Clinical Trials /

Partial Irradiation and Sequential vs. Concurrent Chemo Early Breast Cancer

NCT01928589

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Partial Irradiation and Sequential vs. Concurrent Chemo Early Breast Cancer
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: J13104
  • NCT ID: NCT01928589

Conditions

  • Breast Cancer
  • Adenocarcinoma of the Breast

Purpose

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.

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
    

Trial Arms

NameTypeDescriptionInterventions
PBIActive Comparator270 cGy (centigray) x 15
    PBI with chemotherapyExperimental270 cGy (centigray) x 15 concurrent with chemotherapy of the treating medical oncologist's choice

      Eligibility Criteria

              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.
            
      Maximum Eligible Age:100 Years
      Minimum Eligible Age:18 Years
      Eligible Gender:Female
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Grade 3 or 4 short-term toxicity
      Time Frame:6-7 month follow-up
      Safety Issue:
      Description: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

      Measure:1st tumor recurrence
      Time Frame:6-7 months
      Safety Issue:
      Description:Evaluate and compare any first tumor recurrence (local plus distant) between arms of the study.
      Measure: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
      Safety Issue:
      Description:Evaluate long term toxicity with concurrent chemotherapy and compare between arms of the study.
      Measure: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
      Safety Issue:
      Description:Evaluate and compare Ipsilateral Breast Tumor Recurrence (IBTR), local recurrence, distant recurrence, and disease free survival.
      Measure: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
      Safety Issue:
      Description:Evaluate and compare quality of life.
      Measure: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
      Safety Issue:
      Description:Give a description of the risks and benefits observed in each arm of the study over the duration of the trial.

      Details

      Phase:Phase 1/Phase 2
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Richard Zellars

      Trial Keywords

      • Cyclophosphamide
      • Doxorubicin
      • Docetaxel
      • Carboplatin
      • Herceptin
      • Partial Breast Irradiation
      • Concurrent Chemotherapy

      Last Updated

      September 21, 2017