTR resection cavity at the time of the resection surgery (23). Lastly, utilization of high dose-rate intraluminal brachytherapy (i.e., Mammosite®) (24) and external-beam partial breast techniques (25) for re-irradiation of the high-risk area after repeat BCT have also been reported. The results of published studies are shown in Table 69-2. For patients who received partial breast irradiation as part of their primary, definitive treatment who subsequently experience IBTR, the data to salvage these patients with a repeat breast conserving approach are very limited.

Factors to consider when evaluating a patient for re-irradiation after BCT include interval between initial radiation treatment and recurrence, anatomic considerations (such as close proximity to skin) that may preclude safe and cosmetically favorable delivery, and whether there is ample residual breast volume amenable to re-irradiation. It is important to note that because safe thresholds for normal breast tissue, skin, muscle, bone and subcutaneous tissue are not established in this setting and existing data are limited, all BCT patients being considered for a second breast conserving approach with re-irradiation should be treated on Institutional Review Board (IRB)-approved protocols with the informed consent of the patient.

Currently, a phase II national trial, RTOG 1014, is underway and will evaluate the adverse events associated with the use of a repeat breast conserving approach after IBTR. In this trial, patients who experience an IBTR less than 3 cm in size with a time interval of greater than one year from completion of their initial course of radiation will undergo a second
local excision followed by partial breast irradiation utilizing 3D-conformal external beam radiation techniques to deliver 45 Gy in 1.5 Gy fractions bid. The primary endpoint being evaluated is adverse effects after re-irradiation, with secondary endpoints including in-breast recurrence rates, mastectomy-free survival, overall survival, monitoring/correlating circulating tumor cells with relapse, and cosmesis (Fig. 69-4).

TABLE 69-2 Results of Re-irradiation Using a Partial Breast Technique after Repeat Breast Conservation for Local Relapse

Study	Technique of rPBI	N	Median FU (months)	2nd LR N (%)	5 year OS
Deutsch (25)	EBRT, electron	39	51.5	8 (21%)	78%
Hannoun-Levi (22)	LDR	69	50	11 (16%)	92%
Chadha (26)	LDR	15	36	1 (7%)	100%^*
Trombetta (24)	Interstitial or intra-cavitary	26	38	1 (4%)	NR
Resch (27)	Pulsed dose rate (+EBRT)	17	59	5 (29%)	76%
Maulard (28)	LDR	38	40	8 (21%)	NR
Mullen (29)	EBRT	16	NR	4 (25%)	NR
Kraus-Tiefenbacher (23)	Intraoperative radiation	15	26	0 (0%)	100%
Guix (30)	High dose rate	36	89	1 (89%)	NR
Kauer-Dorner (75)	High dose rate	39	57	2(93%)
^*Reported at 3 years (not 5-years). rPBI, re-irradiation with partial breast irradiation; LR, local relapse; OS, overall survival; N, number of patients