Partial Irradiation and Sequential vs. Concurrent Chemo Early Breast Cancer (PBI 3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01928589
Recruitment Status : Recruiting
First Posted : August 26, 2013
Last Update Posted : September 25, 2017
Information provided by (Responsible Party):
Richard Zellars, Indiana University School of Medicine

Brief Summary:

Women with ER negative breast cancer have a higher risk of the cancer returning in the breast after whole or partial breast radiation than women with ER positive breast cancer. In a small study at Johns Hopkins, women were treated with partial breast irradiation and chemotherapy given at the same time. This combined treatment was safe and women with ER negative breast cancer did just as well as women with ER positive cancer.

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Adenocarcinoma of the Breast Radiation: PBI Other: PBI with chemotherapy Phase 1 Phase 2

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Detailed Description:

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized trial of PBI with concurrent or sequential chemotherapy
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II Study of Partial Breast Irradiation and Sequential vs. Concurrent Chemotherapy in Women With Early Stage Breast Cancer (PBI 3.0)
Study Start Date : September 2013
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: PBI
270 cGy (centigray) x 15
Radiation: PBI
270 cGy x15
Other Name: partial breast irradiation

Experimental: PBI with chemotherapy
270 cGy (centigray) x 15 concurrent with chemotherapy of the treating medical oncologist's choice
Other: PBI with chemotherapy
270 cGy x15 concurrent with chemotherapy of the treating medical oncologist's choice
Other Name: partial breast irradiation with chemotherapy

Primary Outcome Measures :
  1. Grade 3 or 4 short-term toxicity [ Time Frame: 6-7 month follow-up ]
    The primary endpoint will be short term (from baseline to the 6-7 month follow-up) grade 3 or 4 toxicity: confluent moist desquamation, pitting edema, ulceration, hemorrhage or necrosis. Our primary objective is to determine if chemotherapy and PBI can be given concurrently with short term toxicity comparable to standard of care, whole breast radiation (WBR) without chemotherapy, and not inferior to that of PBI plus chemotherapy given sequentially.

Secondary Outcome Measures :
  1. 1st tumor recurrence [ Time Frame: 6-7 months ]
    Evaluate and compare any first tumor recurrence (local plus distant) between arms of the study.

  2. Long-term grade 3-4 toxicities [ Time Frame: Q6-12M 12-18, 24-30, 36-42, 48-54, 60-66, 72-78, 84-90, 96-108, 120 ]
    Evaluate long term toxicity with concurrent chemotherapy and compare between arms of the study.

  3. Time to tumor recurrence [ Time Frame: Q6-12M 12-18, 24-30, 36-42, 48-54, 60-66, 72-78, 84-90, 96-108, 120 ]
    Evaluate and compare Ipsilateral Breast Tumor Recurrence (IBTR), local recurrence, distant recurrence, and disease free survival.

  4. Quality of Life assessment [ Time Frame: Q6-12M 12-18, 24-30, 36-42, 48-54, 60-66, 72-78, 84-90, 96-108, 120 ]
    Evaluate and compare quality of life.

  5. Quantify risks and benefits comparison for each arm [ Time Frame: Q6-12M 12-18, 24-30, 36-42, 48-54, 60-66, 72-78, 84-90, 96-108, 120 ]
    Give a description of the risks and benefits observed in each arm of the study over the duration of the trial.

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01928589

Contact: Jill Deluca 317-944-1189

United States, District of Columbia
Sibley Memorial Hospital Recruiting
Washington, D.C., District of Columbia, United States, 20016
Contact: Ruth Chamberlain    202-660-6420   
Principal Investigator: Victoria Croog, MD         
United States, Indiana
Indiana University Health Hospital Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Jill Deluca    317-944-1189   
Principal Investigator: Richard Zellars, MD         
Indiana University Health Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Jill Deluca    317-944-1189   
Principal Investigator: Richard Zellars, MD         
United States, Maryland
Suburban Hospital Recruiting
Bethesda, Maryland, United States, 20814
Contact: Julie Ambrozak, RN    301-896-2016   
Principal Investigator: Susan Stinson, MD         
United States, Pennsylvania
Reading Hospital Recruiting
West Reading, Pennsylvania, United States, 19611
Contact: Leah Ernst    484-628-8194   
Principal Investigator: Michael Haas, MD         
York Cancer Center Recruiting
York, Pennsylvania, United States, 17403
Contact: Debi Oxenberg, RN    717-741-8124   
Principal Investigator: Amit Shah, MD         
Sponsors and Collaborators
Richard Zellars
Principal Investigator: Richard Zellars, MD Indiana University School of Medicine, Indiana University Simon Cancer Center

Responsible Party: Richard Zellars, Professor and Chairman of the Department of Radiation Oncology, Indiana University School of Medicine Identifier: NCT01928589     History of Changes
Other Study ID Numbers: J13104
First Posted: August 26, 2013    Key Record Dates
Last Update Posted: September 25, 2017
Last Verified: September 2017

Keywords provided by Richard Zellars, Indiana University School of Medicine:
Partial Breast Irradiation
Concurrent Chemotherapy

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type