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

PRIMARY OBJECTIVES:

I. To compare the risk of developing lymphedema, defined as a 10% difference in volume
between the affected and unaffected arm, within 24 months of regional nodal irradiation (RNI)
between patients assigned to short versus standard RNI.

SECONDARY OBJECTIVES:

I. 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.

II. To compare maximal acute (within 6 weeks of treatment) and late (more than 6 weeks after
treatment) skin and soft tissue toxicities using the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) version (v)4.0 scale between patients
assigned to short versus standard RNI.

III. To compare patient-reported arm and shoulder function for the two treatment arms using
the 9-item Disabilities Arm Shoulder and Hand questionnaire (QuickDASH-9).

IV. To compare patient quality of life for the two treatment arms using EQ-5D-3L and the
Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue SF 6a.

V. To compare the peripheral blood cytokine profile at the end of radiation between patients
assigned to short versus standard RNI.

VI. To evaluate the effect of the peripheral blood cytokine profile at the end of radiation
on developing lymphedema.

VII. To evaluate the effect of homocysteine levels prior to radiation on developing
lymphedema.

VIII. To evaluate time to locoregional recurrence, time to distant metastasis, disease-free
survival and overall survival for patients assigned to short versus standard RNI.

IX. To evaluate the effect of lipid profiles prior to radiation on the time to locoregional
recurrence.

X. To evaluate if deoxyribonucleic acid (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.

XI. To evaluate changes in echocardiography global longitudinal strain measurements and
cardiac serum biomarkers, based on measurements performed before and after radiation therapy
(RT), in patients assigned to short versus standard RNI.

XII. In a separate cohort of 30 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.

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.

Inclusion Criteria:

- POSTOPERATIVE RADIATION THERAPY: Radiation oncologist recommends radiation treatment
to the supraclavicular and infraclavicular fossa (i.e. RNI)

- POSTOPERATIVE RADIATION THERAPY: 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

- POSTOPERATIVE RADIATION THERAPY: 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

- POSTOPERATIVE RADIATION THERAPY: Documentation of arm volume measurement by perometer
prior to axillary surgery

- POSTOPERATIVE RADIATION THERAPY: 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

- POSTOPERATIVE RADIATION THERAPY: Patients must be enrolled on the trial within 12
weeks of the later of two dates: the final breast cancer surgical procedure or
administration of the last cycle of cytotoxic chemotherapy

- PREOPERATIVE RADIATION THERAPY: Surgeon and radiation oncologist recommend
preoperative radiation therapy

- PREOPERATIVE RADIATION THERAPY: Pathologically-confirmed invasive breast cancer. The
clinical stage must be T0-T3, N0-N3a

- PREOPERATIVE RADIATION THERAPY: Planned treatment with mastectomy and axillary
evaluation (sentinel node evaluation, axillary sampling, or axillary lymph node
dissection)

- PREOPERATIVE RADIATION THERAPY: 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:

- Pathologic or clinical evidence for a stage T4 breast cancer

- 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

- Any prior diagnosis of invasive or ductal carcinoma in situ breast cancer in either
breast

- 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

- Patient is pregnant