BR01: Proton Therapy for Lymph Nodes in Breast Cancer

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT01365845
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arms: 2
• Actual Duration (Months): 73.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if proton radiation therapy will reduce the amount of heart that is exposed to radiation, thereby decreasing the frequency and/or severity of any cardiac side effects.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Radiation: Photon; Radiation: 3D-Proton/Conventional plan or 3D-proton only	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Proton Therapy for Peripheral Lymph Nodes in Breast Cancer
• Actual Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: May 23, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Conventional photon plan	Radiation: Photon; 50.4 Gy to the breast/chest wall and peripheral lymph nodes at 1.8 Gy per fraction
Experimental: 2 3D-Proton/Conventional plan or 3D-proton only	Radiation: 3D-Proton/Conventional plan or 3D-proton only; 50.4 Cobalt Gray Equivalent/Gray to the breast/chest wall and peripheral lymph nodes at 1.8 Cobalt Gray Equivalent/Gray per fraction

Outcome Measures

Primary Outcome Measures

1. Volume of Heart Receiving ≥ 5 Gray (Gy)/Cobalt Gray Equivalent (CGE) [2 weeks prior to starting radiation therapy.]

   A reduction of 50% in heart volume exposed to radiation doses ≥ 5 Gy/CGE was considered preferred outcome in this study plan.

Secondary Outcome Measures

1. Secondary Dosimetric Endpoint [2 weeks prior to starting radiation therapy.]

   Assess improvements in other dosimetry endpoints including lung dose (mean lung dose, V20, V5), heart dose (mean heart, V20, V5), mean dose to the thyroid, mean esophageal dose, D95 coverage for axillary, supraclavicular and internal mammary nodes, maximal spinal cord dose (Dmax) and skin Dmax.

2. Assessment of Acute Side Effects [Participants will be assessed weekly during radiation therapy for an expected average of 7 weeks.]

   Assess acute toxicities including pericarditis, pneumonitis, dermatitis, fatigue, and nausea.

3. Assessment of Longterm Side Effects and Disease Specific End Points. [1 month following completion of treatment, then every 6 months for 5 years, then annually thereafter.]

   Assess late toxicities including clinical and sub-clinical heart disease, pulmonary fibrosis, soft tissue fibrosis, rib fracture, and secondary malignancies. Analyze local control, progression-free survival, and overall survival.

4. Assessment of Cardiac Function Markers [after treatment]

   Assess levels of cardiac function markers Troponin and Brain Naturietic Peptide before and after treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pathologically confirmed invasive adenocarcinoma of the breast stage I-III (TX, T0-4, N0-3) with medially located tumor and/or axillary node invasion.

• Patients must have undergone either mastectomy or breast conservation surgery.

• Patients are required to have axillary staging which can include sentinel node biopsy alone if sentinel node is negative.

• Patient must require peripheral lymph node radiation per physician discretion.

Exclusion Criteria:

• Evidence of distant metastasis (M1).

• Prior radiotherapy to the area of interest.

• Prior history of cardiovascular disease per physician discretion.

• Prior or concurrent cancer other than non-melanomatous skin cancer unless disease free for at least 5 years.

• Collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis or scleroderma.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida Proton Therapy Institute	Jacksonville	Florida	United States	32206

Sponsors and Collaborators

• University of Florida

Investigators

• Principal Investigator: Julie A Bradley, MD, University of Florida Proton Therapy Institute

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Florida Proton Therapy Institute website

Publications

• Arriagada R, Lê MG, Mouriesse H, Fontaine F, Dewar J, Rochard F, Spielmann M, Lacour J, Tubiana M, Sarrazin D. Long-term effect of internal mammary chain treatment. Results of a multivariate analysis of 1195 patients with operable breast cancer and positive axillary nodes. Radiother Oncol. 1988 Mar;11(3):213-22.
• Avisar E, Molina MA, Scarlata M, Moffat FL. Internal mammary sentinel node biopsy for breast cancer. Am J Surg. 2008 Oct;196(4):490-4. doi: 10.1016/j.amjsurg.2008.06.003. Epub 2008 Aug 23.
• Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 Dec 17;366(9503):2087-106. Review.
• Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, Peto R, Baum M, Fisher B, Host H, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994 Mar;12(3):447-53.
• Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005 Aug;6(8):557-65.
• Farrús B, Vidal-Sicart S, Velasco M, Zanón G, Fernández PL, Muñoz M, Santamaría G, Albanell J, Biete A. Incidence of internal mammary node metastases after a sentinel lymph node technique in breast cancer and its implication in the radiotherapy plan. Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):715-21.
• Freedman GM, Fowble BL, Nicolaou N, Sigurdson ER, Torosian MH, Boraas MC, Hoffman JP. Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist? Int J Radiat Oncol Biol Phys. 2000 Mar 1;46(4):805-14. Review.
• Heuts EM, van der Ent FW, von Meyenfeldt MF, Voogd AC. Internal mammary lymph drainage and sentinel node biopsy in breast cancer - A study on 1008 patients. Eur J Surg Oncol. 2009 Mar;35(3):252-7. doi: 10.1016/j.ejso.2008.06.1493. Epub 2008 Aug 5.
• Højris I, Overgaard M, Christensen JJ, Overgaard J. Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet. 1999 Oct 23;354(9188):1425-30.
• Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. doi: 10.3322/CA.2007.0010. Epub 2008 Feb 20.
• Kahán Z, Csenki M, Varga Z, Szil E, Cserháti A, Balogh A, Gyulai Z, Mándi Y, Boda K, Thurzó L. The risk of early and late lung sequelae after conformal radiotherapy in breast cancer patients. Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):673-81. Epub 2007 Mar 9.
• Kwa SL, Lebesque JV, Theuws JC, Marks LB, Munley MT, Bentel G, Oetzel D, Spahn U, Graham MV, Drzymala RE, Purdy JA, Lichter AS, Martel MK, Ten Haken RK. Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys. 1998 Aug 1;42(1):1-9.
• Lind PA, Marks LB, Hardenbergh PH, Clough R, Fan M, Hollis D, Hernando ML, Lucas D, Piepgrass A, Prosnitz LR. Technical factors associated with radiation pneumonitis after local +/- regional radiation therapy for breast cancer. Int J Radiat Oncol Biol Phys. 2002 Jan 1;52(1):137-43.
• Marks LB, Munley MT, Bentel GC, Zhou SM, Hollis D, Scarfone C, Sibley GS, Kong FM, Jirtle R, Jaszczak R, Coleman RE, Tapson V, Anscher M. Physical and biological predictors of changes in whole-lung function following thoracic irradiation. Int J Radiat Oncol Biol Phys. 1997 Oct 1;39(3):563-70.
• N. Xu, M. Ho, C.G. Morris, N.P. Mendenhall. Proton treatment of peripheral lymph nodes in breast cancer. Int J Radiat Oncol Biol Phys 2010; 78: S803.
• Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT, Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997 Oct 2;337(14):949-55.
• Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC, Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8.
• Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, Wilson KS, Knowling MA, Coppin CM, Paradis M, Coldman AJ, Olivotto IA. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997 Oct 2;337(14):956-62.
• TURNER-WARWICK RT. The lymphatics of the breast. Br J Surg. 1959 May;46:574-82.
• Veronesi U, Arnone P, Veronesi P, Galimberti V, Luini A, Rotmensz N, Botteri E, Ivaldi GB, Leonardi MC, Viale G, Sagona A, Paganelli G, Panzeri R, Orecchia R. The value of radiotherapy on metastatic internal mammary nodes in breast cancer. Results on a large series. Ann Oncol. 2008 Sep;19(9):1553-60. doi: 10.1093/annonc/mdn183. Epub 2008 May 7.
• Veronesi U, Marubini E, Mariani L, Valagussa P, Zucali R. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Eur J Cancer. 1999 Sep;35(9):1320-5.
• Wennberg B, Gagliardi G, Sundbom L, Svane G, Lind P. Early response of lung in breast cancer irradiation: radiologic density changes measured by CT and symptomatic radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1196-206.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT01365845
• Other Study ID Numbers: IRB201701740; UFPTI 1016-BR01
• First Posted: Jun 3, 2011
• Last Update Posted: Jun 29, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Florida: Proton Radiation; Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Arm/Group Title	Induction Phase	Conventional Photon Plan	3D-Proton/Conventional Plan or 3D-proton Only
Arm/Group Description	During this phase, each patient will have both a proton and conventional radiation plan performed. The superior plan in regard to minimizing dose to heart will be the plan actually chosen for treating the patient.	Conventional (photon): 50.4 Gray (Gy) to the breast/chest wall and peripheral lymph nodes at 1.8 Gy per fraction This number will automatically be equal to 0 during the 'induction phase' period and will only have a count in the 'treatment phase' period if a patient was actually assigned to this treatment.	3D-Proton/Conventional plan or 3D-proton only: 50.4 Cobalt Gray Equivalent (CGE)/Gray (Gy) to the breast/chest wall and peripheral lymph nodes at 1.8 CGE/Gy This number will automatically be equal to 0 during the 'induction phase' period and will only have a count in the 'treatment phase' period if a patient was actually assigned to this treatment.
Period Title: Induction Phase
STARTED	18	0	0
COMPLETED	18	0	0
NOT COMPLETED	0	0	0
Period Title: Induction Phase
STARTED	0	0	18
COMPLETED	0	0	18
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Breast Patients Planned With Both Proton & Conventional Plans
Arm/Group Description	Each patient is planned with both proton and conventional plans and the superior plan is chosen for treatment. Conventional plan: 50.4 Gy to the breast/chest wall and peripheral lymph nodes at 1.8 Gy per fraction Proton plan: 50.4 Cobalt Gray Equivalent/Gray to the breast/chest wall and peripheral lymph nodes at 1.8 Cobalt Gray Equivalent/Gray per fraction
Overall Participants	18
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	52
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 83.3%
>=65 years	3 16.7%
Sex: Female, Male (Count of Participants)
Female	18 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%

Outcome Measures

1. Primary Outcome

Title	Volume of Heart Receiving ≥ 5 Gray (Gy)/Cobalt Gray Equivalent (CGE)
Description	A reduction of 50% in heart volume exposed to radiation doses ≥ 5 Gy/CGE was considered preferred outcome in this study plan.
Time Frame	2 weeks prior to starting radiation therapy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Conventional Photon Plan	3D-Proton/Conventional Plan or 3D-proton Only
Arm/Group Description	Photon: 50.4 Gray (Gy) to the breast/chest wall and peripheral lymph nodes at 1.8 Gy per fraction	3D-Proton/Conventional plan or 3D-proton only: 50.4 Cobalt Gray Equivalent (CGE)/Gray (Gy) to the breast/chest wall and peripheral lymph nodes at 1.8 CGE/Gy per fraction
Measure Participants	18	18
Median (Full Range) [% of heart receiving >= 5 Gray (Gy)]	34.7	2.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Conventional Photon Plan, 3D-Proton/Conventional Plan or 3D-proton Only
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0078
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Non-parametric paired t-test (Wilcoxon)
	Estimated Value	29.1
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Secondary Dosimetric Endpoint
Description	Assess improvements in other dosimetry endpoints including lung dose (mean lung dose, V20, V5), heart dose (mean heart, V20, V5), mean dose to the thyroid, mean esophageal dose, D95 coverage for axillary, supraclavicular and internal mammary nodes, maximal spinal cord dose (Dmax) and skin Dmax.
Time Frame	2 weeks prior to starting radiation therapy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Assessment of Acute Side Effects
Description	Assess acute toxicities including pericarditis, pneumonitis, dermatitis, fatigue, and nausea.
Time Frame	Participants will be assessed weekly during radiation therapy for an expected average of 7 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Assessment of Longterm Side Effects and Disease Specific End Points.
Description	Assess late toxicities including clinical and sub-clinical heart disease, pulmonary fibrosis, soft tissue fibrosis, rib fracture, and secondary malignancies. Analyze local control, progression-free survival, and overall survival.
Time Frame	1 month following completion of treatment, then every 6 months for 5 years, then annually thereafter.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Assessment of Cardiac Function Markers
Description	Assess levels of cardiac function markers Troponin and Brain Naturietic Peptide before and after treatment.
Time Frame	after treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From start of radiation therapy to date of last follow-up.
Arm/Group Title	Breast Patients Planned With Both Proton & Conventional Plans
Arm/Group Description	All patients ultimately treated under the proton plan, so the denominator for all adverse events refers exclusively to the proton arm and not conventional. Each patient was planned with both proton and conventional plans and the superior plan was chosen for treatment. Conventional plan: 50.4 Gy to the breast/chest wall and peripheral lymph nodes at 1.8 Gy per fraction Proton plan: 50.4 Cobalt Gray Equivalent/Gray to the breast/chest wall and peripheral lymph nodes at 1.8 Cobalt Gray Equivalent/Gray per fraction
All Cause Mortality
	Breast Patients Planned With Both Proton & Conventional Plans
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Breast Patients Planned With Both Proton & Conventional Plans
	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)
Infections and infestations
Skin infection	2/18 (11.1%)	2
Injury, poisoning and procedural complications
Radiation dermatitis	4/18 (22.2%)	4
Other (Not Including Serious) Adverse Events
	Breast Patients Planned With Both Proton & Conventional Plans
	Affected / at Risk (%)	# Events
Total	11/18 (61.1%)
Gastrointestinal disorders
Esophagitis	5/18 (27.8%)	5
General disorders
Fatigue	7/18 (38.9%)	7
Nausea	1/18 (5.6%)	1
Infections and infestations
Wound infection	2/18 (11.1%)	2
Infection	1/18 (5.6%)	1
Reproductive system and breast disorders
Breast atrophy	1/18 (5.6%)	1
Breast pain	5/18 (27.8%)	5
Lymphedema	1/18 (5.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/18 (5.6%)	1
Pneumonitis	1/18 (5.6%)	1
Skin and subcutaneous tissue disorders
Hyperpigmentation	1/18 (5.6%)	1
Skin ulceration	1/18 (5.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.