Partial Irradiation and Sequential vs. Concurrent Chemo Early Breast Cancer
Partial Irradiation and Sequential vs. Concurrent Chemo Early Breast Cancer
In a small study at Johns Hopkins, women were treated with partial breast irradiation and
 chemotherapy given at the same time.

 We are now testing in a bigger study whether giving partial breast irradiation and
 chemotherapy at the same time (our new method) has the same side effects and outcomes as
 giving partial breast irradiation and chemotherapy at different times(older method). In this
 study women who had their breast cancer removed but need radiation to the breast will be
 randomized to partial breast irradiation at the same time as chemotherapy or partial breast
 radiation at a different time than chemotherapy. Randomization is like flipping a coin but in
 this study about 2 of every 3 women will get the new method.
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 or positive 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
 withTrastuzamab (TCH) prior to registration; or Paclitaxel and Trastuzumab. 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 treatment and
 chemotherapy. 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.