Partial Irradiation and Sequential vs. Concurrent Chemo Early Breast Cancer (PBI 3)
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|ClinicalTrials.gov Identifier: NCT01928589|
Recruitment Status : Recruiting
First Posted : August 26, 2013
Last Update Posted : September 25, 2017
|First Submitted Date ICMJE||August 21, 2013|
|First Posted Date ICMJE||August 26, 2013|
|Last Update Posted Date||September 25, 2017|
|Start Date ICMJE||September 2013|
|Estimated Primary Completion Date||September 2019 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||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.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01928589 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Partial Irradiation and Sequential vs. Concurrent Chemo Early Breast Cancer|
|Official Title ICMJE||Randomized Phase II Study of Partial Breast Irradiation and Sequential vs. Concurrent Chemotherapy in Women With Early Stage Breast Cancer (PBI 3.0)|
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.
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 ICMJE||Interventional|
|Study Phase||Phase 1
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized trial of PBI with concurrent or sequential chemotherapyMasking: None (Open Label)
Primary Purpose: Treatment
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||108|
|Estimated Completion Date||September 2021|
|Estimated Primary Completion Date||September 2019 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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.
|Ages||18 Years to 100 Years (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01928589|
|Other Study ID Numbers ICMJE||J13104|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Richard Zellars, Indiana University School of Medicine|
|Study Sponsor ICMJE||Richard Zellars|
|Collaborators ICMJE||Not Provided|
|PRS Account||Indiana University|
|Verification Date||September 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP