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10.1245/s10434-006-9154-1
Annals of Surgical Oncology 14:660-669 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Feasibility of Breast Preserving Therapy with Single Fraction In Situ Radiotherapy Delivered Intraoperatively

David W. Ollila, MD1, Nancy Klauber-DeMore, MD1, Leora J. Tesche, MD1, Cherie M. Kuzmiak, DO2, Dag Pavic, MD2, Lav K. Goyal, MD3, Jun Lian, MD3, Sha Chang, MD3, Chad A. Livasy, MD4, Rachel F. Sherron, BSN, OCN and Carolyn I. Sartor, MD3

1 Department of Surgery, UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 3010 Old Clinic Building, CB #7213, Chapel Hill, NC 27599-7213, USA
2 Department of Radiology, UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7213, USA
3 Department of Radiation Oncology, UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7213, USA
4 Department of Pathology, UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7213, USA

Correspondence: Address correspondence and reprint requests to: David W. Ollila, MD; E-mail: David_Ollila{at}med.unc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Accelerated partial breast irradiation (APBI) has gained widespread interest as a means of improving the convenience and availability of breast conserving radiotherapy. Intraoperative radiation therapy (IORT) is an APBI technique that delivers breast radio-therapy as a single dose at the time of partial mastectomy. We adapted the technique of Veronesi to deliver IORT prior to tumor excision to improve delivery to the region at risk and reduce the volume of normal tissue irradiated.

Methods: Patients age ≥55 with ultrasonographically defined tumors ≤3 cm and invasive ductal carcinoma confirmed by core biopsy were eligible. Pre-operative ultrasound was performed at the time of needle localization and radiocolloid injection. IORT treatment planning was performed prior to surgery using ultrasound tumor definition, selecting cone size and electron energy to optimize dose distribution. In the operating room, the surgeon retracted the skin over the tumor, cone was placed and radiotherapy delivered. Standard partial mastectomy was then performed.

Results: Twenty-three patients were enrolled in the study. Eighteen patients completed IORT with 10 patients having successful IORT no additional local therapy necessary. In five patients, the intraoperative radiation therapy served as the boost and in three patients unsuspected larger tumors or multicentric disease necessitated a mastectomy. The majority of patients had a good to excellent cosmetic result.

Conclusions: Single fraction in situ IORT prior to partial mastectomy is feasible for patients with small breast cancers in achieving a good to excellent cosmetic result. Based on this early preliminary data, we plan to expand our feasibility trial.

Key Words: Intraoperative radiotherapy for breast cancer


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The standard of care for patients undergoing breast conservation therapy is segmental mastectomy followed by whole breast radiotherapy. Results from several randomized trials show that patients who undergo a partial mastectomy alone and do not receive adjuvant whole breast radiotherapy, have at least a three-fold increase of in-breast recurrences compared to those who receive external beam radiotherapy.1–4 Based on randomized trial results, the 1990 National Institutes of Health Consensus Conference concluded that breast conserving surgery should be accompanied by whole breast radiotherapy5 and this was re-iterated in the 2001 Consensus Conference.6

Unfortunately, despite properly powered randomized clinical trial results and NIH consensus statements, Patterns of Care Studies demonstrate increasing deviation from these recommendations. Data from the SEER registry demonstrates that the percentage of patients receiving appropriate breast conservation therapy declined from 1983 to 1995, with the proportion of patients receiving inadequate breast conserving therapy (i.e. lacking radiotherapy or axillary node evaluation) increasing from 10% in 1989 to nearly 20% in 1995.7 Barriers to appropriate care appear to be in part due to difficulties inherent in long courses of radiotherapy. The likelihood of receiving radiotherapy decreases with increasing distance to radiotherapy centers, decreased socioeconomic status, insurance coverage, and older age.8–14 Logistical difficulties inherent in daily radiotherapy may also influence surgical choices. For instance, women over age 70 are as likely to choose breast conserving therapy as younger women,12 but older women are more likely to be treated with mastectomy.8 More convenient and less costly radiotherapy regimens may improve compliance with adjuvant therapy recommendations and allow more women to choose breast conserving therapy.

Accelerated partial breast irradiation (APBI) is a potentially attractive way to significantly reduce the duration of time a patient spends in radiotherapy treatment course. The vast majority of in-breast cancer recurrences occur in the same quadrant as the primary tumor, whereas, non-tumor bed recurrences and new primaries in the contralateral breast occur with similar frequency in irradiated and non-irradiated patients, suggesting that the primary efficacy of radiotherapy in early stage disease is due to eradication of residual disease in the region of the tumor bed.3,15–18 Thus, the majority of tumors may be controlled by radiotherapy delivered only to the region of the tumor bed, sparing the remainder of the breast. Restricting the volume of treatment may allow radiotherapy to be delivered at larger dose per fraction without increasing normal tissue toxicity. APBI options include interstitial catheter-based brachy-therapy, endocavitary brachytherapy, three-dimensional conformal radiotherapy and intraoperative radiotherapy.19–21 Accumulating evidence suggests that APBI is well tolerated, with acceptable cosmesis and low in breast recurrence rates with short-term follow-up.

In Europe, intra-operative radiotherapy (IORT) is used to treat the tumor bed with a single dose of radiotherapy delivered in the operating room after the tumor has been excised.22,23 This approach has the advantage of shortening the treatment course further, conveniently delivering the entire course of local therapy at the time of initial excision. However, IORT also presents significant technical challenges, not the least due to the need for accuracy of target definition and treatment delivery inherent in a single-dose radiotherapy delivery. One issue is the accuracy of tumor bed definition when tissues are re-approximated following excision. Another is the variable margin of normal tissue irradiated in the reopposed tissues.

In order to address these issues, we modified the IORT technique of Veronesi et al.23 Instead of delivering the IORT after the tumor is excised by quadrantectomy and the tissues re-approximated, we elected to treat the tumor and surrounding tissues with IORT prior to excision. This allows us to more clearly define the target, tumor plus normal tissue margin, in conventional terms, using ultrasound. This sequence also affords a unique opportunity to evaluate tumor and normal tissue radiation response, by obtaining biopsies before and after IORT. We present our initial experience with in situ IORT.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
Patients age 55 or older diagnosed by core biopsy with clinically node negative infiltrating ductal carcinoma less than three centimeters in greatest diameter and visible by pre-operative breast ultrasound were eligible for this study. Patients with multicentric disease, bilateral breast cancer, contraindications to breast conserving surgery, ductal carcinoma in situ or invasive lobular carcinoma were ineligible. This protocol was approved by the University of North Carolina Institutional Review Board and informed consent was obtained on all patients. Pre-operatively, each patient underwent breast ultrasound and ultrasound-guided needle localization of the cancer. In the operating room each patient underwent lymphatic mapping and sentinel lymphadenectomy, exposure of the breast cancer, intraoperative radiation therapy and then a needle localized partial mastectomy.

Pre-operative Preparation
On the morning of the surgery, the patient first reports to the breast imaging department. The patient then undergoes a focused breast ultrasound by a radiologist trained in breast imaging. The mass is visualized with a high frequency (12–14 MHz) linear array transducer (General Electric Medical Systems Logiq 7, Milwaukee, WI, USA). After the tumor is identified, and the optimal angle of approach is determined to minimize the distance to tumor while maximizing distance to lung. At this angle, the width of the tumor, depth from skin to posterior anterior and posterior edges of the tumor, and from skin to the pleural surface is measured. Dosimetric pre-planning is performed using these parameters to determine the cone size necessary to cover the tumor width plus 1.5–2 cm margin, the electron energy necessary to cover a depth of 1 cm deep to the posterior edge of the tumor with the 90% isodose line while delivering at least 1,500 cGy to the tumor iso-center. The pleural/chest wall interface is limited to a dose of 1,000 cGy.

After completion of the above measurements for radiation therapy, the breast is cleansed with betadine and a predetermined skin location is anesthetized with 1% lidocaine. Using ultrasound guidance, the mass is again visualized and a 20-gauge Modified Disposable Kopans Spring Hook Localization Needle (Cook Incorporated, Bloomington, IN, USA) is placed through the anesthetized skin into the mass. The hook wire is deployed and the needle is removed from the breast. A metallic marker is placed at the wire entrance site and on the nipple of the breast. A post-procedure mammogram in orthogonal projections is obtained for confirmation of wire placement and the images are marked for the surgeon. If the patient is undergoing a sentinel lymph node dissection on the same day, the patient is then taken back to the ultrasound suite for ultrasound-guided lymphoscintigraphy.

Techniques for lymphatic mapping and sentinel lymphadenectomy (LM/SL) combining both blue dye an technetium 99m (99mTc)-labeled sulfur colloid (Nicomed Amersham Canada, Oakville, ON, Canada) have been described previously.24 Patients with medial hemisphere tumors underwent combined blue dye and 99mTc-labeled sulfur colloid lymphatic mapping and sentinel lymphadenectomy. For patients with lateral hemisphere lesions, lymphatic mapping and sentinel lymphadenectomy was performed using either blue dye alone or the combination of blue dye and 99mTc-labeled sulfur colloid, as determined by the operating surgeon.

The technique for LM/SL utilized at our institution have been described previously.25 Briefly, filtered 99mTc-labeled sulfur colloid was prepared in the following manner: (1) the radiopharmaceutical was filtered through a 0.22-µm Millex-GV filter unit (Millipore SA, Malsheim, France); (2) 250 µCi (9.25) MBq) of 99mTc-labeled sulfur colloid were drawn up into each of four 3-mL syringes; (3) 0.9% sodium chloride was used to make a final volume of 2 mL in each syringe; (4) each syringe was affixed with a 25-gauge x1.5-in. needle that was used for injection. The 99mTc-labeled sulfur colloid was injected into the parenchyma adjacent to the primary tumor or into the wall of the biopsy cavity under sonographic guidance by a dedicated breast radiologist.

Surgical and Intra-operative Radiation Methods
Preoperative room set-up is critical in ensuring timeliness of this procedure. The radiation dose is administered using is a mobile, self-shielded, linear accelerator radiation (Mobetron, Intraop Medical Inc., Norcross, GA, USA) (Fig. 1Go). The Mobetron has several articulating joints that allow for positioning above the patient. In our set-up the Mobetron is stationary and the operating table and anesthesia team are arranged to facilitate easy access for the surgeon as well as smooth transport of the patient to the radiation field. All members of the surgical team and radiation team are present prior to incision to discuss the appropriate approach in each case, guided by the preoperative simulations. In the operating room, the breast tissue adjacent to the primary tumor or the wall of the biopsy cavity was injected with 3–5 mL of isosulfan blue dye (Lymphazurin, Hirsch Industries, Richmond, VA, USA). The area then was compressed for 3–7 min. The sentinel node was then identified by a combined blue dye and intraoperative gamma probe technique and the axillary incision closed. Intraoperative frozen section analysis of the sentinel node was performed at the discretion of the surgeon.


Figure 1
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  		FIG. 1. Mobetron unit prior to patient entry into the operating room.

 
After completion of LM/SL, a curvilinear incision is made in the standard fashion over the appropriate quadrant of the breast. The incision is long enough (approximately 6–7 cm) to ensure adequate exposure of the breast tissue and to allow for placement of the appropriate size radiation cone, as determined pre-operatively by the ultrasound measurements and dosimetric planning. Subcutaneous skin flaps are raised circumferential from the incision for approximately 2–3 cm. The skin edges are protected with moist gauze sponges and retracted from the radiation field using a circular retractor with metal hooks (Lonestar Retractor, Lonestar Medical Products, Houston, TX, USA). At this point a core biopsy of the tumor is obtained and saved for later tumor analysis as part of the correlative science portion of our protocol. The radiation cone is then locked into position so that the edge is just abutting the breast tissue, at the angle of approach pre-determined by ultrasound guidance (Fig. 2Go). In order to correspond to the ultrasound measurements, it is essential that the breast tissue not be excessively compressed or distorted by the cone, nor should there be an air gap. Bolus is typically not necessary, as the breast tissue overlying the tumor serves to provide the dose buildup region. The tumor as localized by the needle and pre-operative ultrasound is sited in the center of the radiation field. Care is taken to again ensure that skin edges are not within the radiation cone.


Figure 2
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  		FIG. 2. Radiation cone in place with skin retracted using the Lonestar retractor.

 
After the surgeon and radiation oncologist have placed and secured the cone, the patient is brought to the position underneath the Mobetron for the docking (Fig. 3Go). The docking of the Mobetron treatment head is performed by a medical physicist who lines up the treatment head to the cone applicator with the aid of a laser alignment system. The docking must be exact or the control system will generate an interlock, which will prevent the treatment console from delivering the dose. Once docked, the entire team exits the room. The pre-planned dose is delivered at a dose rate of 1,000 monitor units per minute. It typically takes about 1–2 min for the actual radiation delivery. The entire procedure adds 20–30 min to the case.


Figure 3
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  		FIG. 3. Mobetron unit docked to radiation cone.

 
Once the radiation phase of the procedure is complete, lumpectomy is performed in the standard fashion. A 1 cm margin is taken around the needle localized tumor and the specimen marked for orientation. The specimen is then sent to breast imaging for a specimen radiograph to ensure that the cancer is within the removed tissue. After confirmation of removal of the cancer, the limits of the resection are marked with titanium surgical clips (Liga, Ethicon Endosurgical, Cincinnati, OH, USA). The breast wound is closed in a standard fashion. The patient is discharged from the post-anesthesia care unit.

Post-operative treatment
If, on review of final pathology, the tumor is found to have features indicating that the patient is not a good candidate for APBI, additional therapy is recommended. These features are defined a priori, and patients are informed that the protocol requires additional therapy if specific histologic features are identified. For positive margins, re-excision to negative margins or mastectomy is performed. If an extensive intraductal component is present, the final tumor size is greater than 3 cm, or histology demonstrates infiltrating lobular carcinoma, standard whole breast radiotherapy is delivered if the patient desires breast conserving therapy. In this case, the IORT serves as the boost, and 46 Gy in 23 fractions is delivered to the breast using opposed tangential fields. Systemic therapy is recommended per standard of care, independent of local therapy.

Follow-up
Patients are evaluated 1 week and 3 months following surgery to assess acute toxicity, then evaluated every 3 months for the first 3 years, every 6 months for years 2–5, and annually thereafter for complications and recurrence. Mammograms are acquired of the treated side every 6 months for the first 2 years and annual thereafter, with annual screening mammogram of the contralateral side. Cosmesis is assessed every 6 months following treatment by both patient and physician questionnaires, using the RTOG breast toxicity scale. Photographs are taken every 6 months for objective evaluation of cosmesis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics
Twenty-three patients have been enrolled as of 31 December 2004. Accrual was initially slow, but currently is progressing at a rate of approximately 2–3 patients per month. The demographics and clinical disease characteristics of the patient population are shown in Table 1Go. The median age was 63, with a range from 55 to 82 years. The median follow-up is 6 months, with a range of 1–22 months. The median clinical tumor size as defined by ultrasound was 1.1 cm, with a range from 0.5 to 2.1 cm. The majority of patients had estrogen or progesterone receptor positive disease that did not over-express HER2.


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  		TABLE 1. Patient demographics
 
IORT Delivery
Five of 23 patients were enrolled but did not receive IORT. In one patient, IORT was not delivered due to a machine fault. In two patients, the tumor could not be conclusively located by ultrasound after initial biopsy, and therefore dosimetric planning could not be accomplished with confidence. In two additional patients the tumor was adjacent to the chest wall so that the radiation dose constraints to the lung could not be satisfied.

Radiotherapy parameters varied depending on the tumor and location. The typical cone size needed to cover the tumor width with a 1–2 cm margin was 5 or 6 cm. In the initial phase of the trial, there was a tendency to use smaller cone sizes. When thin-walled cones became available, we uniformly used a 2 cm margin, as the skin incision required to fit the larger cone was reduced with the thin-walled cones. The electron energy was selected to provide adequate depth dose to cover 1 cm deep to the posterior aspect of the tumor with the 90% isodose line while limiting the lung dose to less than 10 Gy. The distances from the skin to the posterior edge of the tumor and the pleural surface were measured by ultrasound performed the day of surgery, at the time of needle localization and sentinel lymph node dye injection. The average depth from the surface to the deepest point of the tumor was 1.9 cm, with a range from 0.9 to 2.9 cm. The average estimated distance as measured by ultrasound from the skin surface to the pleural surface was 3.9 cm, with a range from 2.9 to 4.7 cm. In all cases, 9 or 12 MeV electrons were used. The average maximum dose (Dmax) was 1,560 cGy, with a range from 1354 to 1850 cGy, to cover 1 cm deep to the posterior edge of the tumor with the 90% isodose line.

Additional Local Therapy
One disadvantage of treatment at the time of surgery is that the final tumor characteristics are not known, such as margin status, extent of DCIS, pathologic nodal and tumor stage. These factors are important in selecting appropriate candidates for partial breast treatment. We anticipated that approximately a quarter of patients who met the initial eligibility criteria based on clinical staging would ultimately have pathologic tumor characteristics indicating that whole breast radiotherapy should be added. Therefore, the protocol stipulates that patients who are found on final histologic examination to have an extensive intraductal component (EIC) of the tumor, involved lymph nodes, infiltrating lobular carcinoma, pure DCIS, or tumor size greater than 3 cm were to receive additional external beam radiotherapy to the whole breast. In this case, the external beam dose would be 46 in 2 Gy fractions, with the IORT serving as the tumor bed dose. Re-excision to 1 mm tumor-free surgical margins was required for patients with positive or close (<1 mm) surgical margins, but did not in itself obligate whole breast radiotherapy. Patients who were ultimately deemed not to be breast conserving therapy candidates were to undergo mastectomy. Finally, patients who were not candidates for partial breast radio-therapy based on final histologic tumor features were offered mastectomy in lieu of whole breast radio-therapy.

Table 2Go shows the final histologic assessment of disease and additional surgical, radiotherapy, and systemic therapy delivered, if any. Five of the first 18 patients received whole breast radiotherapy, and three received mastectomy. Thus, only 10/18 patients were treated with IORT partial breast radiotherapy. Two patients underwent a re-operative segmental mastectomy for tumor-involoved surgical margins. The reasons for receiving whole breast radiotherapy were as follows: extensive intraductal component (2), invasive lobular carcinoma (2), involved lymph nodes (1). Reasons for mastectomy included: unable to achieve negative margins with re-excision (2), and patient request in lieu of whole breast radiotherapy recommended for extensive intraductal component (1). The patient who had mastectomy due to primary tumor extent also had involved lymph nodes. Systemic therapy use was not stipulated by the protocol, but left to the discretion of the treating medical oncologist. No patients treated with IORT partial breast radiotherapy received systemic chemotherapy, but the majority received systemic endocrine therapy, reflecting the good prognostic features of the tumors eligible for treatment with partial breast radiotherapy per protocol. On the other hand, patients who were not ultimately found to be candidates for partial breast radiotherapy typically had indications for systemic chemotherapy due to poor prognostic features identified on final pathologic evaluation.


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  		TABLE 2. Histopathologic parameters and additional therapy
 
Toxicity and Cosmesis
Acute toxicity was evaluated in every patient 1 week and 3 months following RT. One patient developed post-surgical mastitis following treatment which resolved with a course of oral antibiotic therapy. No other patients suffered infection possibly related to the procedure. One patient had wound-healing delay after a second re-excision attempt to achieve clear margins. Her disease ultimately required mastectomy due to inability to achieve tumor-free surgical margins. No other patients had wound-healing complications. No patients developed skin erythema.

We hypothesized that cosmesis following IORT would be comparable to that following APBI using brachytherapy, and cosmesis is a primary endpoint of our study. Cosmesis was first evaluated 6 months following IORT and then every 6 months consecutively. The cosmesis evaluation included both physician and patient subjective grading, as well as patients’ satisfaction with the cosmetic outcome. Photographs were taken for objective evaluation. Table 3Go characterizes the results of the cosmetic assessments to date. Two patients’ cosmetic evaluations could not be performed due to mastectomy. Not unexpectedly, the cosmesis appears to be better in patients treated with IORT alone, compared to those who also received whole breast radiotherapy. Overall, most patients related a high degree of satisfaction with the outcome, and stated that, given the results, they would choose IORT again.


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  		TABLE 3. Cosmetic and patient satisfaction assessment
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Since the vast majority of in-breast recurrences occur in the lumpectomy bed, several approaches to partial breast irradiation (APBI) have emerged to treat only the portion of the breast harboring the index lesion.19–21 The rational for this approach is that with smaller treatment volumes, the treatment can be delivered over a significantly shorter period by using larger dose per fraction, without excess normal tissue toxicity. Options for APBI include interstitial catheter-based brachytherapy, endocavitary, brachytherapy, conformal three-dimensional radiation therapy and IORT.

With interstitial catheter-based brachytherapy, the hollow catheters can be placed across the lumpectomy bed either at the time of tumor excision or as a separate procedure. The radiation source is then loaded through the catheters, either in the outpatient setting with a high-dose-rate (HDR) 34 Gy delivered in ten twice-daily fractions, or using low dose rate sources over a course of several days. The most mature APBI experience uses this technique, with 5-year follow-up available from several single-institution experiences suggesting that interstitial brachytherapy APBI can achieve recurrence rates comparable to those seen with whole breast radiotherapy.17,26–30 A phase II multi-institutional trial was completed, and initial results confirm the general applicability of this approach.31

The endocavitary brachytherapy device (Mammo-Site, Proxima Therapeutics, Alpharetta, GA, USA) can also be placed in the lumpectomy cavity either at the time of tumor excision or as a separate procedure. The device has an inflation channel, which allows the radiologist to instill a contrast agent to verify position, and a treatment channel, which allows for delivery of the HDR radiation source. As with interstitial brachytherapy, treatment is typically delivered in 10 fractions over 5 days. The safety of the endocavitary brachytherapy device has been reported, however, long-term efficacy data is pending.32,33 The American Society of Breast Surgeons is conducting a MammoSite Registry Study (Beitsch, Principal Investigator, American Society of Breast Surgeons, Los Angeles, March 2005) for patients with T1, N0, M0 tumors and tumor-free surgical margins with a primary endpoint of disease-free survival.

Another approach to APBI is conformal external beam radiotherapy. Treatment is delivered using three-dimensionally defined fields targeting the tumor bed plus a margin of surrounding tissue. As with the brachytherapy techniques, treatment is typically delivered over the course of 1 week with twice-daily treatment. Several institutions have published their initial results, and a phase II trial run by the Radiation Therapy Oncology Group (RTOG) recently completed accrual.34,35 A newly-opened NSABP/ RTOG trial testing the efficacy of APBI versus standard whole breast radiotherapy will allow any of the above techniques for APBI delivery.

A non-randomized European trial23 testing APBI compared to receiving standard whole breast radio-therapy is already near completion of accrual goals. In this trial, the APBI is delivered by a single dose of IORT. Reports indicate that APBI via IORT is well tolerated to date. Two hundred thirty-seven patients with clinical T1, N0 breast cancers were treated with a quadrantectomy and axillary sentinel node procedure. Following the wide local excision of the breast tumor, IORT is delivered to the quadrantectomy bed. With a median follow-up of 19 months, 4 (1.7%) patients developed mild or severe post-treatment breast fibrosis. Furthermore, 3 (1.4%) patients have developed an ipsilateral breast cancer and 2 (1.0%) patients a contralateral breast cancer.23 With short-term follow-up, IORT appears to have an acceptable cosmetic result, but longer follow-up is necessary before conclusions regarding efficacy can be made.

While certainly very convenient for patients, delivery of the entire course of therapy in a single dose raises concerns regarding accuracy of the radiotherapy delivery, tumor control, and normal tissue toxicity. When IORT is delivered after the tumor has been excised and normal breast tissue re-approximated, it is theoretically more difficult to define the target volume, which must take into account not only distribution of residual tumor cells, but also invaginations of the margin tissue that has been re-approximated as well as surgically shed tumor cells. This uncertainty may be compensated by irradiating a wider margin of surrounding breast tissue. We elected to irradiate the tumor in situ in order to deliver treatment to an undisturbed tumor bed, using a smaller margin of surrounding breast tissue. Irradiating the tumor in situ allows us to define the target volume by pre-operative ultrasound, which allows us to select the appropriate cone size and electron energy, as well as the incision site and cone angle, for each tumor individually. However, a potential drawback to our approach is the smaller treatment volume. The optimal dose for IORT is not known. Veronesi et al found 21 Gy to be well tolerated after a dose escalation study. However, a single dose of 15 Gy is estimated to be biologically equivalent to standard dose and fractionation (25 treatments of 50 Gy) for breast cancer.36–39

The lower dose and smaller volume may result in better cosmesis, but it may also result in increased risk of local recurrence, an issue that we are studying. For this reason, we have carefully chosen criteria, including age, which must be satisfied for delivery of IORT as sole treatment; disease not meeting these restrictions requires additional external beam radio-therapy, per protocol. The full histopathologic features of the tumor are not known at the time of the procedure, therefore whole breast radiotherapy was added for pre-defined adverse histologic features. This was another reason for the lower IORT dose, as additional whole breast radiotherapy was well tolerated.

With short-term follow-up, the initial analysis of toxicity and feasibility of our in situ IORT indicates that the technique is well tolerated thus far. We have had two cases of acute toxicity in 18 patients, one whole breast mastitis and one delayed wound healing. In either case, it is not certain that IORT was related to the complication. To date, we have seen no grade 3 or 4 subcutaneous toxicity in the 20 patients with >90 day follow-up (the time at which toxicity is de-fined as non-acute by RTOG), or in the 10 patients with >6 month follow-up. Grade 3 or 4 subcutaneous toxicity, including fat necrosis, has been report in 4–27% in other series.23,30,40,41 In series where the time to development of fibrosis or fat necrosis is recorded, it appears that 12 months is sufficient to see significant alteration, with fat necrosis occurring around 6 months after interstitial brachytherapy treatment.30,41 It is interesting that some of our patients appear to have more fibrosis than others. While it appears that cosmetic outcome is worse in those receiving whole breast radiotherapy in addition to IORT, and it is possible that interpatient differences reflect variability in normal tissue response to radio-therapy, an intriguing question that we may be able to answer with our planned correlative studies.

In conclusion, this is the first reported use of in-traoperative radiotherapy delivered in the operating room to the primary breast cancer while the tumor is still in vivo. Technically, from a breast imaging, radiation oncology and surgical oncology standpoint, IORT is a feasible option for patients desiring BCT. The patients have high satisfaction scores and the early cosmetic results are good to excellent. A larger clinical trial and longer term follow-up of the patients is necessary to draw conclusions, but the early results are promising.


   ACKNOWLEDGMENTS
 
UNC Breast SPORE P50 CA58223, CIS K08 CA83753.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1993; 328(22):1587–91.[Abstract/Free Full Text]
  2. Clark RM, Whelan T, Levine M, et al. Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update. Ontario Clinical Oncology Group. J Natl Cancer Inst 1996; 88(22):1659–64.[Abstract/Free Full Text]
  3. Liljegren G, Holmberg L, Bergh J, et al. 10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial. J Clin Oncol 1999; 17(8):2326–33.[Abstract/Free Full Text]
  4. Fisher B, Anderson S, Redmond CK, et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995; 333(22):1456–61.[Abstract/Free Full Text]
  5. NIH consensus conference Treatment of early-stage breast cancer. JAMA 1991; 265(3):391–5.[Abstract/Free Full Text]
  6. The National Institutes of Health Consensus Development Conference adjuvant therapy for breast cancer. Bethesda, Maryland, USA, November 1–3, 2000. Proc J Natl Cancer Inst Monogr 2000; 30:1–152.
  7. Nattinger AB, Hoffmann RG, Kneusel RT, et al. Relation between appropriateness of primary therapy for early-stage breast carcinoma and increased use of breast-conserving surgery. Lancet 2000; 356(9236):1148–53.[CrossRef][Medline]
  8. Morrow M, White J, Moughan J, et al. Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol 2001; 19(8):2254–62.[Abstract/Free Full Text]
  9. Hillner BE, McDonald MK, Penberthy L, et al. Measuring standards of care for early breast cancer in an insured population. J Clin Oncol 1997; 15(4):1401–8.[Abstract]
  10. Hebert-Croteau N, Brisson J, Latreille J, et al. Compliance with consensus recommendations for the treatment of early stage breast carcinoma in elderly women. Cancer 1999; 85(5):1104–13.[CrossRef][Medline]
  11. Hebert-Croteau N, Brisson J, Latreille J, et al. Variations in the treatment of early-stage breast cancer in Quebec between 1988 and 1994. CMAJ 1999; 161(8):951–5.[Abstract/Free Full Text]
  12. Ballard-Barbash R, Potosky AL, Harlan LC, et al. Factors associated with surgical and radiation therapy for early stage breast cancer in older women. J Natl Cancer Inst 1996; 88(11):716–26.[Abstract/Free Full Text]
  13. Riley GF, Potosky AL, Klabunde CN, et al. Stage at diagnosis and treatment patterns among older women with breast cancer: an HMO and fee-for-service comparison. JAMA 1999; 281(8):720–6.[Abstract/Free Full Text]
  14. Potosky AL, Merrill RM, Riley GF, et al. Breast cancer survival and treatment in health maintenance organization and fee-for-service settings. J Natl Cancer Inst 1997; 89(22):1683–91.[Abstract/Free Full Text]
  15. Veronesi U, Marubini E, Mariani L, et al. Radiotherapy after breast-conserving surgery in small breast carcinoma: long-term results of a randomized trial. Ann Oncol 2001; 12(7):997–1003.[Abstract/Free Full Text]
  16. Clark RM, Wilkinson RH, Miceli PN, MacDonald WD. Breast cancer. Experiences with conservation therapy. Am J Clin Oncol 1987; 10(6):461–8.[Medline]
  17. Vicini F, Arthur D, Polgar C, Kuske R. Defining the efficacy of accelerated partial breast irradiation: the importance of proper patient selection, optimal quality assurance, and common sense. Int J Radiat Oncol Biol Phys 2003; 57(5):1210–3.[CrossRef][Medline]
  18. Smith TE, Lee D, Turner BC, et al. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys 2000; 48(5):1281–9.[CrossRef][Medline]
  19. Sarin R. Partial-breast treatment for early breast cancer: emergence of a new a paradigm. Nat Clin Prac Oncol 2005; 2(1):40–47.
  20. Pawlik TM, Buchholz TA, Kuerer HM. The biologic rationale for and emerging role of accelerated partial breast irradiation for breast cancer. J Am Coll Surg 2004; 199(3):479–92.[CrossRef][Medline]
  21. Wallner P, Arthur D, Bartelink H, et al. Workshop on partial breast irradiation: state of the art and the science, Bethesda, MD, December 8–10, 2002. J Natl Cancer Inst 2004; 96(3):175–84.[Abstract/Free Full Text]
  22. Orecchia R, Ciocca M, Lazzari R, et al. Intraoperative radiation therapy with electrons (ELIOT) in early-stage breast cancer. Breast 2003; 12(6):483–90.[CrossRef][Medline]
  23. Veronesi U, Gatti G, Luini A, et al. Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery. Arch Surg (Chicago, IL: 1960) 2003; 138(11):1253–6.[Abstract/Free Full Text]
  24. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276(22):1818–22; [see Comments].[Abstract/Free Full Text]
  25. Stitzenberg KB, Calvo BF, Iacocca MV, et al. Cytokeratin immunohistochemical validation of the sentinel node hypothesis in patients with breast cancer. Am J Clin Pathol 2002; 117(5):729–37.[Abstract/Free Full Text]
  26. King TA, Bolton JS, Kuske RR, et al. Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J Surg 2000; 180(4):299–304.[CrossRef][Medline]
  27. Kuske RR, Bolton JS, McKinnon WMP. 5-Year results of a prospective phase II trial of wide-volume brachytherapy as the sole method of breast irradiation in Tis, T1, T2, N0-1 breast cancer. Int J Radiat Oncol Biol Phys 1998; 42:181 [Abstract].
  28. Perera F, Engel J, Holliday R, et al. Local resection and brachytherapy confined to the lumpectomy site for early breast cancer: a Pilot Study. J Surg Oncol 1997; 65(4):263–7.[CrossRef][Medline]
  29. Baglan KL, Martinez AA, Frazier RC, et al. The use of high-dose-rate brachytherapy alone after lumpectomy in patients with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2001; 50(4):1003–11.[CrossRef][Medline]
  30. Arthur DW, Koo D, Zwicker RD, et al. Partial breast brachytherapy after lumpectomy: low-dose-rate and high-dose-rate experience. Int J Radiat Oncol Biol Phys 2003; 56(3):681–9.[CrossRef][Medline]
  31. Kuske RR, Winter K, Arthur DW, et al. A phase II trial of brachytherapy alone following lumpectomy for stage I or II breast cancer: initial outcomes of RTOG 9517. Proc J Clin Oncol 2004; 22(14S):S565 [Abstract].
  32. Edmundson GK, Vicini FA, Chen PY, et al. Dosimetric characteristics of the MammoSite RTS, a new breast brachytherapy applicator. Int J Radiat Oncol Biol Phys 2002; 52(4):1132–9.[CrossRef][Medline]
  33. Keisch M, Vicini F, Kuske RR, et al. Initial clinical experience with the MammoSite breast brachytherapy applicator in women with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2003; 55(2):289–93.[CrossRef][Medline]
  34. Vicini FA, Remouchamps V, Wallace M, et al. Ongoing clinical experience utilizing 3D conformal external beam radio-therapy to deliver partial-breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2003; 57(5):1247–53.[CrossRef][Medline]
  35. Formenti SC, Truong MT, Goldberg JD, et al. Prone accelerated partial breast irradiation after breast-conserving surgery: preliminary clinical results and dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2004; 60(2):493–504.[CrossRef][Medline]
  36. Thames HD Jr, Withers HR, Peters LJ, Fletcher GH. Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships. Int J Radiat Oncol Biol Phys 1982; 8(2):219–26.[Medline]
  37. Matthews JH, Meeker BE, Chapman JD. Response of human tumor cell lines in vitro to fractionated irradiation. Int J Radiat Oncol Biol Phys 1989; 16(1):133–8.[Medline]
  38. Williams MV, Denekamp J, Fowler JF. A review of alpha/beta ratios for experimental tumors: implications for clinical studies of altered fractionation. Int J Radiat Oncol Biol Phys 1985; 11(1):87–96.[Medline]
  39. Yamada Y, Ackerman I, Franssen E, et al. Does the dose fractionation schedule influence local control of adjuvant radiotherapy for early stage breast cancer? Int J Radiat Oncol Biol Phys 1999; 44(1):99–104.[CrossRef][Medline]
  40. Wazer DE, Lowther D, Boyle T, et al. Clinically evident fat necrosis in women treated with high-dose-rate brachytherapy alone for early-stage breast cancer. Int J Radiat Oncol Biol Phys 2001; 50(1):107–11.[CrossRef][Medline]
  41. King TA, Bolton JS, Kuske RR, et al. Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J Surg 2000; 180(4):299–304.[CrossRef][Medline]



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