A Study to Evaluate the Use of Supine MRI Images in Breast Conserving Surgery
Phase: NA
Conditions: Breast Cancer
Sponsor: Dartmouth-Hitchcock Medical Center

 
Version  5.6.14 
 
1
 
 
 
 
 
 
 
 
 
D0928  
 
A Study to Evaluate the Use of Supine MRI Images 
In Breast Conserving Surgery 
 
 
 
Principal Investigators: 
Richard J. Barth Jr., MD 
Keith D. Paulsen, PhD 
 
Co-investigators: 
Steve Poplack, MD 
Kari Rosenkranz, MD 
Burton Eisenberg, MD 
Tor Tosteson, PhD 
Wendy Wells, MD 
 
 
 
 
 
 
 
 
 
 
 
Breast Oncology Program 
Radiobiology and Bioengineering Research Program 
Norris Cotton Cancer Center 
 
 
 
 
 
 

 
Version  5.6.14 
 
2
 
SUMMARY 
 
 
 
Section 1.  INTRODUCTION 
 
Most women with breast cancer have their tumors detected by screening 
mammography or breast MRI, before the tumors become clinically palpable.  
Most of these women with small breast cancers will choose breast conserving 
surgery. The goal of breast conserving surgery is to completely resect the tumor 
with negative margins and simultaneously preserve the shape of the breast.  The 
standard technique for breast conserving surgery for patients with non-palpable 
breast cancer is to place a wire into the cancer pre-operatively (in Radiology 
under mammographic, ultrasound or MRI guidance) and then, in the Operating 
Room, to excise the tissue around the wire.  This technique, initially developed in 
the 1970’s, has several limitations.  It adds a separate procedure to the surgical 
resection, thereby complicating and lengthening the process.  Standard 
localization involves placement of one wire as close as possible to the clip left at 
the time of diagnostic core biopsy, or close to residual masses or calcifications.  
Mammographic images are then taken in two projections and the surgeon must 
then estimate the location of the cancer from these wire localization films.  In 
many cases this imprecisely localizes the cancer, resulting in positive margin 
rates from 30-50% (1,2).  Additional precision can be gained by placing additional 
wires, but this increases the length of time for the localization procedure (3).  
Wire localization is an inefficient and imprecise technique.  
 
Because of these limitations, efforts have been made to find alternatives 
to wire localization.  Intra-operative ultrasound has been evaluated and been 
shown to be superior to wire localization (4-6), but over half of mammographically 
visible invasive cancers and most ductal carcinoma in situ lesions are not visible 
on US.  Targeting the resection at the hematoma left from the initial core biopsy 

 
Version  5.6.14 
 
3
has had some success in early retrospective studies (7,8).  Neither of these 
techniques has been widely adopted. 
 
MRI of the breast has been shown by multiple studies to be more sensitive 
than mammography (9-12) for the detection of breast cancer.  Furthermore, 
several studies have demonstrated the ability of MRI to detect mammo-
graphically and clinically occult foci of cancer in the ipsilateral breast in 
approximately 25% of patients (9,13-15).  In many cases the local extent of the 
tumor is better defined by MRI, while in some cases additional foci of cancer are 
seen in other quadrants of the breast.  
While it seems intuitive that a surgeon would want to precisely know the 
extent of disease prior to lumpectomy, some argue that MRI is not justified 
unless it is shown to have a significant clinical impact, i.e., that MRI appropriately 
changes the surgical management, or that the positive margin rate is decreased, 
or that the local recurrence rate is less in patients who undergo pre-op MRI.  The 
retrospective studies described above did demonstrate that MRI resulted in a 
change in surgical management in 25% of patients (performing larger 
lumpectomies so as to try to completely resect the tumor or excising additional 
multicentric tumors in the breast).  These studies did not address whether the 
positive margin rate was decreased by the use of MRI.  This will be addressed in 
the Comparative effectiveness of MRI in breast cancer (COMICE) trial in Great 
Britain, where 1600 patients were randomized to receive MRI or no MRI prior to 
breast conserving therapy.  Two studies retrospectively evaluated whether the 
local recurrence rate in breast conservation patients undergoing MRI was lower 
than that seen in concurrent patients not receiving MRI.  These studies had 
conflicting results.  In one, 215 women who had MRIs had a LR rate of 3%, which 
was not significantly different than the rate of 4% in 541 women not undergoing 
MRI (16).  In contrast, Fischer found a lower rate of in breast recurrence in pts 
who had MRI (1% vs 7%) (17).  In summary, breast MRI has been shown to 
better define the local extent of the breast cancer than mammography and 
results in changes in surgical management, but has not yet been demonstrated 
to decrease the positive margin rate or the rate of local recurrence.  While it is 

 
Version  5.6.14 
 
4
being used as part of the initial diagnostic evaluation for patients newly 
diagnosed with breast cancer in many centers, and is reimbursed in NH and VT, 
it is not yet considered to be standard of care. 
 
A limitation of all of these MRI studies is that the MRI exams are 
performed with the patient prone and the breasts in a pendant position, which is 
markedly different than the position of the breast when the patient is supine on 
the Operating Room table.  The spatial information the surgeon receives from the 
prone MRI about the site of the tumor in the breast is hard to mentally translate 
into the actual site of the tumor in the breast of a supine patient prepared for 
surgery.  Of particular interest is a recent Japanese study that evaluated 
resections based on supine MRI in 24 patients with DCIS and compared them to 
28 patients who had prone MRI and wire localized resections (18).  The positive 
margin rate was lower in the supine MRI group (12% vs 39%, p=0.03) and the 
volume of breast tissue removed was less (27 vs 57 cm3, p=0.001).  In this study 
the supine MRI image was correlated to the position on the OR table by taking 
plain xrays in the OR and lining up a metallic button on the surface of the breast 
with a clip left at the time of biopsy. 
 
 
Section 2.  OBJECTIVES 
 
We propose to use a novel technique (optical scanning) to correlate the 
supine MRI image to the surgical position in the OR and then to confirm and 
extend the Japanese study described above.  In the first phase of the study, 5-25 
patients with palpable invasive breast cancer will undergo pre-operative supine 
MRI and optical scanning in the surgical position.  The purpose of this phase will 
be ensure that the images created from the optical scanner-adjusted supine MRI 
images closely correspond to the location of the palpable tumors in these 
breasts.  All patients will then have their tumor resected using the standard 
method of either palpation or image guided wire localization.  
 

 
Version  5.6.14 
 
5
In the second phase of the study, patients with non-palpable invasive 
breast cancer or DCIS who desire breast conservation will be randomized to 
either a usual care group, or a group receiving a supine MRI in addition to 
conventional imaging (mammogram and prone MRI) and undergoing breast 
cancer resection without the wire localization technique. 
 
The primary objective will be to determine whether the addition of supine MRI to 
conventional imaging with mammography and or sonography and prone MRI will 
result in a lower positive margin rate in patients undergoing breast conserving 
surgery. 
 
Our secondary objectives will be to determine: 
1. whether there are differences between the two groups in the volume of 
breast tissue removed. 
2. whether diagnostic information obtained from a supine MRI is equivalent 
to that obtained from the prone MRI. 
 
 
Section 3. ELIGIBILITY CRITERIA 
 
 
Inclusion Criteria Phase 1 
 
1. Age > 18 years 
2. Histologic diagnosis of palpable invasive breast cancer or ductal 
carcinoma in situ 
3. Patient desire to undergo breast surgery 
3. Patients will have provided informed consent to participate, documented 
by their signature on the study consent form 
4. The cancer enhances on breast MRI imaging. 
 
 
 

 
Version  5.6.14 
 
6
Inclusion Criteria Phase 2 
 
1. Age > 18 years 
2. Histologic diagnosis of invasive breast cancer or ductal carcinoma in situ 
3. The tumor is visible and enhances on prone MRI and is > 1 cm in greatest 
diameter. 
5. Determination by the surgeon that the neoplasm is non-palpable. A patient 
with a palpable hematoma from core biopsy, but a non-palpable 
neoplasm, will be eligible for study 
6. Patient desire to undergo breast conserving surgery 
7. Patients will have provided informed consent to participate, documented 
by their signature on the study consent form. The process of informed 
consent will be documented in the medical record and a copy of the 
signed consent form will be given to the patient. 
 
Exclusion Criteria (Phases 1 and 2) 
 
1. Absolute contraindication to MRI, including presence of implanted 
electrical device (pacemaker or neurostimulator), aneurysm clip or metallic 
foreign body in or near eyes 
2. Severe claustrophobia 
3. Contraindication to use of gadolinium based intravenous contrast, 
including life threatening allergy or compromised renal function (creatinine 
> 2.0) 
4. History of median sternotomy 
5. Pregnancy (Patient attestation that they are not pregnant will be 
acceptable, as per standard policy for MRIs at DHMC)  
6. Multicentric breast cancer, defined as two or more tumors in different 
quadrants of the breast. 
An eligibility worksheet will be completed for each patient prior to enrollment and 
will be signed and dated by the surgeon investigator. 

 
Version  5.6.14 
 
7
 
Section 4.  TREATMENT PLAN 
 
Phase 1   Patients with a percutaneous core biopsy demonstrating invasive 
carcinoma or ductal carcinoma in situ will undergo contrast enhanced bilateral 
breast MRI in the prone position, as is the current clinical standard at Dartmouth. 
At the time of surgical consultation, patients with palpable invasive breast cancer 
or DCIS who desire breast surgery will be invited to be a part of the study.  Prior 
to surgery these patients will undergo a contrast enhanced supine MRI and an  
optical scan.  The optical scan will be done with the patient in the surgical 
position.  This image will be used to adjust the MRI image obtained pre-
operatively into a highly accurate representation of the breast and the MRI-
defined tumor mass to correspond to the position of the patient at the time of 
surgery.  This image will be projected on a screen above one side of the patient’s 
head for easy viewing.  This image display will indicate the distances at a 
particular radian (measured in terms of clock hours and minutes) from the nipple 
to all aspects (cranial, caudal, medial, lateral) of the tumor.  The image display 
will also indicate the distances from the skin to the tumor and from the tumor to 
the chest wall.  Measurements of the distance from the nipple to these edges of 
the palpable tumor at specified, measured radians will also will be made by the 
surgeon and will be compared to the optical scanner adjusted supine MRI 
images.  
 
 
Phase 2.  
Patients with  histologic evidence of invasive carcinoma or ductal 
carcinoma in situ will undergo bilateral breast MRI in the prone position, as is the 
current standard at Dartmouth.  At the time of surgical consultation, patients with 
non-palpable breast cancers who desire breast conservation will be invited to be 
a part of the study.  Consenting patients will undergo randomization, stratified by 
DCIS vs invasive cancer and for invasive lobular cancer vs invasive ductal 
cancer.  Patients in Group W will undergo wire-localized partial mastectomy.  

 
Version  5.6.14 
 
8
Patients randomized to Group S will undergo a contrast enhanced supine MRI 
and optical scan, followed by partial mastectomy using the image guidance 
system we developed and verified in Phase I (19).  
 
Standard radiologic images (mammograms, ultrasounds, prone MRI 
images) will be available to the surgeon at the time of surgery for all patients.  
Patients in Group W, the usual care group, will undergo standard of care breast 
conserving surgery as practiced at our institution for non-palpable breast 
cancers. 
Patients in Group S will undergo a supine MRI at a convenient time within 
a week of surgery. They will have an optical scan of the breast surface while on 
the OR table on the day of surgery. Using the methods described and validated 
in Phase I, the scan data will be used to adjust (coregister) the supine MRI image 
volume obtained pre-operatively into a highly accurate representation of the 
breast and MRI defined tumor mass at the time of surgery. This coregistered 
image will be projected on a screen for easy viewing by the surgeon. A hand 
held, sterile stylus pointer will be tracked during surgery and will allow the 
surgeon to point to a specific location on the breast and see exactly where that 
point is on the screen image display. The image display will indicate the 
distances from the nipple to all aspects (cranial, caudal, medial, lateral) of the 
tumor, as well as the distances from the tumor to the skin and from the tumor to 
the chest wall. Guided by the coregistered image information the surgeon will 
mark on the surface of the breast the extent of resection. The sterile stylus probe 
may be used during the procedure to relate points in the surgical field to their 
corresponding location on the coregistered supine MRI image. The surgeon will 
resect the breast tumor volume that is identified by the image guidance system.  
The surgical specimens will be water displaced to determine their volume. 
The specimen will then be inked by the surgeon with 6 different colors to orient 
the specimen (black: deep, blue: superficial, green: caudal, orange: cranial, 
yellow: lateral and red: medial), and will undergo specimen mammography. 
Specimens will then be sent to Pathology.  Margins for invasive cancers will be 
considered positive if cancer cells are present at the edge.  Margins will be 

 
Version  5.6.14 
 
9
considered positive for DCIS if there are tumor cells < 1 mm from the edge.  The 
distance to the nearest margin will be determined in all cases. 
At the end of patient accrual, prone and supine MRIs from patients in 
Group S will be separately interpreted by two radiologists.  The cases will be 
divided in halves.  One radiologist will initially interpret half of the supine and half 
of the prone MRIs, the other will initially interpret the other half.  After a 6-week 
interval, each Radiologist will interpret the other half of the images.  Concerning 
lesions on each study will be identified, and then a comparison will be made 
between the supine and prone images to determine if lesions identified on the 
supine images are concordant with the number and size of lesions identified on 
the prone images. 
   
 
Section 5.  POTENTIAL TOXICITY 
 
Supine MRIs are administered according to standard-of-care practice for 
prone breast MRI and represent no more additional risk than would be 
experienced by women receiving these exams as part of their (non-research) 
breast care.  The risk of contrast enhanced MRI is very low, reflecting the minute 
risk of life threatening allergy and development of nephrogenic sclerosis related 
to gadolinium based intravenous contrast.  Patients deemed to be at higher risk 
for gadolinium induced nephrogenic sclerosis because of compromised renal 
function will not be eligible for participation.  Patients who experience a 
significant allergic reaction to gadolinium based intravenous contrast at the time 
of their clinical prone MRI will also be considered ineligible for study participation. 
 
Optical scans will be performed using a GO!Scan 3D optical scanner 
(Creaform, Levis, Quebec, Canada). This scanner will be able to scan the entire 
breast in 1 minute. It uses white light (LED) to form the image, like a flashlight. 
There are no anticipated risks associated with the use of this scanner.   
 
Section 6.  DRUG FORMULATION AND PREPARATION 
 
Not applicable. 

 
Version  5.6.14 
 
10
 
 
Sections 7 and 8.  Clinical ENDPOINTS AND STATISTICAL ANALYSIS 
 
 
The primary objective of the first phase will be to determine how closely 
the optical scan adjusted images of the tumor location correspond with the 
location as identified by intraoperative tumor palpation and measurement.  
Precise distances from the nipple to the superior, inferior, medial and lateral 
edges of the tumor will be taken from the adjusted MRI images and then marked 
on the patient’s skin.  The surgeon will then palpate the tumor and measure the 
distance between the palpable superior, inferior, medial and lateral tumor edges 
and the spots located by MRI. An adjusted image will be considered acceptable if 
all 4 image guided measurements are < 1 cm from the palpable tumor edge.  We 
will enroll at least 5 patients on this phase of the study.  We will move on to 
Phase II when 90% of the measurements in the previous 5 patients are 
acceptable, as defined above.  If by technical modifications we cannot meet 
these criteria for moving to phase II after 25 patients the protocol will be closed. 
The primary objective of the second phase is to determine whether the 
addition of supine MRI to conventional imaging with mammography and prone 
MRI will result in a lower positive margin rate in patients undergoing breast 
conserving surgery.  Following informed consent and enrollment, patients will be 
assigned to usual care or usual care plus supine MRI.  A permuted block 
randomization will be used within strata defined by DCIS and type of invasive 
cancer to achieve balance in treatment totals within strata.  The positive margin 
rate in the two groups will be computed and compared using a chi-squared 
statistic. 
Our senior breast Pathologist, Dr. Wendy Wells, has performed a detailed 
analysis of the surgical margins for patients who had a core biopsy which was 
positive for cancer or DCIS and then underwent partial mastectomy at Dartmouth 
in the year 2005.  A total of 125 patients with invasive ductal carcinoma were 
identified: 31 (25%) had positive margins.  Twenty six of 53 patients undergoing 
partial mastectomy for DCIS had positive margins (45%).  Overall, 57/178 

 
Version  5.6.14 
 
11
patients (32%) had positive margins.  A two-thirds decrease in the positive 
margin rate (i.e., from 32% to 11 percent or less) would be clinically meaningful. 
The primary analysis will consist of computing the positive margin rate observed 
in the two groups and comparing them with a chi-squared test.  Based on a chi-
squared test with a significance level of 0.05 and a power of 80%, a sample size 
of 69 patients will be required in each group.  
We will adopt a sequential testing procedure to assure that possible 
increases in the expected margin rate are detected.  After 10% of the patients 
are enrolled, or 7 in each group, an exact test for proportions will be applied.  If 
proportion of positive margins is greater than 32% and the p-value for the test is 
less than 0.004, the trial will be stopped as possibly increasing the rate.  This 
procedure maintains the significance level at 0.05 and the power at 80% using 
Pocock boundaries for the Lan and Demets alpha spending function.[20] 
Annually at Dartmouth we care for approximately 300 patients with 
invasive ductal cancer and 100 patients with DCIS.  Approximately ⅔ of these 
patients (266) will undergo breast conserving surgery.  Approximately ¾ of these 
patients will have non-palpable tumors (200).  We anticipate that it will be 
possible to accrue one third (67) of these patients per year.  Thus, we expect that 
it will take 2 years to complete accrual. 
Secondary endpoints will be analyzed as follows.  The mean specimen  
volume from Group S will be compared to the mean specimen volume from 
Group W using t - statistics.  The concordance between lesion volumes identified 
on the supine MRI images and the prone MRI images will be evaluated through 
correlation and regression analysis.  
Relevant data will be saved in Velos case report forms.  The NCCC Safety 
and Data Monitoring Committee will monitor this trial quarterly.  
 
Section 9.  HUMAN SUBJECTS 
 
 
The patients for this study will be accrued from the population treated at 
the Dartmouth-Hitchcock Medical Center.  All patients will sign an informed 

 
Version  5.6.14 
 
12
consent, which describes the treatment to be performed and discusses the risks 
and benefits of participation in the study. 
 
Risk/Benefit analysis:  
Risks associated with the experimental arm of this study include the risks 
of an additional MRI and all participants have potential confidentiality risks.  The 
risk of an additional MRI is negligible and reflects the minute risk of life 
threatening allergy and development of nephrogenic sclerosis related to 
gadolinium based intravenous contrast.  Patients deemed to be at higher risk for 
gadolinium induced nephrogenic sclerosis because of compromised renal 
function will not be eligible for participation.  Patients who experience a 
significant allergic reaction to gadolinium based intravenous contrast at the time 
of their clinical prone MRI will also be considered ineligible for study participation.  
Risk of breach of confidentiality of the medical records of participants will 
be minimized.  Subject identity is numerically coded and is not available to 
research investigators or otherwise stored on the databases maintained by the 
researchers to archive the clinical encounters accrued as part of the studies 
conducted under this protocol.  In this regard, all conventional clinical image data 
is de-identified prior to its use for analysis.  Databases which are used to store 
subject-sensitive information, even though completely de-identified as stored, are 
password-protected and encrypted during file/data transfers from viewing 
terminals.  As further safe-guard, the Data Safety Monitoring and Accrual 
Committee of the Norris Cotton Cancer Center will oversee the conduct of the 
trial. 
The potential benefits associated with the experimental arm of this study 
include lower positive margin rates, smaller excision volumes, and less 
discomfort since they will avoid the wire placement.  
The importance of the knowledge to be gained and the ultimate potential 
for benefit for future patients if this new technology is effective far outweighs the 
nominal risks experienced by the women who participate in this clinical study.  

 
Version  5.6.14 
 
13
Pregnant women will be excluded due to the potential risk of gadolinium to 
the fetus.  
Women with child-bearing potential are eligible for enrollment into the 
study.  The risks of participating in the imaging sessions for these women is no 
greater than for any other participant.  Risks associated with breast surgery vis-à-
vis child-bearing potential is outlined as part of standard of care.  Thus, any 
woman of child-bearing years enrolled in this protocol would already understand 
(and have accepted) the surgical risks to her fertility.  
Only women will be enrolled in the study because breast cancer is 
predominantly a female disease.  The imaging apparatus is design to 
accommodate the size and shape variations associated with the adult female 
breast.  While a very small proportion of breast cancer appears in males, the 
imaging systems are not designed to image the male breast.  All racial and ethnic 
categories will be recruited commensurate with the racial/ethnic composition of 
the DHMC patient catchment area. 
Patients will be considered “on study” and will be monitored for adverse 
events by the operating surgeon from the time of registration until 2 weeks after 
surgery.  
 
Section 10.  REFERENCES 
 
1. Kaufman CS, Delbecq R, Jacobson L.  Excising the reexcision: stereo-
tactic core-biopsy decreases the need for reexcision of breast cancer. 
World J Surg 1998; 22:1023-8. 
2. Cangiarella J, Groos J, Symmans W et al.  The incidence of positive 
margins with breast conserving therapy following mammotome biopsy for 
microcalcification. Surg Oncol 2000; 74:263-6. 
3. Kirstein L, Rafferty E, Specht M, et al.  Outcomes of multiple wire 
localization for larger breast cancers: when can mastectomy be avoided? 
J Am Coll Surg 2008; 207: 342-6. 

 
Version  5.6.14 
 
14
4. Harlow S, Krag D, Ames S, et al.  Intraoperative US localization to guide 
surgical excision of non-palpable breast carcinoma. J Am Coll Surg 1999; 
189:241-6. 
5. Rahusen F, Bremers A, Fabry H et al.  US guided lumpectomy of non-
palpable breast cancer vs wire-guided resection: a randomized clinical 
trial. Ann Surg Oncol 2002; 9: 994-8. 
6. Kaufman C, Jacobson L, Bachman B et al.  Intraoperative US facilitates 
surgery for early breast cancer. Ann Surg Oncol 2002; 9: 988-93. 
7. Rahman R, Crawford S, Larkin A.  Superiority of sonographic hematoma 
guided resection of mammogram only visible breast cancer: wire 
localization should be an exception- not the rule. Ann Surg Oncol 2007; 
14: 2228-32. 
8. Smith L, Henry-Tillman R, Harmes S et al.  Hematoma directed and 
ultrasound guided breast biopsy. Ann Surg 2001; 233:669-75. 
9. Berg W, Gutierrez L, NessAiver M, et al.  Diagnostic accuracy of 
mammography, clinical examination, US and MR imaging in preoperative 
assessment of breast cancer. Radiology 2004; 233: 830-49. 
10. Kriege M, Brekelmans CT, Boetes C, et al.  Efficacy of MRI and 
mammography for breast-cancer screening in women with a familial or 
genetic predisposition.  N Engl J Med 2004; 351:427-437. 
11. Leach MO, Boggis CR, Dixon AK, et al.  Screening with magnetic 
resonance imaging and mammography of a UK population at high familial 
risk of breast cancer: a prospective multicentre cohort study (MARIBS). 
Lancet 2005;365:1769–1778. 
12. Warner E, Plewes DB, Hill KA, et al.  Surveillance of BRCA1 and BRCA2 
mutation carriers with magnetic resonance imaging, ultrasound, 
mammography, and clinical breast examination. JAMA 2004;292:1317–
1325. 
13. Hwang E, Kinkel K, Esserman L, et al.  MRI in patients diagnosed with 
DCIS: value in the diagnosis of residual disease, occult invasion and 
multicentricity. Ann Surg Onc 2003; 10:381-88. 

 
Version  5.6.14 
 
15
14. Bedrosian I, Mick R, Orel S et al.  Changes in the surgical management of 
patients with breast carcinoma based on preoperative magnetic 
resonance imaging. Cancer 2003; 98: 468-73. 
15. Schell A, Rosenkranz K, Lewis P.  Role of breast MRI in the preoperative 
evaluation of patients with newly diagnosed breast cancer.  AJR Am J 
Roentgenol. 2009 May;192(5):1438-44. 
16. Solin L, Orel S, Hwang W, et al.  Relationship of breast MRI to outcome 
after breast conservation treatment with radiation for women with early 
stage invasive breast carcinoma or DCIS. J Clin Onc 2008; 26: 386-91. 
17. Fischer U, Zachariae O, Baum F et al.  The influence of preoperative MRI 
of the breasts on recurrence rate in patients with breast cancer. Eur Radiol 
2004; 14:1725-31. 
18. Sakakibara M, Nagashima T, Sangai T et al. Breast conserving surgery 
using projection and reproduction techniques of surgical position breast 
MRI in patients with DCIS. J Am Coll Surg 2008; 27:62-8. 
19. Pallone M, Poplack S, Avutu H, Paulsen K, Barth R. Supine breast MRI 
and 3D optical scanning: a novel approach to improve tumor localization 
for breast conserving surgery. Ann Surg Onc 2014, in press.  
20. Reboussin, D M, DeMets, D L, Kim, K M, and Lan, K K G.  Computations 
for group sequential boundaries using the Lan-DeMets spending function 
method. Controlled Clinical Trials 2000, 21:190-207