Keystone Trials
Over the past 50 years, patient education, screening, and early detection with advancements in mammography, ultrasound, magnetic resonance imaging (MRI), breast-specific gamma imaging (BSGI), and positron emission mammography (PEM) have continued to shape the management of breast cancer. It is the summation of several early studies that have culminated in identifying the equivalency of mastectomy and BCT. For instance, rates of survival of those undergoing a mastectomy in comparison to lumpectomy with radiation achieved no significant differences in outcome. Defined predictors of local recurrence after BCT have led to modifications in surgical and radiation techniques to reduce local recurrence.
NSABP B-06
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-06, a federally sponsored clinical trial, raised several aspects of comparisons between surgical options, use of radiation, and systemic therapy. In a step further, it compared the efficacy of chemotherapy in patients with positive axillary nodes after surgical treatment, as well as determining the clinical significance of microscopic multicentricity. The study took place between 1976 and 1984, with a total of 1,851 patients with tumors up to 4 cm in diameter and clinically negative lymph nodes, T1 or T2, N0 or N1, M0. Patients were randomly assigned to a total mastectomy, lumpectomy alone, or lumpectomy with postoperative radiation of the breast. All patients with histologically positive axillary nodes received chemotherapy.
Based on this study, rates of ipsilateral breast cancer recurrence after lumpectomy, with or without breast radiation, were compared. At 20 years follow-up, local recurrence rate in women treated with lumpectomy and radiation was 14.3 % versus those treated with lumpectomy alone with a recurrence rate of 39.2 %. For patients with positive nodes who received chemotherapy, the local recurrence rate was 44.2 % for lumpectomy alone, as opposed to 8.8 % for lumpectomy and radiation therapy. The study concluded that lumpectomy, paired with radiation therapy, and adjuvant chemotherapy in women with positive nodes, was appropriate in patients with tumors equal to or less than 4 cm, placing them at stage I or II disease, provided that the resected margins are free of tumor [2].
EORTC
At about the same time, a similar study compared the overall survival between those patients that underwent a modified radical mastectomy (MRM) and breast conservation therapy (BCT) with radiation. The results would similarly echo those found in the NSABP B-06 trial. The European Organization for Research and Treatment of Cancer Trial 10801 took place between 1980 and 1986, in eight centers in the UK, Netherlands, Belgium, and South Africa. It randomized 868 women to MRM and BCT with radiation. The size of tumors was up to 5 cm, though 80 % of women had tumors larger than 2 cm, and patients with axillary node-negative or axillary node-positive disease were included.
At 20 year follow-up, there was no difference in survival between MRM and BCT with radiation [8]. The overall survival was 44.5 % in MRM group and 39.1 % in the BCT group. There was no difference in time to distant metastases or overall survival by age. The study concluded that as a standard of care, patients with early-stage breast cancer can be offered BCT with radiation as an alternative to MRM.
Danish Breast Center Cooperative Group
From 1983 to March 1989, the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial comparing breast conservation to mastectomy in patients with invasive breast cancer. From a total of 1,153 women, 905 were placed on either mastectomy or breast conservation. The remaining 248 were not randomized. Those placed in the breast conservation arm obtained radiotherapy afterward. Tumor diameter was more than 2 cm in over 50 % of cases. Patients were excluded based on the following criteria: sarcoma of the breast or carcinoma in situ, fixation of the tumor to the muscles, evidence of metastatic disease, history of other malignancies, signs of multicentricity by palpation or mammography, and concerns in cosmesis, such as a large tumor in a small breast. In this trial, patients had the choice of changing arms in terms of the proposed operation. Hence, 33 patients randomly assigned to a mastectomy chose breast conservation, while 55 chose a mastectomy over breast conservation. Regardless of tumor size and palpable nodes, all patients underwent an axillary dissection. The dissection consisted of removal of at least all level I lymph nodes.
The median follow-up was 40 months for all patients. For the purpose of consistency, both patient and tumor characteristics were similar in both breast conservation and mastectomy group. Overall survival in the breast conservation group was 79 %, compared to that of the mastectomy group of 82 %. The recurrence-free survival at 6 years was similar in both groups, 70 % versus 66 % [9].
Milan National Tumor Institute Trial
Under the guidance of the National Cancer Institute in Milan, between the years of 1973 and 1980, this trial enrolled 701 women with breast cancer up to 2 cm in size for the primary tumor and clinically negative nodes. These patients would undergo either a radical mastectomy or quadrantectomy with axillary dissection and postoperative radiation to the ipsilateral residual breast tissue. Chemotherapy was reserved for patients with pathologically positive nodes. Of the 701 patients, 349 had a mastectomy and 352 a quadrantectomy. Factors such as age, size and site of primary tumor, and axillary metastases were similar in both groups.
At a 20 year follow-up, no differences between the two groups were found in overall or disease-free survival [10]. Interestingly, the contralateral breast cancer rates were similar. These findings contraindicated the previous thought that radiation increased the incidence of contralateral breast cancer. Based on this trial, patients with a breast cancer lesion less than 2 cm in size have the option of either a mastectomy or quadrantectomy, without concern for decrease in survival.
The Institute Gustave-Roussy Trial
The trial randomized 179 women with breast cancer into modified radical mastectomy versus lumpectomy. Eighty eight patients had lumpectomy and radiotherapy, while 91 patients underwent mastectomy. Axillary dissection was performed in all patients regardless of the lack of palpable axillary lymph node. At a 15-year follow-up, no differences were observed between the two surgical groups in risk for death, metastases, contralateral breast cancer, or locoregional recurrence [9].
Patient Selection for Lumpectomy
As the advent of mammography and early detection improved, the average tumor sizes of the 1970s and 1980s fell to 2.5 cm, allowing the majority of women to undergo BCT. BCT is indicated in women with a T1 (<2 cm) tumor, T2 that is ≤5 cm, N0, N1 (ipsilateral moveable axillary nodes), and M0 (no metastasis) tumors, which correlates to clinically stages I and II breast cancer. An important consideration as to which patients are candidates for BCT is practicality and cosmesis. The tumor to breast volume as well as location of the tumor, such as central or lower inner quadrant, may require nipple-areola complex removal or result in significant deformity of the breast and preclude standard approaches to BCT. Newer techniques of oncoplastic surgery described by Clough and Silverstein may allow for the accommodation of BCT in otherwise compromising locations. Nearly all BCT has been done on unifocal lesions with multicentric lesions being a contraindication for BCT [4]. Certain cases of closely approximated or “kissing lesions” have been successfully treated with BCT. More extensive areas when completely excised with oncoplastic techniques can result in excellent outcomes with BCT.
To be eligible for breast-conserving therapy, three conditions must be met. One must be able to obtain negative surgical margins, patient is able to undergo adjuvant radiation therapy, and the result must be cosmetically acceptable. Positive margins, due to lobular invasive or ductal in situ disease, require excision to negativity and are amenable to BCT, as long as they meet the aforementioned criteria [4].
Contraindications of lumpectomy are multicentric disease, persistently positive margins, early pregnancy, diffuse microcalcifications on preoperative mammogram, or prior history of breast radiation. Early pregnancy is a contraindication since whole breast radiation is contraindicated during pregnancy. However, breast cancer detected during pregnancy in the second or third trimester may be able to be treated with lumpectomy and sentinel node biopsy after which chemotherapy can be administered followed by radiation following delivery.
With the advent of accelerated partial breast irradiation (APBI) and intraoperative radiation therapy (IORT), some patients may be offered shielded breast irradiation during the second or third trimester of pregnancy. Multicentric disease is defined as two or more primary tumors in separate quadrants of the same breast and is a contraindication to BCT. However, some patients with out-of-field recurrences are now being offered APBI or IORT to those new areas of disease. Relative contraindications include whole breast radiation to a very large breast, lobular carcinoma in situ (LCIS), active connective tissue disease (such as systemic lupus erythematosus, scleroderma or radiosensitivity due to inherited ataxia telangiectasia), and a tumor larger than 5 cm in a patient with small breasts (due to a poor cosmetic result) [4].
Surgical Principles: Techniques in Breast Lumpectomy
BCT is routinely performed for malignant breast diseases. Particularly for malignant processes, there are myriad of surgical techniques and complementary therapies being performed. All of these techniques have similar efficacy rates, and selection should be a patient-centered decision.
Needle-Localized Lumpectomy
Preoperative image-guided needle localization of breast masses has been performed since the 1960s [11–13]. After being refined to include a hook wire to prevent needle migration, the technique quickly became the standard of care in excising breast masses [12]. Mammography, ultrasonography, and magnetic resonance imaging are all used to guide needle placement. After placement, standard lumpectomy incisions are used to gain a rectangular or cylindrical block of tissue around the wire. Needle localization is a time-tested method, but effective excision depends both on the precision of radiological placement and surgical technique. Unfortunately, it does add another step in the procedure, which could lead to patient discomfort and inconvenience [13]. Nonetheless, it is arguably the most popular technique among surgeons.
Palpable Mass Excision
Excision of a palpable mass is indicated for those masses that are not visualized on mammography or for those with features that portend malignancy. Incisions should be made to facilitate excision while maintaining a good cosmetic result.
Hematoma Ultrasound-Guided Lumpectomy
Ultrasonography can be utilized to directly visualize lesions and post-biopsy hematomas. The hematoma ultrasound-guided lumpectomy was described in 2001 and has become widely performed [14]. After routine biopsy of breast lesions, a hematoma forms that is sometimes palpable and most of the time is easily visualized under ultrasound guidance. Intraoperative ultrasound is used to localize the lesion, which guides incision placement. The ultrasound can then be used to ensure proper margin-free excision, and ex vivo ultrasonography ensures that the lesion is removed. Hematomas do resorb with time, so operative scheduling should be close to the biopsy date (within 6 weeks). This technique obviates the need for needle localization in many patients, but if lesions are not visualized with sonography, needle localization should be performed [14, 15].
Radioisotope (Seed) Localization Lumpectomy
Tc99m radioisotope sulfur colloid is used to identify draining lymph nodes of the primary tumor. It follows that if a different radioisotope could be inserted into target lesions, excision could be similarly guided by gamma counts. This has been performed and widely published since the early 2000s [16]. Radiological or ultrasound placement of radioactive I125 seeds can be used to localize the malignant lesion, and any of the gamma detection probes set on the I125 setting can detect the seed even in the presence of the Tc99m which has been injected for lymphatic mapping of sentinel nodes. A gamma counter is used to guide both the incision and the extent of excision. This technique does require a preoperative radiological implantation, but improvements in margin negativity have cemented the use of this procedure in the breast surgeon’s armamentarium [17].
Cryoablation-Assisted Lumpectomy
Cryoablation can be used in conjunction with intraoperative ultrasound to guide lumpectomy. Essentially, the lesion is visualized under ultrasound guidance and a cryoablation of the area is performed, followed by an ultrasound-guided lumpectomy of the area that was ablated. Margin negativity is acceptable using this technique for lesions less than 18 mm [18]. Larger lesions are more difficult to adequately ablate, and the ablation process makes postoperative pathological analysis more difficult [19]. To further analyze the ability of cryoablation to eradicate intraductal carcinoma, the Cryoablation Trial Z0172 is in clinical Phase II trials at present.
Lumpectomy with Radiofrequency Ablation
Intraoperative radiofrequency ablation of the lumpectomy bed was examined in the early part of year 2000. Performance of this technique requires some specialized equipment and surgical precision, but the consistent 1 cm margin of ablation confirmed on post-ablation cavity wall biopsy could prevent re-excision rates for specimen margin positivity. After lumpectomy, RFA probe is secured in the lumpectomy bed with a purse-string suture. Care is taken to keep the probe from causing skin burns, and Doppler ultrasonography can be used to manipulate the probe to prevent this [20]. It is possible that this could be definitive breast conservation therapy for some patients with favorable lesions, but this requires more evaluation [21].
Lumpectomy with Brachytherapy
Some patients with favorable tumors can avoid whole breast radiation therapy and undergo accelerated partial breast irradiation (APBI) [22] (see Table 13.1). This entails 1 week of radiation therapy that is often delivered through exteriorized catheters placed into or through the lumpectomy cavity. Surgeons can assist with partial breast irradiation by placing brachytherapy catheters through externalized catheters placed into or through the lumpectomy cavity devices into the lumpectomy cavity either intraoperatively or in the office after lumpectomy. The catheter can be cumbersome for some patients, but given that the total radiation time is 1 week, it is widely tolerated [23]. Techniques of multiple polyethylene catheters placed in an array through and through the breast tissue traversing the lumpectomy cavity were first implemented over 30 years ago. Subsequent balloon catheter devices (MammoSite, ClearPath) were developed as well as bundled and strutted device with multiple polyethylene catheters (SAVI) device. Treatment programs of 34 Gy delivered in 10 × 3.4 Gy fractions twice daily have been employed (see Table 13.2).
Table 13.1
Professional medical society consensus guidelines for patient selection for APBI
ABSa | ASBSb | ACROc | ASTROd | |||
|---|---|---|---|---|---|---|
Suitable | Cautionary | Unsuitable | ||||
Age | ≥50 | ≥45 | ≥45 | ≥60 | 50–59 | <50 |
Diagnosis | Unifocal, invasive ductal carcinoma | Invasive ductal carcinoma or DCIS | Invasive ductal carcinoma or DCIS | Invasive ductal or other favorable subtypes (i.e., mucinous, tubular, colloid) | Pure DCIS ≤3 cm EIC ≤3 cm | – |
Tumor size (cm) | ≤3 | ≤3 | ≤3 | ≤2 | 2.1–3.0 | >3 |
Surgical margins | Negative microscopic margins of excision | Negative microscopic margins of excision | Negative microscopic margins of excision | Negative by at least 2 mm | Close (<2 mm) | Positive |
Nodal status | NØ | NØ | NØ | NØ (i−, i+) | – | Positive |
Table 13.2
APBI data review
Institution | # of cases | Median F/U(months) | Localrecurrence (%) | Cosmesis good/excellent (%) |
|---|---|---|---|---|
ASBS MammoSite Registry | 1,440 | 60.5 | 1.8 | 90 |
Virginia Commonwealth University | 483 | 24 | 1.2 | 91 |
National Institute of Oncology,Hungary Phase III Triala | APBI 127 | 66 | APBI 4.7 | APBI 81 |
WBI 131 | WBI 3.4 | WBI 62 | ||
William Beaumont Hospital | 199 | 71 | 1.6 | 92 |
Ochsner Clinic | 164 | 65 | 3 | 75 |
RTOG 95–17 | 99 | 51 | 4 | Not reported |
Mass General Hospital | 48 | 84 | 2 | 68 |
National Institute of Oncology,Hungary Phase I/II Trial | 45 | 80 | 6.7 | 84 |
MammoSite FDA Trial | 43 | 66 | 0 | 83 |
Tufts/Brown | 33 | 84 | 6.1 | 88 |
Total | 2,681 | 65 | APBI 3.1 | 84 |
WBI 2.8 |
Lumpectomy with Intraoperative Radiation Therapy
Intraoperative radiation therapy is a development in the spectrum of breast conservation therapy. This collaboration between breast surgeons and radiation oncologists begins by localizing and removing the tumor. Next, the radiation device (Intrabeam, Xoft) is placed within the lumpectomy cavity and secured the radiation is delivered to the tumor and peritumoral tissues in a single fraction of 20 Gy. Proper therapy can be completed even in noncompliant patients given the one stage lumpectomy and radiation [25]. While intraoperative cost is higher, this eliminates the long-term radiation therapy costs and ensures patient compliance with therapy [26]. The recent results of the TARGIT trial demonstrate excellent short-term results with single 20 Gy doses of IORT.
Margin Assessment
Obtaining adequate margins is of the utmost importance in breast-conserving surgery. Excision of the lesion in its entirety with adequate margins is vital to minimizing the risk of a local tumor recurrence. However, overzealous resection may lead to a less than desirable cosmetic outcome. Although there is no clear consensus as to what constitutes a negative margin, many authors define a positive margin as tumor at the inked margin and a close margin as tumor less than 2 mm from the inked margin. Definition for an adequate margin in the breast literature ranges from no tumor at ink to 10 mm.
It is important to ensure a negative margin at the time of the initial resection. Although re-excision is possible and often performed for positive margins, this adds patient discomfort, cost and further anesthesia, and surgical risk. Currently re-excision rates for positive margin status vary greatly in the literature. A recent multi-institutional study of 2,206 women undergoing partial mastectomy found an overall re-excision rate of 22.9 %, with 9.4 % of patients requiring re-excision of two or more re-excisions with 8.5 % of patients ultimately requiring a total mastectomy. The study found that younger women (age <35), thinner women (BMI <18.5), and those with initial margins of less than 1 mm are more likely to require a re-excision.
A study by Morrow et al. analyzing the SEER data from several institutions nationwide demonstrated a stunning 40 % re-excision rate. DCIS, lobular carcinoma, and lymphovascular invasion also had higher re-excision rates. Obtaining a negative margin is important because margin status affects the rate of local and overall recurrence. Local recurrence rates with negative margins found in the literature vary between 2 and 13 % and increase to 6–31 % if the margins are positive. However, it is important to remember that negative margins do not guarantee total eradication of disease but that the residual tumor burden is low enough to be treated with chemoradiation. Thus, factors such as intrinsic tumor biology and clinical stage play an important role in the risk of overall recurrence.
Margin assessment is especially difficult in clinically non-palpable lesions or lesions with poorly defined borders. Various techniques have been used to assess specimen margins to ensure adequate resection including optical assessment, intraoperative frozen section, and imprint cytology. Ensuring an adequate margin begins with preoperative imaging. Standard imaging such as mammography, ultrasound, and MRI should be used to determine the size, location, and character of the tumor. Ultrasound- or mammography-guided needle localization or clip placement near non-palpable tumors is helpful in identifying suspicious regions. However, this technique does not define the borders of the lesion in a three-dimensional setting and thus does not ensure a negative margin. After careful surgical dissection, the specimen should be orientated and marked carefully as to ensure facile re-excision if necessary. A gross visual inspection of the specimen is always necessary to assess macroscopic disease. In addition, a number of surgeons use a variety of techniques to ensure adequate margins intraoperatively. Portable radiography systems, such as the Faxitron® and Kubtec® (XPERT 40) systems, allow for immediate radiographic analysis of specimen margins following needle-localized excisions. The images can be sent immediately to radiology for further evaluation.
Although wire-guided localization has traditionally been viewed as the standard of care for localizing non-palpable breast lesions in breast-conserving therapy. Various new technologies have been introduced to augment and even substitute its role in localization and margin assessment. Intraoperative specimen mammography provides an immediate image of the entire excised specimen. This allows radiographic visualization of suspicious areas and allows the surgeon to excise additional margins at the time of lumpectomy, thus decreasing the rate of re-operative surgery. In Bathla et al.’s study of the utility of Faxitron mammographically guided intraoperative re-excision, 84.3 % of patients who underwent primary lumpectomy using this method had histologically clear margins at initial excision versus national rates of 55–68 % [27]. A total of 17.6 % of excisions had positive margins despite the use of 2D Faxitron imaging. The sensitivity and specificity of intraoperative margin assessment via 2D Faxitron imaging for patient with primary breast cancer quoted in this study were 58.5 and 91.8 %, respectively, with a positive predictive value of 82.7 % and negative predictive value of 76.7 %. Thus, although intraoperative specimen mammography improves the rate of negative margins at initial excision, it does not always predict negative histological margin. It should be used carefully in conjunction with the already established assessment tools available to ensure a negative margin.
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