Partial Irradiation and Sequential vs. Concurrent Chemo Early Breast Cancer

Breast conserving therapy (BCT) defined as lumpectomy and adjuvant whole breast irradiation
(WBI) is integral to the treatment of early stage breast cancer (ESBC). In these patients,
BCT provides equivalent survival to mastectomy. Despite equivalent survival, many patients
still choose mastectomy over the BCT in light of the 5-7 week commitment required for
radiation therapy (XRT). Partial breast irradiation, however, has provided women with ESBC an
alternative option for XRT. Worth noting, is PBI offers several advantages over WBI
including; decreased duration of XRT, and reduced radiation dose delivery to normal breast
tissue and surrounding organs.

Several large trials have advanced the adoption of PBI as a treatment option for women with
ESBC. Results of these trials unfortunately differ in regards to patient outcomes. Some
trials report no significant difference in the local failure rate (LFR) between
intraoperative radiation therapy, interstitial brachytherapy and standard WBI following
lumpectomy (Vaidya et al. Lancet 2010; Polgar et al. IJROBP 2004). While others, have
demonstrated similar outcomes for PBI and WBI only apply to a select group of patients. (Khan
et al. International Journal of Radiation Oncology *Biology *Physics (IJROBP) 2012;
Shaitelman et al. Cancer 2010; Stull et al. ASTRO 2012).

A growing body of evidence now suggests, that there is in fact a subgroup of patients for
which PBI may not be appropriate. In particular, patients with estrogen receptor (ER)
negative tumors have been observed to have higher LFR than patients with ER positive tumors.
Stull et al. reported a 3-year LFR of 2% and 12% in ER positive (n=149) and ER negative
(n=17) tumors, respectively (Stull et al. ASO 2012). Additionally, Shaitelman et al. reviewed
patients treated on the Mammosite registry and found the hazard ratio for local failure was
4.01 in women with ER negative compared to ER positive disease (n=991). (Shaitelman et al.
Cancer 2010)

To address the variation in patient outcomes for women treated with PBI, American Society for
Radiation Oncology (ASTRO) published a consensus statement grouping patients into "suitable,"
"cautionary," or "unsuitable" categories. These groupings sought to identify populations best
suited for PBI. Patients with ER negative breast cancer were assigned to either the
cautionary or unsuitable categories. Shah et al. published a pooled analysis (n=1978) that
found the only significant factor associated with ipsilateral breast recurrence (IBRT ) in
women who received PBI was ER status. (Shah et al. IJROBP 2012). Leonardi et al. reported
similar findings; local recurrence was 2.68 (p = 0.0003) more likely in ER negative (n=189)
than in ER positive (n=1608) breast cancers (Leonardi et al. IJROBP 2012). These results
suggest that perhaps, patients with ER negative disease are not the most appropriate patients
to be treated with PBI.

In addition to radiation therapy, patients are often treated with chemotherapy. Chemotherapy
has traditionally been administered either before or after PBI. There are potentially
significant benefits, however, that can be gained by the simultaneous administration of
chemotherapy and PBI. Administrations of radiation with concurrent chemotherapy soon after
surgery will not only shorten the overall duration of therapy, but has the potential to
capitalize on the synergy between the two treatment modalities and improve local control.
Reports of prohibitive toxicity with concurrent administration of anthracycline-based
chemotherapy with WBI have made this approach unpopular. The smaller fields employed during
PBI may provide an alternative option. PBI has the potential to reduce toxicity and
accelerate the radiation treatment schedule.

To date, we have been able to conduct two phase I trials of PBI and concurrent chemotherapy
(PBICC). In both trials we tested whether the toxicity remained prohibitive with this
combined treatment regimen. In the first trial, 25 patients were treated with PBI and
concurrent dose dense doxorubicin and cyclophosphamide. In the second trial, 34 patients were
treated similarly but selection of the chemotherapy regimen was at the discretion of the
treating medical oncologist. Results from both trials revealed that PBICC well appears to be
tolerated. Specifically, there was no grade 3 or 4 acute or late radiation induced toxicity
in either trial. Although these trials were not powered for local failure, one significant
finding from these trials was there were no local failures in the first trial (median follow
up 6 years), and only one failure (low grade DCIS) in the second trial (median follow up 2.5
years). Interestingly, there were no recurrences in the 21 patients with ER negative tumors
or the 17 patients with triple negative tumors.

Our center is the only center to have investigated and published phase I trials of PBICC.
Through these trials we have demonstrated preliminary information that PBICC is safe,
feasible, and effective treatment option for women with ESBC. Based on our unique experience,
we hypothesize that women with ER negative ESBC treated with PBICC will have local control
rates similar to women with ER positive disease. Additionally, we hypothesize that women
placed in the prone position will have an even more favorable toxicity profile than women
placed in the supine position for both PBI and WBI. To further substantiate the low toxicity
associated with PBICC and to test this our improved local control hypothesis, we will conduct
a randomized prospective trial of PBI with concurrent vs. sequential chemotherapy in women
with ER negative ESBC. Our primary endpoint is acute grade 3-4 radiation toxicity and our
secondary endpoints will be local control and breast specific quality of life

Inclusion Criteria Age ≥ 18 years. Patient must have histologically confirmed (by routine
H&E staining) invasive adenocarcinoma of the breast. Primary tumor ≤ 4cm and 0-3 positive
axillary lymph nodes (T1-2, N0-1, M0). Margin negative surgery. For subjects with two
breasts, they must have had a bilateral mammogram prior to surgery. Patient must have a
Medical Oncology consult with the recommendation of chemotherapy. Recommended regimens are
as follows: Cyclophosphamide and Doxorubicin (AC); Taxotere, Doxorubicin and
Cyclophosphamide (TAC); Taxotere and Cyclophosphamide (TC); or Taxotere, Carboplatin and
Trastuzamab (TCH) prior to registration. The use of additional chemotherapy, hormonal
therapy or Trastuzumab after the initial regimen is at the discretion of the Medical
Oncologist. Other primary regimens are possible but the PI must be notified prior to
enrollment. Partial breast irradiation must be scheduled to begin less than 71 days from
the last breast surgical procedure. ECOG performance status ≤ 1. Women of child-bearing
potential must have a negative (urine or blood) pregnancy test within 6 weeks prior to
start of protocol therapy. Women of childbearing potential must also use effective
non-hormonal contraception while undergoing radiation therapy. Ability to understand and
the willingness to sign a written informed consent document.

Exclusion Criteria Patients who have received neoadjuvant chemotherapy or neoadjuvant
hormonal therapy for the current cancer. Patients with squamous or sarcomas of the breast.
Patients who have active local-regional disease prior to registration. Patient has other
prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in
sity cervical cancer, or any other cancer from which the patient has been disease-free for
less than 5 years.

Patient is pregnant. Patient has a serious medical or physciatric illness which prevents
informed consent or adherence with treatment Study team (PI, Co-I, and or research nurse)
may deny enrollment if in the study team's opinion, the candidate may not be adherent to
the treatment protocol including scheduled follow-ups.