Hypofractionated Regional Nodal Irradiation Clinical Trial for Women With Breast Cancer

The HeNRIetta Trial is a phase 2 non-randomized clinical trial to evaluate the safety and
effectiveness of hypofractionated RNI for women with resected node-positive breast cancer.
The study hypothesis is that a 3-4 week hypofractionated course of post-lumpectomy or
postmastectomy EBRT is as safe and effective as the biologically equivalent dose given in
conventional fractionation over 5-7 weeks.

Eligible patients are women ≥ 40 years old who have undergone definitive surgery for
node-positive breast cancer. Surgery may have been lumpectomy, mastectomy without
reconstruction, or mastectomy with reconstruction. Nodal staging may have been performed by
only sentinel lymph node (SLN) or by axillary lymph node (ALN) dissection. Patients may have
received neoadjuvant or adjuvant chemotherapy at the discretion of the treating medical
oncologist.

Breast and RNI will be administered to 42.56 Gy in 16 fractions. (RNI will exclude the axilla
in patients who have had an ALN dissection.) A treatment boost of 4 to 6 fractions of 2.66
Gy/fraction to the lumpectomy cavity will be included for all patients who have had
lumpectomy; a chestwall boost (4 to 6 fractions of 2.66 Gy/fraction) will be administered to
patients who had mastectomy (with or without reconstruction) and close (< 2 mm) surgical
margins. Total number of EBRT fractions will be 20 to 22 with a boost; 16 without a boost.

Bilateral measurements of arm circumference will be used to assess lymphedema by comparing
the ipsilateral arm to the contralateral arm. Patients will also be assessed for and will
complete questionnaires related to lymphedema, decreased arm function, breast and chestwall
pain, other EBRT-related toxicities, cosmetic outcome, and local, regional, and distant
breast cancer recurrence.

Inclusion Criteria:

- Karnofsky performance status of 70-100%

- Histologic documentation of invasive adenocarcinoma of the breast

- One of the breast disease stages listed below:

- Note: In the definitions below, definitive surgery is defined as the final
surgery performed to obtain clear surgical margins

- Neoadjuvant chemotherapy was not administered ** If neoadjuvant chemotherapy was
NOT administered, pathologic staging must be T1-3, N1-2a following definitive
surgery

- Neoadjuvant chemotherapy was administered

- If prior to initiation of neoadjuvant chemotherapy clinical staging was
T1-3, N0, pathologic staging must be T1-3, N1-2a following definitive
surgery

- If prior to initiation of neoadjuvant chemotherapy clinical staging was
T1-3, N1, pathologic staging must be T0-3, N0-2a following definitive
surgery

- If prior to initiation of neoadjuvant chemotherapy there was cytologic or
pathologic confirmation of axillary nodal involvement (per any of the
criteria listed below), pathologic staging must be T0-3, N0-2a following
definitive surgery

- Positive fine-needle aspiration (FNA) (ie, demonstrating malignant
cells)

- Positive core needle biopsy (ie, demonstrating invasive adenocarcinoma)

- Positive sentinel lymph node biopsy (ie, demonstrating invasive
adenocarcinoma)

- Complete resection of known breast disease by one of the following surgeries:

- Lumpectomy with sentinel lymph node or axillary lymph node dissection

- Mastectomy alone with sentinel lymph node or axillary lymph node dissection

- Mastectomy plus reconstruction with sentinel lymph node or axillary lymph node
dissection

- Margins of the resected specimen or re-excision specimen must be histologically free
of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the pathologist

* Notes: Additional operative procedures may be performed to obtain clear margins;
focally positive margins are acceptable based on technical feasibility of additional
surgery and/or the potential for benefit with further surgery based on the extent and
location of the positive margin (eg, focally positive deep margin at the pectoralis
fascia); also, patients with margins positive for lobular carcinoma in situ (LCIS) are
eligible without additional resection

- Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor
receptor 2 (HER2) testing performed on the primary breast tumor; when applicable,
testing must have been performed prior to neoadjuvant chemotherapy

- Interval between the last surgery for breast cancer (including re-excision of margins)
or the completion of adjuvant chemotherapy and study enrollment must be =< 56 days
(ie, a maximum of 8 weeks)

* Note: Radiotherapy must begin within 10 weeks following the last surgery for breast
cancer or the last dose of adjuvant chemotherapy

- Recovery from surgery with the incision completely healed and no signs of infection

- If adjuvant chemotherapy was administered, chemotherapy-related toxicity that may
interfere with delivery of external beam radiation therapy (EBRT) should have resolved

- Women who are not postmenopausal or have not undergone hysterectomy must have a
documented negative pregnancy test within 14 days prior to study registration

* Note: Postmenopausal is defined as one or more of the following:

- Age >= 60 years

- Age < 60 years and amenorrheic for at least 1 year with follicle-stimulating
hormone (FSH) and plasma estradiol levels in the postmenopausal range

- Bilateral oophorectomy

- Women of child-bearing potential (WCBP) must agree to use a medically accepted form of
pregnancy prevention for the duration of study treatment

- Ability to understand and willingness to sign the consent form written in English
pregnancy test within 14 days prior to study registration

* Note: Postmenopausal is defined as one or more of the following:

- Age >= 60 years

- Age < 60 years and amenorrheic for at least 1 year with follicle-stimulating
hormone (FSH) and plasma estradiol levels in the postmenopausal range

- Bilateral oophorectomy

- Women of child-bearing potential (WCBP) must agree to use a medically accepted form of
pregnancy prevention for the duration of study treatment

- Ability to understand and willingness to sign the consent form written in English

Exclusion Criteria:

- Known definitive clinical or radiologic evidence of metastatic disease

- T4 tumors including inflammatory breast cancer

- Clinical nodal staging of N2 or N3 disease

- Pathologic nodal staging of N2b, N2c, or N3 disease

- Microscopic positive margins after definitive surgery

* Note: Patients with microscopically focally positive margins following lumpectomy or
mastectomy are not excluded if re-excision is not technically feasible and/or there is
no benefit to further surgery based on the extent and location of the positive margin

- Any history, not including the index cancer, of ipsilateral or contralateral invasive
breast cancer or ipsilateral or contralateral DCIS treated with radiation therapy (RT)

* Note: Patients with synchronous or previous ipsilateral LCIS are eligible

- Any radiation therapy (RT) for the currently diagnosed breast cancer prior to study
enrollment

- History of ipsilateral or contralateral breast or thoracic RT for any condition

- History of ipsilateral or contralateral axillary surgery for any condition

- History of lymphedema involving the ipsilateral or contralateral arm at present or at
any time in the past

- Synchronous contralateral breast cancer requiring RT

- Overall geometry (eg, breast size if intact breast) precludes the ability to achieve
dosimetric requirements

* Note: Set-up devices for breast positioning are permitted

- Unresolved post-surgical complications (eg, significant infection) with healing
difficulties

- Active collagen vascular disease, specifically dermatomyositis with a creatine
phosphokinase (CPK) level above normal or with an active skin rash, systemic lupus
erythematosus, or scleroderma

- Pregnancy or breastfeeding

- Diagnosis or treatment for a non-breast malignancy within 5 years of study
registration, with the following exceptions: complete resection of basal cell
carcinoma or squamous cell carcinoma of the skin and any in situ malignancy after
curative therapy

- Medical, psychological, or social condition that, in the opinion of the investigator,
may increase the patient's risk or limit the patient's adherence with study
requirements