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Original Research |
1 Department of Radiation Oncology, Brigham and Women's Hospital and the
Dana-Farber Cancer Institute, 75 Francis St., Boston, MA 02115.
2 Department of Radiology, Brigham and Women's Hospital, Boston, MA.
3 Department of Genetics, Children's Hospital Boston, Boston, MA.
Received November 26, 2007;
accepted after revision March 25, 2008.
Presented at the 2006 annual meeting of the American Roentgen Ray Society,
Vancouver, BC, Canada.
Abstract
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MATERIALS AND METHODS. Seventy-nine patients with core needle biopsy-proven breast cancer, who were eligible candidates for breast-conserving surgery and accelerated partial breast irradiation, underwent bilateral breast MRI examinations. At review, the presence and location of occult tumor sites (detected on MRI only) were documented and subsequently correlated with pathology findings.
RESULTS. From 79 patients, a total of 126 suspicious areas, including the index tumors, were detected by MRI. Additional sites of cancer other than the index tumor were observed in 30 patients (38%). Of these, eight (10%) had an additional cancer in a different quadrant from the index tumor.
CONCLUSION. The treatment effect of whole-breast irradiation on microscopic tumor cells and on additional occult foci in other quadrants of the breast is lost with partial breast irradiation. Our results suggest that MRI before accelerated partial breast irradiation may be of benefit to patients to ensure they do not have multifocal or multicentric disease, remote from the lumpectomy bed.
Keywords: accelerated partial breast irradiation • breast carcinoma • MRI
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Accelerated partial breast irradiation is an approach that allows patients to undergo breast-conserving therapy more quickly (e.g., in 5 days by using a balloon catheter delivery system instead of over the course of 6 weeks with whole-breast irradiation). Several techniques are available to deliver localized radiation therapy, including multiple inter stitial cath eters inserted into the breast, a balloon catheter placed into the lumpectomy cavity, localized external beam delivery, single-dose intra operative treatment, and others such as seed implants [14]. Accelerated partial breast ir radiation delivered with the MammoSite (Cytyc Corporation) balloon brachytherapy applicator has recently gained favor at some facilities as the preferred method.
Several nonrandomized studies using the brachytherapy balloon had excellent 5-year results in preventing ipsilateral breast tumor recurrences, but they included only small numbers of highly selected patients [15–18]. Lack of long-term data from major randomized trials, limited efficacy data, and con cerns regarding progression-free outcome create some reservations in the application of the technique [19]. Breast cancer can remain dormant for years before becoming clinically apparent and may develop from initially undetected sites of cancer. After lumpectomy, the rationale for treating the whole breast with irradiation has been to destroy any residual microscopic tumor cells or additional occult foci anywhere in the ipsilateral breast. The treatment effect of irradiation in quadrants of the breast other than the index tumor is lost with accelerated partial breast irradiation.
Several studies have confirmed the use of contrast-enhanced breast MRI for cancer detection [20–22]. The goal of our study was to evaluate presurgical breast MRI findings in women who were treated with either breast-conserving therapy or mastectomy, but who might have been considered candidates for accelerated partial breast irradiation. On the basis of our MRI review and pathology correlation, it was expected that some of the women who might have been considered for accelerated partial breast irradiation would have been converted either to mastectomy or to standard lumpectomy and whole-breast irradiation.
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Study Population
The patient population was collected from the radiology database of our
institution, a tertiary care academic hospital. From May 1, 2005, to December
30, 2005, 985 diagnostic breast MRI examinations were performed. In 118 (12%)
of the 985 reviewed cases, MRI was performed after a core biopsy-proven cancer
and before surgical treatment. The medical records of these 118 patients were
reviewed to collect the available clinical and imaging information before the
time of breast MRI. Indications for MRI examinations were provided by
referring physicians, including primary care physicians, oncologists, and
breast surgeons, and were noted on the referral form in the patient's clinical
history. The indication was based on the referring physician's judgment and no
standard criteria (i.e., dense breasts, young age, and so forth)
(Table 1). Although a common
indication, extent of disease is not a routine indication for breast MRI in
newly diagnosed breast cancers at our institution.
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From the pre-MRI preoperative clinical and imaging information, eligibility
for accelerated partial breast irradiation was determined by review of notes
on physical examination in conjunction with conventional imaging (mammography
and breast sonography) findings when available. The following criteria, based
on institutional preferences and the American Society of Breast Surgeons
(ASBS) patient selection for treatment with accelerated partial breast
irradiation as the sole form of radiation therapy in lieu of whole-breast
irradiation [23], were used to
determine theoretic eligibility for accelerated irradiation: invasive ductal
carcinoma (IDC) or ductal carcinoma in situ (DCIS), unifocal disease at
clinical evaluation and conventional imaging with a total tumor size (both IDC
and DCIS) 
3 cm, and axillary lymph nodes negative. Patients with lobular
histology were excluded because their disease is often multifocal and
underestimated by imaging; many protocols, including that of our institution,
exclude such patients.
Some common eligibility criteria for accelerated partial breast irradiation, such as distance from the skin and age considerations, were not included in this study. Adequate skin spacing is determined from the postsurgical cavity and skin by sonography after lumpectomy; therefore, this distance can be determined only after surgery. In addition, our institution's guidelines include a postoperative reevaluation, using conventional imaging methods such as mammography and sonography, before brachytherapy. Age criterion was not included in this study because acceptable ages vary among institutional protocols, with some protocols having no age specification at all. For example, our institution recruits only patients 55 years or older to receive partial breast irradiation with MammoSite, whereas ASBS ex panded its patient selection criteria to include women 45 years and older.
During patient record review, other data, such as young patient age (< 40 years old) and family history of first-degree relatives with breast cancer or presence of mutation of the BRCA gene in a first-degree relative or the patient herself, were reviewed irrespective of the referring physician's indications. In each case, histology was reviewed from the pathology reports of the core biopsies.
From the 118 cases of known cancer, we excluded 19 with lobular histology (invasive lobular cancer or invasive carcinoma, duct cell type with lobular features) and 13 with clinically or mammographically apparent advanced disease (multi focal disease or tumors > 3 cm, as well as axillary lymph nodes that were grossly abnormal or proven positive at fine-needle aspiration). Three patients with diffuse cancer were also excluded. From the remaining 83 patients, 79 had available follow-up data. These 79 patients formed our study population.
Imaging Assessment
All MRI examinations were performed on a 1.5-T MRI device (Signa HDx 1.5 T,
GE Healthcare), using an InVivo 7 channel, dedicated breast surface coils (MRI
Devices, InVivo Research) with the patient in the prone position on the breast
coil.
Our standard dynamic contrast-enhanced protocol, which has been in routine clinical use for many years, was used. This protocol consists of a fast three-plane localizer (scout view) sequence to pre scribe sections of the subsequent dynamic series to cover the entire volume of the breasts. Sagittal T2-weighted fast spin-echo fat-saturated and axial T1-weighted non–fat-suppressed fast spoiled gradient-recalled echo (FSPGR) sequences were included before the dynamic series. VIBRANT (volume imaging for breast assessment) dynamic series consisted of one acquisition before and four after an IV bolus injection of 20 mL of gadolinium dime glumine (Magnevist, Schering). Each dynamic volume consisted of 3-mm-thick sections with an acquisition matrix of 256 x 224 x 224 and temporal resolution of 1 minute 36 seconds per dynamic run. A late axial T1-weighted FSPGR contrast-enhanced fat-saturated sequence was also obtained routinely. To eliminate the signal of fat, in addition to fat saturation, image subtraction was performed offine after the actual imaging session.
MRI written reports were reviewed and, if additional findings were described (e.g., additional sites, suspicious enhancement, recommendation for further workup), images of breast studies, including mammograms, sonograms, and MRI examinations, were reviewed by a radiologist with 13 years of subspecialty experience in breast imaging. The findings were classified according to the American College of Radiology BI-RADS lexicon [24]. At review of MRI examinations, the presence of clinically and mammographically occult sites of tumor and quadrant location were documented with relation to the known index tumor. Sizes of suspicious areas were recorded and, if additional biopsy was performed, results were reviewed and correlated.
Pathologic Assessment
Final diagnoses on suspicious areas identified at MRI were made by
histopathology. The imaging and pathologic results of written pathology
reports from each subsequent biopsy or surgical excision, including
mastectomy, were correlated.
Statistical Analysis
We used Microsoft Excel 2003 to collect data and calculate proportions.
Chi-square and Fisher's exact tests for the analysis of patients'
characteristics were performed with SAS/STAT V 9.1 software (SAS).
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Irrespective of physician MRI indications, review of patient records showed that 29 (36%) of the 79 patients had a family history of breast cancer (personal history of mutation of the BRCA gene, first-degree relative with BRCA mutation, or first-degree relative with breast cancer), and 28 (35%) patients were considered to be of a young age (< 40 years old).
At completion of imaging workups, 126 (79% or 126/159) MRI abnormalities were judged suspicious for malignancy in the ipsilateral breasts (including the index lesions). Of the 79 patients, 80 additional MRI findings were seen in the ipsilateral breasts. Of these 80 additional lesions, 46 (57%) were found in the same quadrant and the remaining 34 (42%) in a different quadrant. Twenty-eight lesions (35% of the 80 additional findings) were biopsied by core needle biopsy, 32 lesions (40% of the 80 additional findings) were surgically excised, and 20 lesions (25% of the 80 additional findings) were followed up with MRI at 6 months.
From the 28 core biopsies, 17 (21% or 17/80) showed additional malignancy and 11 (13% or 11/80) revealed a benign cause. Of the 32 surgical excisions, 28 (87%) were malignant and four (12%) were benign on pathology. Finally, of the 20 lesions followed up by MRI, two underwent core needle biopsy and were benign; the remaining 18 have been stable on imaging follow-up.
In 30 (50%) of the 60 patients who underwent core needle or surgical biopsy, the surgical plan was changed to a wider excision, including mastectomy (10 patients). The wider excision was planned to excise possible additional foci or to achieve clear margins based on clinical and imaging findings. In 19 of the 30 patients in whom the treatment was changed, the pathology of the surgical biopsy proved further malignancy, detecting 28 additional cancer foci. MRI showed 33 additional foci in these 19 patients, as compared with the 28 malignant foci detected by pathology. The 10 mastectomies showed multifocal cancer in six breasts, presence of an extensive intraductal component (EIC) in two cases, and unifocal tumor in two cases.
At the summary of all cases, according to the final pathologic interpretation, additional foci of cancer were recognized in addition to the index tumor in 30 patients (38%), all of which were detected on MRI. Of these cases, eight (10% or 8/79) had at least one additional focus in quadrants other than the index tumor (> 2 cm from lumpectomy bed) (Fig. 1A, 1B, 1C, 1D and Table 2). No significant difference was seen in the number of high-risk women (women with germline mutation or with a first-degree relative with a history of breast cancer or a history of germline mutation) versus average-risk women with additional foci of cancer (41% vs 36%; p = 0.635). A trend was noted, however, between groups of women younger and older than 40 years with respect to additional foci of cancer (50% vs 31%, p = 0.103).
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At the conclusion of our review, based on clinical, imaging (including the MRI findings), and pathology results, 49 of the 79 cases (62%) were evaluated as being appropriate for accelerated partial breast irradiation, with T1–T2, N0, M0 breast cancer (American Joint Committee on Cancer/Union Internationale Contre le Cancer classification).
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No data yet exist from randomized trials comparing accelerated partial breast irradiation with whole-breast radiation therapy. Such a clinical study, the recently opened NSABP B-39/RTOG 0413 trial, is currently underway [28]. The interest in partial breast irradiation includes the ability to complete treatment in 5 days instead of over the course of 6 weeks as with conventional whole-breast irradiation treatment. It also may help to pro vide easier access to radiation treatment for women in rural communities or for elderly patients who are unable to attend the full 6- week course due to transportation problems [27].
The goal of accelerated partial breast irradiation is to provide tumor cell damage, equal to that of conventional whole-breast irradiation, to the site of the primary tumor after lumpectomy and to minimize radiation to normal tissue. During accelerated partial breast irradiation, radiation is focused on the lumpectomy bed and includes a 1- to 2-cm margin surrounding the surgical bed. The rationale for this treatment change is that about 75% of recurrences are reported at or near the lumpectomy site [6, 13, 29]. Preliminary results of this novel therapy are promising but also bring up unresolved questions, including that in some patients nonirradiated parenchyma may contain clinically and mammographically occult malignancies. A theoretic possibility is that nonirradiated occult malignancies will manifest as second malignancies in patients after long-term follow-up. In a recently published meta-analysis, reductions in both the 15-year and the overall breast cancer mortality rates were found in patients who underwent breast-conserving therapy with whole-breast irradiation versus those who underwent surgery alone [9]. This benefit may need to be proven with accelerated partial breast irradiation.
Contrast-enhanced breast MRI has diagnostic utility in evaluating invasive carcinoma, reporting sensitivities of greater than 90% in studies using varied patient selection. Sensitivities in detecting DCIS are lower, with a range of 40–95% [20–22, 30, 31]. Breast MRI has also proven extremely useful in the setting of mammographically occult cancers. An occult second carcinoma can be identified on MRI in the ipsilateral breast in 11–34% of women with breast carcinoma [32]. The finding of a separate site of cancer within the same quadrant has been reported in 1–20% of women, and additional cancer in a different quadrant in 2–24% (Table 3). Pathology analyses in mastectomies have confirmed additional sites of ipsilateral cancer in 20–63% of women and cancer in a different quadrant in 20–47% [32].
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In a study from the M. D. Anderson Cancer Center, 284 patients with T1–T2, N0–N1, M0 breast cancer treated with modified radi cal mastectomy from 1974 through 1993 were followed for recurrence and survival [33]. Pathology of the mastectomies showed that 60 patients (21%) had multicentric breast cancers, 30 patients (11%) had two lesions, 13 patients (5%) had three lesions, and 17 patients (6%) had four or more lesions. This study is of interest because it shows a high percentage of multicentric cancers in patients having T1–T2, N0–N1, M0 disease. This group of patients would be eligible for treatment with accelerated partial breast irra diation by most of the applied selection criteria.
A recent publication from Solin et al. [34] described no benefit in the use of MRI at initial diagnosis for improving outcome after breast-conserving therapy with whole-breast irradiation, but stated that it may be valuable for selecting patients for accelerated partial breast irradiation. Breast MRI may provide benefit by potentially refining criteria for selecting patients for treatment with accelerated irradiation, with its ability to detect multifocality and additional tumor sites away from the lumpectomy bed.
As seen in Table 3, the percentage of additional sites of cancer in the current study of 79 women theoretically eligible for partial breast irradiation is relatively high (38%) but within the range of prevalence in other studies [33, 35]. In detecting additional sites of cancer, patients may be referred more frequently for mastectomy. However, mastectomy should not be performed without a definitive pathologic diagnosis of findings detected on MRI.
Further weaknesses of our study include the relatively small number of subjects, which limited the power of the study to detect statistically significant differences between age groups as well as between high-risk versus average-risk patients.
In conclusion, we describe the role of breast MRI in selecting patients who are theoretically eligible for accelerated partial breast radiation therapy. In our retrospective study of 79 such patients, we found that physical examination and conventional imaging with mammography and sonography were insufficient to exclude additional occult lesions, whereas MRI was more revealing. Additional foci of cancer were detected at final pathology in 38% of patients (30/79), all of which were also seen on MRI. Other studies have confirmed the high sensitivity of breast MRI for the detection of occult malignancies [31, 32]. The common statement to justify accelerated partial breast irradiation is that breast cancer recurrences are almost exclusively in or within the immediate vicinity of the tumor bed. This is supported by the pre-MRI literature. Recent evidence, however, has described patterns of breast recurrence outside the lumpectomy site [35]. In our study, additional sites of disease were observed away from the index tumor in eight of our patients (10% of total patients). If these cases, which were clinically assessed and imaged by conventional means, had been considered appropriate for accelerated partial breast irradiation, then we speculate that recurrence may possibly have occurred be cause cancer was present outside the treated area. On the other hand, with the addition of the MRI, these patients would be considered ineligible for accelerated partial breast irra diation and might have been converted to mastec tomy. Our study suggests that patients who are candidates for accelerated partial breast irra diation may benefit from undergoing MRI before irradiation to potentially ensure that no mammographically occult breast cancer is missed.
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