Laurie Kirstein

Hypofractionated Postmastectomy Radiation Therapy Is Safe and Effective: First Results From a Prospective Phase II Trial.

Purpose Conventionally fractionated postmastectomy radiation therapy (PMRT) takes approximately 5 to 6 weeks. Data supporting hypofractionated PMRT is limited. We prospectively evaluated a short course of hypofractionated PMRT, in which therapy was completed in 15 treatment days. Patients and Methods We delivered PMRT at a dose of 36.63 Gy in 11 fractions of 3.33 Gy over 11 days to the chest wall and the draining regional lymph nodes, followed by an optional mastectomy scar boost of four fractions of 3.33 Gy. Our primary end point was freedom from any grade 3 or higher toxicities. We incorporated early stopping criteria on the basis of predefined toxicity thresholds. Results We enrolled 69 women with stage II to IIIa breast cancer, of whom 67 were eligible for analysis. After a median follow-up of 32 months, there were no grade 3 toxicities. There were 29 reported grade 2 toxicities, with grade 2 skin toxicities being the most frequent (16 of 67; 24%). There were two patients with isolated ipsilateral chest wall tumor recurrences (2 of 67; crude rate, 3%). Three-year estimated local recurrence-free survival was 89.2% (95% CI, 0.748 to 0.956). The 3-year estimated distant recurrence-free survival was 90.3% (95% CI, 0.797 to 0.956). Forty-one patients had chest wall reconstructions; three had expanders removed for infection before radiation therapy. The total rate of implant loss or failure was 24% (9 of 38), and the unplanned surgical correction rate was 8% (3 of 38), for a total complication rate of 32%. Conclusion To our knowledge, our phase II prospective study offers one of the shortest courses of PMRT reported, delivered in 11 fractions to the chest wall and nodes and 15 fractions inclusive of a boost. We demonstrated low toxicity and high local control with this schedule. On the basis of our data, we have designed a cooperative group phase III prospective, randomized trial of conventional versus hypofractionated PMRT that will activate soon.

Short-Course Hypofractionated Radiation Therapy With Boost in Women With Stages 0 to IIIa Breast Cancer: A Phase 2 Trial

PURPOSE Conventionally fractionated whole-breast irradiation (WBI) with a boost takes approximately 6 to 7 weeks. We evaluated a short course of hypofractionated (HF), accelerated WBI in which therapy was completed in 3 weeks inclusive of a sequential boost. METHODS AND MATERIALS We delivered a whole-breast dose of 36.63 Gy in 11 fractions of 3.33 Gy over 11 days, followed by a lumpectomy bed boost in 4 fractions of 3.33 Gy delivered once daily for a total of 15 treatment days. Acute toxicities were scored using Common Terminology Criteria for Adverse Events version 4. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Cosmesis was scored using the Harvard Cosmesis Scale. Our primary endpoint was freedom from locoregional failure; we incorporated early stopping criteria based on predefined toxicity thresholds. Cosmesis was examined as a secondary endpoint. RESULTS We enrolled 83 women with stages 0 to IIIa breast cancer. After a median follow-up of 40 months, 2 cases of isolated ipsilateral breast tumor recurrence occurred (2 of 83; crude rate, 2.4%). Three-year estimated local recurrence-free survival was 95.9% (95% confidence interval [CI]: 87.8%-98.7%). The 3-year estimated distant recurrence-free survival was 97.3% (95% CI: 89.8%-99.3%). Three-year secondary malignancy-free survival was 94.3% (95% CI: 85.3%-97.8%). Twenty-nine patients (34%) had grade 2 acute toxicity, and 1 patient had a late grade 2 toxicity (fibrosis). One patient had acute grade 3 dermatitis, whereas 2 patients experienced grade 3 late skin toxicity. Ninety-four percent of evaluable patients had good or excellent cosmesis. CONCLUSIONS Our phase 2 institutional study offers one of the shortest courses of HF therapy, delivered in 15 fractions inclusive of a sequential boost. We demonstrated expected low toxicity and high local control rates with good to excellent cosmetic outcomes. This fractionation scheme is feasible and well tolerated and offers women WBI in a highly convenient schedule.

Attitudes and Decisional Conflict Regarding Breast Reconstruction Among Breast Cancer Patients.

Background: The decision to undergo breast reconstruction (BR) surgery after mastectomy is made during stressful circumstances. Many women do not feel well prepared to make this decision. Objective: Using the Ottawa Decision Support Framework, this study aims to describe women’s reasons to choose or not choose BR, BR knowledge, decisional preparedness, and decisional conflict about BR. Possible demographic, medical, BR knowledge, and attitudinal correlates of decisional conflict about BR were also evaluated. Methods: Participants were 55 women with early-stage breast cancer drawn from the baseline data of a pilot randomized trial evaluating the efficacy of a BR decision support aid for breast cancer patients considering BR. Results: The most highly ranked reasons to choose BR were the desire for breasts to be equal in size, the desire to wake up from surgery with a breast in place, and perceived bother of a scar with no breast. The most highly ranked reasons not to choose BR were related to the surgical risks and complications. Regression analyses indicated that decisional conflict was associated with higher number of reasons not to choose BR and lower levels of decisional preparedness. Conclusions: The results suggest that breast cancer patients considering BR may benefit from decisional support. Implications for Clinical Practice: Healthcare professionals may facilitate decision making by focusing on reasons for each patient’s uncertainty and unaddressed concerns. All patients, even those who have consulted with a plastic surgeon and remain uncertain about their decision, may benefit from decision support from a health professional.

Acceptability and pilot efficacy trial of a web‐based breast reconstruction decision support aid for women considering mastectomy

The study aim was to test the acceptability and preliminary efficacy of a novel interactive web‐based breast reconstruction decision support aid (BRAID) for newly diagnosed breast cancer patients considering mastectomy.

Tracking the dynamic seroma cavity using fiducial markers in patients treated with accelerated partial breast irradiation using 3D conformal radiotherapy

PURPOSE The purpose of the present study was to perform an analysis of the changes in the dynamic seroma cavity based on fiducial markers in early stage breast cancer patients treated with accelerated partial breast irradiation (APBI) using three-dimensional conformal external beam radiotherapy (3D-CRT). METHODS A prospective, single arm trial was designed to investigate the utility of gold fiducial markers in image guided APBI using 3D-CRT. At the time of lumpectomy, four to six suture-type gold fiducial markers were sutured to the walls of the cavity. Patients were treated with a fractionation scheme consisting of 15 fractions with a fractional dose of 333 cGy. Treatment design and planning followed NSABP∕RTOG B-39 guidelines. During radiation treatment, daily kV imaging was performed and the markers were localized and tracked. The change in distance between fiducial markers was analyzed based on the planning CT and daily kV images. RESULTS Thirty-four patients were simulated at an average of 28 days after surgery, and started the treatment on an average of 39 days after surgery. The average intermarker distance (AiMD) between fiducial markers was strongly correlated to seroma volume. The average reduction in AiMD was 19.1% (range 0.0%-41.4%) and 10.8% (range 0.0%-35.6%) for all the patients between simulation and completion of radiotherapy, and between simulation and beginning of radiotherapy, respectively. The change of AiMD fits an exponential function with a half-life of seroma shrinkage. The average half-life for seroma shrinkage was 15 days. After accounting for the reduction which started to occur after surgery through CT simulation and treatment, radiation was found to have minimal impact on the distance change over the treatment course. CONCLUSIONS Using the marker distance change as a surrogate for seroma volume, it appears that the seroma cavity experiences an exponential reduction in size. The change in seroma size has implications in the size of the CTV, PTV, and percent of normal breast tissue irradiated when using 3D-CRT.

Three-year outcomes of a once daily fractionation scheme for accelerated partial breast irradiation (APBI) using 3-D conformal radiotherapy (3D-CRT).

The aim of this study was to report 3‐year outcomes of toxicity, cosmesis, and local control using a once daily fractionation scheme (49.95 Gy in 3.33 Gy once daily fractions) for accelerated partial breast irradiation (APBI) using three‐dimensional conformal radiotherapy (3D‐CRT). Between July 2008 and August 2010, women aged ≥40 years with ductal carcinoma in situ or node‐negative invasive breast cancer ≤3 cm in diameter, treated with breast‐conserving surgery achieving negative margins, were accrued to a prospective study. Women were treated with APBI using 3–5 photon beams, delivering 49.95 Gy over 15 once daily fractions over 3 weeks. Patients were assessed for toxicities, cosmesis, and local control rates before APBI and at specified time points. Thirty‐four patients (mean age 60 years) with Tis 0 (n = 9) and T1N0 (n = 25) breast cancer were treated and followed up for an average of 39 months. Only 3% (1/34) patients experienced a grade 3 subcutaneous fibrosis and breast edema and 97% of the patients had good/excellent cosmetic outcome at 3 years. The 3‐year rate of ipsilateral breast tumor recurrence (IBTR) was 0% while the rate of contralateral breast events was 6%. The 3‐year disease‐free survival (DFS), overall survival (OS), and breast cancer‐specific survival (BCSS) was 94%, 100%, and 100%, respectively. Our novel accelerated partial breast fractionation scheme of 15 once daily fractions of 3.33 Gy (49.95 Gy total) is a remarkably well‐tolerated regimen of 3D‐CRT‐based APBI. A larger cohort of patients is needed to further ascertain the toxicity of this accelerated partial breast regimen.

Ultrashort Courses of Breast Radiotherapy

A review of current intraoperative and ultrashort radiotherapy schedules for the treatment of breast cancer is presented. Both the promise and the pitfalls of this strategy are reviewed.

Abstract P3-10-09: A Phase II trial of doxil, carboplatin and bevacizumab in metastatic triple negative breast cancer and molecular correlates of response

Background. Despite improved outcomes for other breast cancer subtypes, triple negative breast cancer continues to display the worst prognosis with conventional, standard of care chemotherapy. A growing body of evidence suggests that platinating agents may offer superior outcomes in a subset of triple negative breast cancers and that genomic alterations may identify those tumors most likely to respond. Patients and Methods. Eligibility included previously untreated, stage IV ER, PgR, and Her2neu negative breast cancer with measurable disease. Thirty-one patients with ECOG PS≤2 and adequate bone marrow, renal and hepatic function were enrolled to receive doxil (30 mg/m2), carboplatin (AUC 5) and bevacizumab (15 mg/m2) every 4 weeks in an open-label, multicenter, investigator-initiated Phase II trial from 2008-2012. The primary endpoint was median progression free survival (PFS). Secondary endpoints were response rate based on RECIST criteria, survival time, and toxicity profile. Results. Thirty-one patients received a median of 5.6 cycles (range 1-13). Prior adjuvant or neoadjuvant anthracycline or taxane was given in 38.7% or 41.9%, respectively. Clinical benefit rate (CBR= CR+PR+SD ≥ 6months) was 38.7% where 9/18 (50%) with CBR 6 months had prior taxane. Median progression free survival (PFS) was 5.6 months, 95% CI [4.4-6.9] and 6-month PFS rate was 41.9%, 95% CI [24.6-59.3]. Median overall survival was 11.9 months, 95% CI [8.8-21.8] and 1-year survival rate was 47.3%, 95% CI [29.5-65.1]. Thirteen patients were alive at 10 months or longer. Grade 3 non-hematologic and hematologic toxicities included fatigue (n=1), hand-foot skin reaction (n=1), and neutropenia (n=1). Grade 4 hematologic toxicity included thrombocytopenia (n=1). Grade 4 hypertension (n=2) and thrombosis (n=1) were attributable to bevacizumab and this drug was discontinued from the protocol. Neither significant change in cardiac function nor alopecia were observed. Next-generation sequencing from tumors revealed p53 alterations as the most common alteration. For three patients with serial pre- and post-platinum specimens, gain of genomic alterations were observed at time of progression of disease occurring at 5 months, 8 months, and 20 months (eight months of these were off study but receiving doxil and carboplatin). Conclusions. Results demonstrate that the combination of doxil, carboplatin, and bevacizumab is an active and well-tolerated regimen in previously untreated, metastatic, triple negative breast cancer. We anticipated presentation of additional genomic tumor profiling results that may yield insights into markers of sensitivity and mechanism of resistance to anthracycline and/or platinum. Citation Format: Kim M Hirshfield, Shou-En Lu, Serena Wong, Antoinette Tan, Laurie Kirstein, Thomas Kearney, Weichung Shih, Shridar Ganesan, Deborah L Toppmeyer. A Phase II trial of doxil, carboplatin and bevacizumab in metastatic triple negative breast cancer and molecular correlates of response [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-09.

Breast cancer: From radical to minimal surgery

On September 28, 1974 the Breast Cancer Taskforce at the National Cancer Institute debated about the appropriate treatment for breast cancer. The following day the Washington Post reported that the first lady, Mrs. Betty Ford, had undergone a radical mastectomy for a breast cancer that was found on routine physical exam. With the knowledge that breast cancer was the leading cause of death in women at the time, Mrs. Ford was outspoken about her cancer and her surgery in an era when breast cancer was not a topic of public conversation. The example set by Mrs. Ford influenced women nationwide and helped prompt a significant change in public attitude about breast cancer. Prior to Mrs. Ford’s going public with her disease, the diagnosis of breast cancer was greatly feared. Indeed, for centuries breast cancer was known for having a dismal outcome. This was largely due to the lack of understanding of the pathophysiology of the disease and how best to manage it. There are historical documents describing the earliest attempts at treatments for tumors of the breast. In ancient Egyptian culture, these included offering of the amputated breast at altars and burning the cancerous breast. In the middle ages it was believed that breast cancer resulted from an imbalance of bodily humors, and treatments attempted to restore this balance with purging and blood letting. Until the 1700s, surgical options for breast cancer were experimental, ranging from wide local excision to extreme surgery including removal of the chest wall. However, in the mid-1800s the understanding of the disease process began to change, as did the recommended treatments. The cellular theory of cancer began to evolve. The concept that breast cancer starts as a single cell that grows and then spreads through the breast, followed by the chest wall and lymph nodes led to the idea that amputation of these organs could cure some patients of the disease. Around the world surgeons were altering their approach to the disease based on this theory. In the 1870s the British surgeon Mr. Moore implored the importance of, ‘‘cutting out the tumor and the diseased axillary glands,’’ and touched upon the concept that inadequate surgery resulted poorer prognoses [1]. At the same time his British colleague Mr. Banks, and the German surgeon Dr. Kuster both recommended routine axillary dissection with breast surgery. In 1894 Dr. William Halsted published a landmark paper [2] describing the outcome of 50 patients who had undergone a radical amputation of the breast, pectoralis major and minor, and axillary contents, preserving the thoracodorsal and long thoracic nerves, which he named the Halsted Radical Mastectomy. With this procedure, for the first time in history, he was able to demonstrate an improved survival and thus the Halsted Radical Mastectomy became the standard of care in the treatment for breast cancer. Over the following 80 years there were variations on the Halsted Radical Mastectomy. In the 1950s and 1960s Dr. Sugarbaker and Dr. Urban recommended excising the internal mammary nodes and Dr. Dahl-Iverson and Dr. Tobiasson suggested removing the supraclavicular nodes based on the knowledge that breast cancer spreads to these nodal basins in addition to the axilla. Yet these procedures were morbid and fraught with complications. At the same time McWhirter, a British doctor, advocated a simple mastectomy with radiation to the nodal basins. He was able to show equivalent 5-year survival with this technique compared with these large operations, but more importantly, he demonstrated that radiation can treat nodal disease. [3] For the first time, there was now a choice in the treatment of breast cancer between surgery and radiation. To help determine which patients might be best served with a Halsted Radical Mastectomy, who should undergo past-mastectomy radiation, and who might not benefit from surgery, Haagensen devised the Columbia Clinical Classification for Operability. He devised this prognostic system based on patient and tumor characteristics from 568 patients over a 20-year period [4]. This classification system largely helped determine treatment planning until the implementation of the current TNM staging system. While survival from breast cancer improved with the Halsted Radical Mastectomy and radiation therapy, it was clear that there was increased morbidity associated with these techniques. As knowledge of the anatomy and pathophysiology of the disease improved, people began to question whether such radical interventions were necessary. In the mid-1970s, the National Study of the Adjuvant Breast and Bowel Project (NSABP) published the results of the B-04 study, which demonstrated no difference in survival between a radical mastectomy versus a modified radical mastectomy where the pectoralis muscles are left in vivo. This information helped the standard of care for breast cancer once again evolved. In fact, another first lady, Nancy Reagan, benefited from this research when she underwent a modified radical mastectomy for her breast cancer. Since the results of NSABP B-04 landmark trial were reported, there has been an explosion in breast cancer research, with each study moving the surgical management of the disease in a more conservative direction. In the mid-1980s the NSABP B-06 trial demonstrated no difference in survival between mastectomy versus lumpectomy when followed by radiation. Not only did this revolutionize the surgical management of breast cancer, but for the first time in history it allowed women a choice in treatment.