Hypofractionated vs. Conventional Regional Nodal Radiation Therapy for Patients With Invasive Breast Cancer

• ClinicalTrials.gov Identifier: NCT02912312
• Recruitment Status: Recruiting
• First Posted: September 23, 2016
• Last Update Posted: January 20, 2023
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Study Description

Brief Summary:

To compare how often cancer recurs (comes back) after 3 weeks of radiation compared to 5 weeks of radiation in patients who receive radiation therapy delivered to the lymph nodes near the breast. The side effects that can develop during or after radiation treatment, including how often arm swelling (edema) happens, will also be studied.

Condition or disease	Intervention/treatment	Phase
Invasive Breast Carcinoma; Stage I Breast Cancer AJCC v7; Stage IA Breast Cancer AJCC v7; Stage IB Breast Cancer AJCC v7; Stage II Breast Cancer AJCC v6 and v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7	Radiation: Hypofractionated Radiation Therapy; Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Other: Questionnaire Administration; Radiation: Radiation Therapy	Phase 2

Detailed Description:

Primary Objective: To compare the risk of locoregional recurrence, defined as a cancer recurrence in the ipsilateral breast, chest wall, or regional lymph nodes (axillary levels I-III, supraclavicular, or internal mammary)

SECONDARY OBJECTIVES FOR BOTH COHORTS

1. To compare the maximum standardized difference in arm volume between the affected arm and the unaffected arm within 24 months after completion of RNI between the two treatment arms.
2. To compare maximal acute (within 6 weeks of treatment) and late (more than 6 weeks after treatment) skin and soft tissue toxicities using the NCI CTCAE v4.0 scale between patients assigned to short versus standard RNI.
3. To compare patient-reported arm and shoulder function for the two treatment arms using the QuickDASH-9.
4. To compare patient quality of life for the two treatment arms using EQ-5D-3L and PROMIS Fatigue SF 6a.
5. To compare the peripheral blood cytokine profile at the end of radiation between patients assigned to short versus standard RNI.
6. To evaluate the effect of the peripheral blood cytokine profile at the end of radiation on developing lymphedema. (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health)
7. To evaluate the effect of homocysteine levels prior to radiation on developing lymphedema. (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health)
8. To evaluate time to distant metastasis, disease-free survival and overall survival for patients assigned to short versus standard RNI.
9. To evaluate the effect of lipid profiles prior to radiation on acute toxicity, patient reported outcomes, and the time to locoregional recurrence. (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health)
10. To evaluate if DNA repair capacity contributes to the presence of acute radiation related toxicity and patient-reported quality of life decrements including fatigue and arm and shoulder symptoms. (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health)
11. To evaluate changes in echocardiography global longitudinal strain measurements and cardiac serum biomarkers, based on measurements performed before and after RT, in patients assigned to short versus standard RNI. (optional procedure for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health)
12. In a separate cohort of 50 patients who will receive RNI before surgery, to collect information on number of patients developing lymphedema within 24 months of RNI on reconstructive complications, and on patient reported quality of life, in those assigned to short versus standard RNI. Participating Cancer Network Sites, or Orlando Health, are not participating in this cohort.
13. To evaluate patient-reported financial burdens using the Economic Strain and Resilience in Cancer- Financial Well- Being instrument.
14. To determine whether radiation therapy induces de novo detectable clonal hematopoiesis mutations or alters the genetic landscape of existing clonal hematopoiesis mutations (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health).
15. To determine whether radiation therapy or chemotherapy among individuals with pre- and/or post-treatment clonal hematopoiesis mutations is associated with adverse treatment effects and worse oncologic outcomes (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo hypofractionated RNI in 15 fractions 5 consecutive days a week for 3 weeks.

ARM II: Patients undergo standard RNI in 25 fractions 5 consecutive days a week for 5 weeks.

In both arms, patients undergo additional boost dose of radiation therapy in 5 or 7 fractions on consecutive days following completion of RNI.

PATIENT EVALUATION: Patients participating in the trial will have their arm measured prior to radiation, during the final week of radiation and when they return for follow up visits. Patients will be checked for any arm swelling that may develop. Patients will also fill out questionnaires before treatment and when they return for follow up visits. Patients return 3 and 6 months after radiation, then every 6 months through two and a half years after radiation and then on a yearly basis until ten and a half years after finishing radiation. At some of the follow up visits, we measure arm volume and ask participants to complete questionnaires.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 985 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Shortening Adjuvant Photon Irradiation to Reduce Edema (SAPHIRE): A Randomized Trial of Hypofractionated Versus Conventionally Fractionated Regional Nodal Irradiation for Invasive Breast Cancer
• Actual Study Start Date: February 23, 2017
• Estimated Primary Completion Date: February 28, 2030
• Estimated Study Completion Date: February 28, 2031

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I: Hypofractionated Regional Nodal Irradiation (RNI); Patients undergo hypofractionated RNI in 15 fractions 5 consecutive days a week for 3 weeks. Patients also undergo additional boost dose of radiation therapy in 5 or 7 fractions on consecutive days following completion of RNI.	Radiation: Hypofractionated Radiation Therapy; Undergo hypofractionated RNI; Other Names: Hypofractionated Radiotherapy; hypofractionation; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies
Active Comparator: Arm II: Standard Regional Nodal Irradiation (RNI); Patients undergo standard RNI in 25 fractions 5 consecutive days a week for 5 weeks. Patients also undergo additional boost dose of radiation therapy in 5 or 7 fractions on consecutive days following completion of RNI.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies; Radiation: Radiation Therapy; Undergo standard RNI; Other Names: Cancer Radiotherapy; Irradiate; Irradiated; irradiation; Radiation; Radiotherapeutics; RADIOTHERAPY; RT; Therapy, Radiation

Outcome Measures

Primary Outcome Measures :

1. Lymphedema rate as assessed by perometry [ Time Frame: Up to 24 months ]
   Will compare between patients randomized to short versus standard regional nodal irradiation (RNI). Will use a two-sided chi-squared test with a significance level of 0.05.

Secondary Outcome Measures :

1. Volume of affected and unaffected arm as assessed by perometry [ Time Frame: Up to 126 months ]
   The Shapiro-Wilk test will be used to objectively assess the normality of the data and these findings will be visually confirmed by inspecting normal probability quantile-quantile plots. If the data are not normally distributed, a normalizing transformation before using t-test or a non-parametric method such as the Wilcoxon rank sum test to compare the standardized difference between the two arms at each time point may be used.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria, if receiving postoperative radiation therapy

• Radiation oncologist recommends radiation treatment to the supraclavicular and infraclavicular fossa (i.e. RNI).
• Pathologically-confirmed invasive breast cancer. If patients undergo upfront surgery, the pathologic stage must be T0-T3, N0-N2a or N3a. If patients receive neoadjuvant chemotherapy prior to surgery, the clinical stage must be T0-T3, N0-N2a or N3a. T4b disease is permitted if the patient undergoes breast conserving surgery.
• Treatment with mastectomy or segmental mastectomy and axillary evaluation (sentinel node evaluation, axillary sampling, or axillary lymph node dissection). If the patient has T0 disease, breast surgery is not required.
• Age 18 years or older.
• If enrolling on in the arm lymphedema assessment cohort, documentation of arm volume measurement by perometer prior to axillary surgery.
• If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to study registration, and the patient must have no evidence of disease for this prior non-breast cancer.
• Patients must be enrolled on the trial within 24 weeks of the later of two dates: the final breast cancer surgical procedure or administration of the last cycle of cytotoxic chemotherapy. If after trial enrollment it is determined the patient requires additional cytotoxic chemotherapy or additional breast cancer surgery prior to radiation therapy the patient may stay on trial but the patient must start radiation therapy within 24 weeks of the final breast cancer surgical procedure or administration of the last cycle of cytotoxic chemotherapy.

Inclusion Criteria, if receiving preoperative radiation therapy

• Surgeon and radiation oncologist recommend preoperative radiation therapy
• Radiation oncologist recommends radiation treatment to the supraclavicular and infraclavicular fossa (i.e. RNI).
• Pathologically-confirmed invasive breast cancer. The clinical stage must be T0-T3, N0-N3b
• Planned treatment with mastectomy and axillary evaluation (sentinel node evaluation, axillary sampling, or axillary lymph node dissection).
• Planned breast reconstruction with autologous reconstruction.
• Age 18 years or older.
• If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to study registration, and the patient must have no evidence of disease for this prior non-breast cancer.

Exclusion Criteria, if receiving postoperative radiation therapy

• Pathologic or clinical evidence for a stage T4 breast cancer. However, T4b disease is permitted if the patient undergoes breast conserving surgery.
• Pathologic or clinical evidence for a stage N2b, N3b, or N3c breast cancer (supraclavicular, or internal mammary lymph node involvement).
• Clinical or pathologic evidence for distant metastases.
• Current diagnosis of invasive breast cancer in the contralateral breast (ductal carcinoma in situ is permitted).
• Prior diagnosis of invasive breast cancer in the contralateral breast.
• If enrolling on in the arm lymphedema assessment cohort, current diagnosis of bilateral breast cancer.
• History of therapeutic irradiation to the breast, lower neck, mediastinum or other area in which there could potentially be overlap with the affected breast. Except those patients enrolled and treated on the PRECISE trial (MD Anderson 2017-0362).
• Patient is pregnant.
• Patients who are cognitively impaired. Subjects will undergo a brief physical exam including a brief exam to determine cognitive review.

Exclusion Criteria, if receiving preoperative radiation therapy

• Pathologic or clinical evidence for a stage T4 breast cancer.
• Pathologic or clinical evidence for a stage N3c breast cancer (supraclavicular lymph node involvement).
• Clinical or pathologic evidence for distant metastases.
• Current diagnosis of invasive breast cancer in the contralateral breast (ductal carcinoma in situ is permitted).
• Prior diagnosis of invasive breast cancer in the contralateral breast.
• History of therapeutic irradiation to the breast, lower neck, mediastinum or other area in which there could potentially be overlap with the affected breast. Except those patients enrolled and treated on the PRECISE trial (MD Anderson 2017-0362).
• Patient is pregnant.
• Patients who are cognitively impaired. Subjects will undergo a brief physical exam including a brief exam to determine cognitive review.

Contacts and Locations

Contacts

Contact: Karen Hoffman, MD; 713-563-2331; khoffman1@mdanderson.org

Locations

United States, Arizona

MD Anderson Cancer Center (Banner); Recruiting

Gilbert, Arizona, United States, 85234

Contact: Emily Grade, MD 480-256-6444 Emily.Grade@bannerhealth.com

Principal Investigator: Emily Grade, MD

United States, California

Scripps- MD Anderson Cancer; Recruiting

San Diego, California, United States, 92121

Contact: Ray Lin, MD 858-554-8788 lin.ray@scrippshealth.org

Principal Investigator: Ray Lin, MD

United States, Colorado

MD Anderson Cancer Center (Banner)- Northern Colorado; Recruiting

Greeley, Colorado, United States, 80631

Contact: Supriya Jain, MD 970-810-3894 supriya.jain@bannerhealth.com

Principal Investigator: Supriya Jain, MD

United States, Florida

Baptist - MD Anderson Cancer Center; Recruiting

Jacksonville, Florida, United States, 32207

Contact: Cynthia Anderson, MD 855-635-2667 cynthia.anderson@bmcjax.com

Principal Investigator: Cynthia Anderson, MD

Orlando Health Cancer Institute; Not yet recruiting

Orlando, Florida, United States, 32806

Contact: Cameron Swanick, MD 321-841-8650 Cameron.Swanick@orlandohealth.com

Principal Investigator: Cameron Swanick, MD

United States, Georgia

Piedmont Healthcare; Not yet recruiting

Atlanta, Georgia, United States, 30309

Contact: Adam Nowlan, MD 404-425-7900 adam.nowlan@piedmont.org

Principal Investigator: Adam Nowlan, MD

United States, Hawaii

The Queen's Medical Center; Not yet recruiting

Honolulu, Hawaii, United States, 96813

Contact: Stuart Tsuji, MD 808-691-4771 stsuji@queens.org

Principal Investigator: Stuart Tsuji, MD

United States, New Jersey

Cooper Hospital University Medical Center; Recruiting

Camden, New Jersey, United States, 08103

Contact: Stuti Ahlawat, MD 855-632-2667 ahlawat-stuti@CooperHealth.edu

Principal Investigator: Stuti Ahlawat, MD

United States, Ohio

Ohio Health; Recruiting

Columbus, Ohio, United States, 43215

Contact: Virginia Davolitsis, MD 614-566-1250 virginia.diavolitsis@ohiohealth.com

Principal Investigator: Virginia Davolitsis, MD

United States, Texas

M D Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Karen E. Hoffman, MD 713-563-2331

Principal Investigator: Karen E. Hoffman, MD

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Karen Hoffman, MD; M.D. Anderson Cancer Center

More Information

Additional Information:

MD Anderson Cancer Center 

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT02912312
• Other Study ID Numbers: 2016-0142; NCI-2016-01941 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2016-0142 ( Other Identifier: M D Anderson Cancer Center )
• First Posted: September 23, 2016
• Last Update Posted: January 20, 2023
• Last Verified: January 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:

Breast cancer; hypofractionation; radiation therapy; regional nodal irradiation

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases