Phase II Trial of Lumpectomy and Partial Breast Proton Therapy for Early Stage Breast Cancer
Phase: NA
Conditions: Early-Stage Breast Cancer
Sponsor: Loma Linda University

 
 
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Phase II Trial of Lumpectomy and Partial 
Breast Proton Therapy for Early Stage Breast 
Cancer 
 
 
 
 
 
NCT00614172 
 
 
 
 
 
April 8, 2008 

 
 
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OSR# 53294 
 
 
Radiation Medicine Proton Therapy 
 
RMPT  0301 
 
Phase II Trial of Lumpectomy and Partial Breast 
Proton Therapy for Early Stage Breast Cancer 
 
Loma Linda University Medical Center 
Department of Radiation Medicine 
 
 
 
 
 
Principal Investigators 
 
David Bush MD 
 
 
 
 
 
 
 
Jerry Slater MD 
 
 
 
Radiation Medicine  
 
Ryan Grover MD 
 
 
 
 
 
 
 
 
 
 
Clinical Physics 
 
 
Baldev Patyal PhD 
 
 
 
 
 
 
 
 
 
 
Surgical Oncology  
 
Sharon Lum MD 
 
 
 
Medical Oncology  
 
Hamid Mirshahidi MD 
 
 
 
Data Management  
 
Margie Lunt BSN, RN 
 
 
 
 
 
 
 
Radiation Medicine 
 
 
 
Revised April 8, 2008 
 
 
 
 

 
 
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Index 
 
 
 
Schema 
 
 
1.0 
Introduction 
 
2.0 
Objectives 
 
3.0 
Eligibility Criteria 
 
4.0 
Pretreatment Evaluation 
 
5.0 
Radiation Therapy 
 
6.0 
Surgical Therapy 
 
7.0 
Systemic Therapy 
 
8.0 
Patient Assessments 
 
9.0 
Statistics and Data Management 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Radiation Medicine Proton Therapy 
 
RMPT – 0301 
 
Phase II Trial of Lumpectomy and Partial Breast Proton 
Therapy for Early Stage Breast Cancer 
 
Schema 
 
Surgery 
 
 
     Proton Therapy 
         Systemic Therapy 
 
 
 
 
 
 
Eligibility (see section 3.0 for details) 
 
• Invasive ductal, medullary, papillary, colloid or tubular histologies or 
ductal carcinoma in-situ (DCIS) 
• Stages Tis, T1 or T2 (tumors < or = 3 cm) 
• Negative surgical margins (>2mm) 
• Negative sentinel node biopsy or three or fewer histologically involved 
axillary nodes on axillary node dissection. No extra-capsular extension 
• No previous chemotherapy for breast cancer 
• No collagen vascular disease 
• No prior malignancy except non-melanoma skin cancer (unless disease 
free > 5 years) 
• No patients who are pregnant or lactating 
 
Sample Size: 
50 patients 
 
 
 
 
 
 
Lumpectomy and axillary 
dissection or sentinel lymph 
node biopsy. 
Proton therapy to tumor bed. 
Dose = 40 CGE in 10 
fractions. 
Chemotherapy and/or 
hormonal therapy as 
needed per treating 
oncologist. 

 
 
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1.0  Introduction 
 
General 
 
 
Breast cancer is the most common site of cancer for women worldwide and has an 
enormous impact on the health of women. In the United States, approximately 210,000 
new cases of breast cancer are estimated in 2003. Each year, approximately 40,000 women 
die of the disease, making it the second leading cause of cancer death in women.1 
 
Rationale for Whole Breast Irradiation 
 
 
To date, there have been six large prospective randomized trials that have shown 
that the locoregional control and survival rates achieved with breast-conserving therapy are 
comparable to modified radical mastectomy in patients with early stage breast cancer.2-7  
The major advantages of breast conserving therapy are reduced emotional/psychological 
trauma and superior cosmetic outcome. The disadvantage is that this involves a more 
complex, prolonged treatment requiring 5-7 weeks of external beam radiation therapy. 
  
Rationale for Partial Breast Irradiation 
 
 
The rationale for whole breast irradiation following lumpectomy is to reduce the 
breast recurrence rate by eliminating residual foci of cancer in the tumor bed and to treat 
presumed occult multicentric disease in remote areas of the breast. However, the majority 
(67-100%) of ipsilateral breast recurrences after breast conservation therapy are in the 
same quadrant of the initial tumor.8-11 In fact, 80-90% of breast recurrences after breast 
conservation therapy occur in the immediate vicinity of the lumpectomy scar.10, 12  
Upon review of multiple randomized trials and retrospective studies comparing 
lumpectomy alone versus lumpectomy and whole breast irradiation, it is apparent that there 
is no difference in remote breast recurrence (<4%). 7,10,13,33 
NSABP B-06 analyzed 1851 patients with Stage I/II breast cancer randomized to 
total mastectomy, lumpectomy, or lumpectomy and whole breast irradiation. The breast 
recurrence rate in lumpectomy alone was 43% in contrast to a 10% breast failure rate for 
patients receiving lumpectomy and whole breast irradiation.13   The EORTC 22881/10882 
Trial analyzed 5318 Stage I/II breast cancer patients who underwent lumpectomy with 
negative margins and axillary lymph node dissection, followed by 50 Gy to the whole 
breast. They were randomized to receive no boost versus a 16 Gy tumor bed boost. Local 
recurrence was 7.3% vs. 4.3% at 5 years (no boost versus boost), a 41% reduction in local 
recurrence.14  Thus it appears that delivering additional treatment to the tumor bed 
significantly reduces the chance of local tumor recurrence. 
The next question that follows is if the whole breast irradiation can be eliminated 
altogether with delivery of a high dose of radiation limited only to the site at highest risk 
for recurrence. By confining treatment to a limited volume of breast tissue adjacent to the 
lumpectomy cavity, it may allow delivery of higher doses to high risk areas, potentially 
reducing acute and chronic toxicity, thus improving the quality of life in patients. In 
addition, the smaller target volumes may allow hypofractionated treatment schedules, 
which would decrease the time and inconvenience of breast conservation therapy, 

 
 
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eliminate scheduling problems with systemic chemotherapy, and potentially improve 
outcome by reducing delay to local therapy. 
 
Trials Investigating Partial Breast Irradiation 
 
Investigations of partial breast irradiation have, in fact, been performed, with 
excellent early results. Primarily Phase I, II and a few Phase III studies have been initiated 
using: high dose rate (HDR) brachytherapy, low dose rate (LDR) brachytherapy, external 
beam radiotherapy, and intra-operative radiotherapy.15-32 A hypofractionated treatment 
scheme has been used in all cases. Local recurrence rate has been <10% in all studies 
except two, which had poor selection criteria.25,26,29 When evaluated, cosmetic results have 
been rated Good/Excellent in >75% of the patients treated.  
Phase I, II and III studies conducted at the National Institute of Oncology in 
Hungary have some of the longest follow-up data to date. Forty-five patients with T1 
breast cancer were enrolled in the Phase I-II study and underwent lumpectomy followed by 
HDR brachytherapy 7 x 4.33 Gy or 7 x 5.2 Gy to the tumor bed. With a median follow-up 
of 57 months, the local recurrence rate was 4.4%. The 5-year probability of cancer-
specific, relapse-free and local recurrence-free survival was 90.0%, 85.9%, and 95.6%, 
respectively. The phase III study was subsequently performed with an additional 126 
patients randomized to receive 50 Gy WBRT or HDR brachytherapy 7 x 5.2 Gy to the 
tumor bed alone. With a median follow-up of 30 months, this study also confirms excellent 
locoregional tumor control of 100% in both arms. The 3-year probability of cancer-specific 
and relapse-free survival was essentially equivalent, 98.1% and 98.4% in the WBRT group 
and 100% and 94.4% in the HDR brachytherapy group.18  
Several institutions have been evaluating accelerated partial breast irradiation using 
3D conformal external beam radiotherapy.15,29,30 A concern of EBRT is that the breast is a 
moving target that may require larger volumes of normal breast tissue to be irradiated to 
avoid a geographic miss. William Beaumont Hospital has been studying this, with careful 
evaluation of breast motion using standard free-breathing virtual scans compared with CT 
scans obtained at the end of normal inhalation (NI) and exhalation (NE). They found that 5 
mm of margin was sufficient to fully account for breast motion, with minimal use of 
immobilization devices (alpha cradle). Sixteen patients were treated using a CTV of 1.5 cm 
plus 1 cm for breathing motion/set-up uncertainty. A dose of 34-38.5 Gy was delivered in 
10 fractions BID over 5 days using a 4-5 noncoplanar beam arrangement. With a median 
follow-up of 8 months, toxicity has been mild, consisting of mild fatigue, mild breast 
tenderness and mild to moderate erythema/dry desquamation.15 The RTOG also has a 
proposed Phase I/II protocol to evaluate 3D CRT confined to the lumpectomy site in Stage 
I/IIA breast carcinoma. 
 
 
 
 
 
 
 
 
 
Rationale for Partial Breast Irradiation with Protons 

 
 
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Proton therapy has several advantages over other forms of radiotherapy for performing 
partial breast irradiation.  Proton therapy would eliminate the additional surgical procedure 
required for brachytherapy. In addition, it is likely to improve dose homogeneity within the 
target volume, which may improve cosmetic results and reduce the risk of symptomatic fat 
necrosis associated with brachytherapy which has been reported to be as high as 40%. In 
comparison to three-dimensional conformal radiation therapy, the inherently superior depth 
dose characteristics (Bragg peak) would minimize the integral dose delivered to 
surrounding normal tissues, particularly the lung and heart. We anticipate that this will 
result in decreased toxicity and less risk of radiation induced malignancy.  
 
2.0  Objectives 
 
2.1 To evaluate the technical feasibility of delivering partial breast irradiation 
with proton beam. 
 
2.2 To evaluate the acute and long term toxicity associated with partial breast 
proton therapy. 
 
2.3 To evaluate the cosmetic results with partial breast proton therapy 
 
2.4 To determine the local tumor control and survival associated with partial 
breast proton therapy. 
 
3.0 Eligibility Criteria 
 
3.1  Histologic evidence of invasive carcinoma (except lobular carcinoma) or 
ductal carcinoma-in-situ. 
 
3.2  Primary tumor < or = 3 cm. 
 
3.3  AJCC stage 0, I, or II 
 
3.4  Patients with invasive carcinoma must have an axillary node dissection or 
sentinel lymph node biopsy. If the sentinel node is positive an axillary node 
dissection must be performed.  A minimum of 6 nodes must be pathologically 
reviewed.   No more then 3 nodes may contain metastatic carcinoma and there 
can be no evidence of extra-capsular extension.  Axillary staging is not 
required for DCIS. 
 
3.5  Surgical clips will be placed outlining margins of lumpectomy cavity. 
 

 
 
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3.6  Lumpectomy margins negative by at least 2 mm and/or negative reexcision 
 
3.7  No evidence of distant metastasis. 
 
 
3.8  No evidence of extensive intraductal component. 
 
3.9  No patients with multicentric ipsilateral carcinoma or contralateral carcinoma. 
 
3.10 No prior radiation therapy to the breast or chest wall. 
 
3.11 No prior malignancy except non-melanoma skin cancer unless disease free for 
> 5 years. 
 
3.12 No patients who are pregnant or lactating. 
 
3.13 No patients with history of collagen vascular disease. 
 
3.14 No prior chemotherapy for breast cancer 
 
4.0 Pretreatment Evaluation 
 
4.1  History and physical examination. 
 
4.2  Bilateral mammogram. 
 
4.3  Chest x-ray. 
 
4.4  CBC and serum chemistries with liver function tests. 
 
4.5  Bone scan if alk phos is elevated or if there are symptoms of bone metastasis 
 
4.6     Abdominal CT if liver function test are abnormal. 
 
4.7    Breast MRI (optional) 
 
 
 
 
 
5.0 Radiation Therapy 
 

 
 
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5.1  Radiation therapy will start within 4 weeks of surgical resection 
 
5.2  Immobilization and treatment planning CT scan of the chest. 
 
5.3  Treatment Planning 
 
 
 
5.3.1 
Outline tumor bed using surgical clips and clinical information 
 
5.3.2 
Add 1 cm in all directions to create clinical target volume (CTV) 
excluding chest wall and skin. 
 
 
5.3.3 
Create multi-field treatment plan with the 90% isodose covering  
 
  
the CTV while the skin surface receives no more then 70%. 
 
5.4  Dose, Fractionation and Treatment 
 
 
5.4.1 
40 CGE will be delivered to the CTV in 10 equal fractions over  ten 
treatments days. 
 
 
 
5.4.2 
At least 2 fields will be treated each day. 
 
 
5.4.3 
Orthogonal localization radiographs to be taken prior to each treatment 
with surgical clips used as localizing markers. 
 
6.0 Surgical Therapy 
 
6.1 
Excisional biopsy (lumpectomy) will be done per established surgical 
standards.  Surgical clips will be placed to outline the surgical cavity 
(i.e. deep, superior, inferior, right, left). 
 
6.2 
Axillary lymph node sampling or sentinal lymph node biopsy will be 
done per surgeon’s preference.   
 
7.0 Systemic Therapy 
 
7.1 
Chemotherapy and/or hormonal therapy may be given following the  
completion of proton therapy as recommended by the treating 
oncologist. 
 
8.0 Patient Assessments 
 

 
 
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8.1 
 
Study Parameters 
  
    
Assessment 
  
   Pre TX 
1 Mo Post TX 
 6 MO Post TX  
then every 6 months 
 
6 MO Post TX 
   then annually 
H & P 
  
X 
X 
X* 
 
Disease 
Status 
X 
X 
X* 
 
Toxicity 
Assessment 
X 
X 
X* 
 
Mammo 
  
X 
  
 
X 
CBC & 
LFT 
  
X 
As indicated 
As indicated 
As indicated 
Bone scan 
or CT scan 
  As 
  needed 
As indicated 
      As indicated 
  As indicated 
Photos 
X 
  
 
X 
Cosmesis 
Assess. 
(MD&Pt.) 
  
  
X 
X 
Chest X-ray 
  
X 
  
  
X 
 * Until year 5 at which time complete assessment will be conducted  
annually  
 
 
8.2 
Definitions for Cosmetic Outcomes 
 
Cosmetic outcome will be graded by the study subject, radiation 
oncologist, and surgical oncologist periodically following 
treatment according to section 8.1.  The grading scale will be as 
follows: 
Excellent – the treated breast, when compared to the untreated 
breast, shows minimal or no changes in shape or size.  There 
may be minimal subcutaneous fibrosis or scarring.  
 
Good – there are mild changes in the size and shape of the 
treated breast.  Scarring within the breast causes mild alterations 

 
 
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in breast shape. 
 
Fair – there is a clear difference in the size and/or shape of the 
treated breast that involves ¼ or less of the treated breast. 
 
Poor – marked changes in the treated breast that involves more 
then ¼ of the breast.  
 
8.3 
Photographs 
 
Photographs will be taken of the post-surgical breast and 
periodically following proton therapy per section 8.1.  These will 
be used to document cosmetic outcome.  Photos will include a 
“close up” view of the treated breast with the subjects arms 
raised over the head and a photo of both breasts with the subjects 
hands on hips.  Photographs will not include the subjects’ face. 
 
9.0 Statistics and Data Management 
 
9.1 
Initially 25 subjects will be enrolled into this trial.  After a  
toxicity evaluation is completed and felt to be acceptable, 25 
additional subjects will be enrolled for a total of 50 subjects. 
 
An additional 50 subjects will be enrolled under the new 
eligibility criteria defined in the April 4, 2008 revision.  
 
 
 
 
9.2 
All acute toxicities will be scored according to the NCI Common 
Toxicity Criteria v2.0.  Late toxicity will be scored per RTOG 
guidelines.  Any toxicities with a threshold of Grade 3 or above 
will be reported as an adverse event.  Frequencies of toxicities 
will be tabulated and compared to published reports. 
 
9.3 
Frequency and type of recurrence (local, regional, distant) will  
be tabulated and compared to prior studies. 
 
9.4 
Data Management and Publications 
 
Treatment records and study data will be collected, stored and 
maintained in the department of radiation medicine.  Data 

 
 
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analysis and publications will be performed under the direction 
of the study principal investigators.  All presentations, posters, 
abstracts and manuscripts that include data from this study will 
be reviewed and approved by the study PI’s prior to presentation 
or submission.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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