The Evolving Role of Partial Breast Irradiation in Early-Stage Breast Cancer

Whole breast irradiation (WBI) over 5–7 weeks has long been considered standard adjuvant treatment after breast-conserving surgery. Recently the concept of irradiating the whole breast has been challenged by accelerated partial breast irradiation (APBI), which exclusively targets the lumpectomy site plus margin. We review the evidence supporting APBI from modern clinical trials, the pros and cons of various APBI techniques, and the controversies regarding the applicability of APBI to specific patient groups.     

Trends in Radiotherapy After Breast-Conserving Surgery in Elderly Patients with Early-Stage Breast Cancer

Background

The benefit of adjuvant radiotherapy (RT) in elderly breast cancer patients is debatable. The purpose of this study was to evaluate trends in RT rates after breast-conserving surgery.

Methods

Breast cancer patients ≥70 years treated from 2000 to 2009 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Patients were estrogen receptor positive with negative or unknown lymph node status. Trends in RT recommendation over years were evaluated with the Jonckheere–Terpstra test. Multiple logistic regression and Cox proportional hazard tests were used to determine factors associated with radiation recommendation and survival.

Results

Of 46,581 patients, 31,989 (68.7 %) were recommended RT and 14,592 (31.3 %) were not. The recommendation for RT decreased from 70.3 % in 2000 to 67.4 % in 2009 (p < 0.0001). Seven of 18 registries exhibited decreased radiation recommendation rates, and 4 of 18 exhibited an increase. Recommendation of RT was associated with earlier year of diagnosis, younger age, Asian/Pacific Islander race, and negative lymph nodes. Predictors of worse survival were no radiation [hazard ratio (HR) 1.68, 95 % confidence interval (CI) 1.61–1.75], no nodes examined (HR 1.83, 95 % CI 1.75–1.91), large (>2–5 cm) tumor size (HR 2.02, 95 % CI 1.86–2.19), older age (80+, HR 2.38, 95 % CI 2.25–2.53), and black race (HR 1.13, 95 % CI1.03–1.23).

Conclusions

Rates of radiation recommendation in the elderly have been steadily decreasing without appreciable acceleration in this decline. This trend was not consistent across all registries. Continued research is necessary to assess differences in clinical practice and its impact on patient outcomes.     

Local Control Following Single-Dose Intraoperative Radiotherapy Prior to Surgical Excision of Early-Stage Breast Cancer

Background

Multiple partial breast radiotherapy techniques are available. We have previously presented the technical details of our procedure of delivering partial breast irradiation with a single fraction of intraoperative radiotherapy (IORT) targeting the tumor in situ prior to partial mastectomy. This study details our completed, single-institution trial.

Materials and Methods

An IRB-approved, DSMB-monitored phase II trial was performed with the following inclusion criteria: women age ≥48, ultrasound-visible invasive ductal cancers <3 cm, clinically negative axillary nodes. IORT was delivered using mobile electron irradiator, at least a 1.5-cm radial and 1-cm deep margin; patients received 15 Gy and immediately underwent partial mastectomy. Ipsilateral breast recurrence was classified as true/marginal, elsewhere in the breast or nodal basin. Kaplan-Meier methods were used to estimate survival functions and exact 95% confidence intervals are reported.

Results

Between 2003 and 2007, 71 women underwent IORT (median follow-up: 3.5 years). For patients with tumor-involved or close margins, additional therapy was required: 7 patients, total mastectomy; 11, whole breast radiation. Four women experienced invasive ipsilateral breast failures (1 new primary, 3 margin recurrences) for a 3-year local control rate of 49 of 53 (94.8%; 95% confidence interval 92.4% [95% CI] 84.2–98.3%), actuarial three-year in breast recurrence was 8% (95% CI 2–18%), and breast cancer-specific survival was 100%.

Conclusions

Intraoperative radiotherapy delivered to an in situ tumor is feasible, but our local control rate at 3.5 years is concerning. Possible changes to this technique to improve local control rates include better preoperative imaging (MRI), routine intraoperative ultrasound, and improved IORT delivery (larger cone, increased dose).     

Geographical Differences in Primary Therapy for Early-Stage Breast Cancer

Background: Breast-conserving surgery may not be uniformly available to all women. We evaluated geographical differences across Connecticut in the proportions of cases with early stage breast cancer treated by partial mastectomy PM. We also looked at geographical variation in PM with axillary lymph node dissection AND and PM with adjuvant radiotherapy RAD.Methods: The Connecticut Tumor Registry identified 9106 cases of early disease for 1991 to 1995. Latitude-longitude coordinates for place of residence at diagnosis and initial form of therapy were available for 8795 records. A spatial scan statistic was used to detect geographical differences in treatment rates across the state.Results: A total of 57.7% of early breast cancer cases were treated by PM. Women living around New Haven were less likely than others to be treated in that manner relative risk [RR] = .86; P = .0001, whereas those living around Norwalk were more likely RR = 1.26; P = .0001. PM with AND, relative to PM alone, was reported less often for cases from a large area of southwestern Connecticut RR = .89; P = .0001, but more often for those in north central Connecticut RR = 1.13; P = .0001. PM with RAD, relative to PM alone, was less common for cases around Danbury RR = .40; P = .0001 but more common among cases around Hartford RR = 1.14; P = .0001.Conclusions: Geographical analysis is a way for physicians and health officials to identify groups of women who may not yet benefit from preferred surgical procedures.     

Partial Breast Irradiation or Whole Breast Radiotherapy for Early Breast Cancer: A Meta‐Analysis of Randomized Controlled Trials

Abstract: The purpose of the study was to compare treatment outcomes in patients with breast cancer treated with partial breast irradiation (PBI) and of those treated with whole breast‐radiation therapy (WBRT). We conducted a systematic review and meta‐analysis of published randomized clinical trials comparing PBI versus WBRT. Primary outcome was overall survival and secondary outcomes were locally, axillary, supraclavicular, and distant recurrences. A search of the literature identified three trials with pooled total of 1,140 patients. We found no statistically significant difference between partial and whole breast radiation arms associated with death (OR 0.912, 95% CI 0.674–1.234, p = 0.550), distant metastasis (OR 0.740, 95% CI, 0.506–1.082, p = 0.120), or supraclavicular recurrences (pooled OR 1.415, 95% CI 0.278–7.202, p = 0.560). However, PBI was statistically significantly associated with an increased risk of both local (pooled OR 2.150, 95% CI, 1.396–3.312; p = 0.001) and axillary recurrences (pooled OR 3.430, 95% CI, 2.058–5.715; p < 0.0001) compared with whole breast‐radiation. Partial breast irradiation does not seem to jeopardize survival and may be used as an alternative to whole breast‐radiation. Nevertheless the issue of loco‐regional recurrence needs to be further addressed.     

Locoregional Recurrence Following Accelerated Partial Breast Irradiation for Early-Stage Invasive Breast Cancer: Significance of Estrogen Receptor Status and Other Pathological Variables

Background

Understanding risk factors for locoregional recurrence (LRR) after accelerated partial breast irradiation (APBI) can help to guide patient selection for treatment with APBI. Published findings to date have not been consistent. More data are needed as these risk factors continue to be defined.

Methods

A total of 277 women with early-stage invasive breast cancer underwent lumpectomy and were treated adjuvantly at our institution with APBI using high-dose rate brachytherapy. APBI was delivered using multicatheter interstitial brachytherapy (91 %) or single-entry catheter brachytherapy (9 %) to a dose of 32–34 Gy in 8–10 twice daily fractions. Failure patterns and risk factors for recurrence were analyzed.

Results

With a median follow-up of 61 months, the 5-year locoregional control rate was 94.4 %. Negative estrogen receptor (ER) status was strongly associated with LRR on multivariate analysis (p < 0.005). Lobular histology, the presence of an extensive intraductal component, and lymphovascular invasion also were significant but to a lesser degree than ER-negative status. Patients with multiple risk factors were at highest risk for LRR. Age was not significantly associated with increased risk for LRR.

Conclusions

The presence of specific pathological features, particularly ER negative status, was associated with increased risk of LRR in this cohort of women treated with APBI. Further investigation is warranted to determine whether patients with adverse pathological risk factors are at higher risk of LRR after APBI than after conventional whole breast irradiation (WBI), as these same features also may place women at risk for LRR after WBI.     

Cost-Effectiveness Analysis of Intraoperative Radiation Therapy for Early-Stage Breast Cancer

Background

Shortened courses of radiation therapy have been shown to be similarly effective to whole-breast external-beam radiation therapy (WB-EBRT) in terms of local control. We sought to analyze, from a societal perspective, the cost-effectiveness of two radiation strategies for early-stage invasive breast cancer: single-dose intraoperative radiation therapy (IORT) and the standard 6-week course of WB-EBRT.

Methods

We developed a Markov decision-analytic model to evaluate these treatment strategies in terms of life expectancy, quality-adjusted life years (QALYs), costs, and the incremental cost-effectiveness ratio over 10 years.

Results

IORT single-dose intraoperative radiation therapy was the dominant, more cost-effective strategy, providing greater quality-adjusted life years at a decreased cost compared with 6-week WB-EBRT. The model was sensitive to health state utilities and recurrence rates, but not costs. IORT was either the preferred or dominant strategy across all sensitivity analyses. The two-way sensitivity analyses demonstrate the need to accurately determine utility values for the two forms of radiation treatment and to avoid indiscriminate use of IORT.

Conclusions

With less cost and greater QALYs than WB-EBRT, IORT is the more valuable strategy. IORT offers a unique example of new technology that is less costly than the current standard of care option but offers similar efficacy. Even when considering the capital investment for the equipment ($425 K, low when compared with the investments required for robotic surgery or high-dose-rate brachytherapy), which could be recouped after 3–4 years conservatively, these results support IORT as a change in practice for treating early-stage invasive breast cancer.     

Stereotaxic Interstitial Laser Therapy of Early-Stage Breast Cancer

Abstract: Coagulation leading to fibrosis of mammo-graphically detected breast cancers by interstitial laser therapy was tested as an alternative to surgical removal. Availability of computerized stereotaxic digital imaging allows the precise placement of laser and thermal needles into the target tumor and its controlled ablation by heat. The methodology of interstitial laser therapy (ILT), evolution of the subsequently removed tumors, and their histologic appearance are outlined.
Eight patients with mammographically well-defined tumors were selected. Definitive diagnosis and receptor evaluation were made on core biopsies. Under local anesthesia, stereotaxically guided diode laser energy at 5–10 w was delivered via a 400 xm fiber in a 19-gauge needle placed into the center of the tumor until the peripheral temperature exceeded 60°C. Patients experienced transient pain and pyrexia. Subsequent to ILT, seven invasive carcinomas were excised while one case of multiple papillomas was kept under surveillance. Histologic study revealed central necrosis but some peripheral residual tumor in the first five cases. In the last two, central necrosis surrounded by concentrically arranged, recognizable but severely injured, focally "windswept" and "ghostlike" tumor and granulation tissue were noted. The multiple papillomas showed radiologic shrinkage at 5 months and extensive fibrosis on needle biopsy.
ILT is an attractive new method of treating small, well-defined breast tumors and offers a potentially significant alternative to surgical removal; further exploration is warranted.     

Triple-Negative Breast Cancer is Not Associated with Increased Likelihood of Nodal Metastases

Background

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. The purpose of this study was to determine if patients with TNBC have a higher risk of lymph node (LN) metastases.

Methods

A prospective database review identified 3,289 patients treated with a mastectomy or with breast-conserving surgery between January 2000 and May 2012. The final analysis included those patients who underwent sentinel node biopsy (SNB) and/or axillary lymph node dissection (ALND), and the following information: age at diagnosis, tumor size, grade, stage, histologic subtype, presence of lymphovascular invasion (LVI), and the status of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2).

Results

A total of 2,967 patients met the inclusion criteria. SNB was performed in 1,094 patients, ALND in 756, and both SNB and ALND in 1,117 patients. LN metastases were detected in 1,050 (35 %) patients. On univariate analysis, the LN positivity varied across subtypes with 33 % in luminal A, 42 % in luminal B, 39 % in TNBC, and 45 % in HER-2 (p = 0.0007). However, on multivariable analysis, there was no difference in LN positivity among subtypes. Age <50, grade 2 or 3 tumors, size ≥2 cm, and presence of LVI were significant predictors of LN positivity. Four or more involved nodes were observed most commonly in the HER2 (19.4 %) and luminal B (13.7 %) subtypes, but only 9.4 % in TNBC (p < 0.0001).

Conclusions

Predictors of LN metastases include younger age, higher grade, larger tumor size, and presence of LVI. Patients with TNBC are not more likely to have involved nodes than those with non-TNBC.     

Impact of Endocrine Therapy Adherence on Outcomes in Elderly Women with Early-Stage Breast Cancer Undergoing Lumpectomy Without Radiotherapy

Annals of Surgical Oncology - National Comprehensive Center Network guidelines recommend radiotherapy (RT) omission in women age ≥ 70 years with estrogen receptor-positive (ER+), cN0, T1...     

Sequential Adjuvant CMF Chemotherapy Followed by Radiotherapy in the Treatment of Early-Stage Breast Cancer: The Lankenau Hospital Experience

Abstract: The optimal timing of systemic cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy and local radiation in adjuvant breast cancer has been a debatable subject. To evaluate the Lankenau Hospital experience with sequential CMF chemotherapy followed by radiation in the adjuvant therapy of stage I and stage II breast cancer we reviewed the records of patients at our center. This group of 34 patients was treated in a homogenous manner, all receiving standard CMF for six cycles followed by radiotherapy after lumpectomy with axillary lymph node dissection. The radiation course was 5040cGy to the entire breast (28 fractions in 45 elapsed days) followed by a boost to the tumor site of 1800cGy in 10 fractions. Thirty-four patients were identified and followed for an average of 5 years (range 1.5–11.5 years). One patient had local recurrence and with subsequent treatment is disease-free at 5 years postrecurrence (8 years from initial diagnosis). Two deaths were not breast-cancer related (1 myocardial infarction at year 3, 1 melanoma at year 7.5). The estimated probability of no relapse at 5 years and 8 years by Kaplan-Meier analysis is 79% and 60% respectively. Overall and disease-free survival in this group of patients treated with breast-conserving surgery and CMF chemotherapy followed by radiation is excellent. There appears to be no detriment to delaying radiotherapy until full doses of systemic treatment are given as local recurrence was rare (6%) and was amenable to further treatment.     

Predicting the Extent of Nodal Disease in Early-Stage Breast Cancer

Background

The role of regional nodal ultrasound (US) has been questioned since publication of the American College of Surgeons Oncology Group (ACOSOG) Z0011 data. The goal of this study was to determine if imaging and clinicopathologic features could predict the extent of axillary nodal involvement in breast cancer.

Study Design

Patients with T1–T2 tumors who underwent regional nodal US and axillary lymph node dissection from 2002 to 2012 were identified from a prospective database excluding those who received neoadjuvant chemotherapy. Patients whose metastases were identified by US confirmed by needle biopsy were compared with those identified by sentinel lymph node dissection (SLND) after a negative US.

Results

Metastases were identified by US in 190 patients, and by SLND in 518 patients. SLND patients had fewer positive nodes (2.2 vs. 4.1; p < 0.0001), smaller metastases (5.3 vs. 13.8 mm; p < 0.0001), and a lower incidence of extranodal extension (24 vs. 53 %; p < 0.0001) than the US group. Even when US identified ≤2 abnormal nodes, patients were still more likely to have ≥3 positive nodes (45 %) than SLND patients (19 %; p < 0.001). After adjusting for tumor size, receptor status, and histology, multivariate analysis revealed that metastases identified by US [odds ratio (OR) 4.01; 95 % confidence interval (CI) 2.75–5.84] and lobular histology (OR 1.77; 95 % CI 1.06–2.95) predicted having ≥3 positive nodes.

Conclusions

Imaging and clinicopathologic features can be used to predict the extent of nodal involvement. Patients with US-detected metastases, even if small volume, have a higher burden of nodal involvement than patients with SLND-detected metastases and may not be comparable with patients in the ACOSOG Z0011 trial.     

Improved Lymphatic Mapping Technique for Breast Cancer

Abstract: Breast sentinel lymph node biopsy is becoming more common. However, the best injection technique is not well established. Currently the gold standard is peritumoral injection. However, for upper outer quadrant tumors there is considerable axillary “shine through” which makes the identification of the radioactive sentinel lymph node difficult. We undertook a study to compare an injection in Sappey's subareolar plexus to the gold standard of peritumoral injection. Between December 1997 and March 1998, 85 patients with breast cancer were enrolled in the study. All patients were injected with 2 cc of normal saline containing 1.0 mCi of unfiltered technetium sulfur colloid in Sappey's subareolar plexus in the clock position of the breast cancer. In the operating room the patients underwent a peritumoral injection of 5 cc of 1% isosulfan blue. All blue and radioactive lymph nodes were identified and removed. The majority of the tumors were in the upper outer quadrant and were diagnosed by core biopsy. Only half of the patients had palpable tumors and approximately 25% had previous upper outer quadrant biopsy incisions. Peritumoral blue dye injection yielded an identification rate of 94%, with 99% of these being blue and radioactive. Three patients had radioactive lymph nodes with no blue lymph nodes identified. One of these patients had a micrometastasis. Injection in Sappey's subareolar plexus in the clock position of the tumor drained to the same sentinel lymph node as peritumoral injection. This injection technique solved the two major problems confronting the wide adoption of sentinel lymph node biopsy for breast cancer staging. First, it eliminates axillary “shine through” which will allow nonspecialist surgeons to more easily identify the radioactive axillary sentinel lymph node. Second, it allows for easier isotope injection by the technician or nuclear medicine physician, by eliminating the need for three-dimensional localization. This new technique should allow the majority of breast cancer patients who are treated by nonspecialist surgeons to be offered this less morbid, more accurate procedure.     

Optimal Use of Re-Excision in Patients Diagnosed with Early-Stage Breast Cancer by Excisional Biopsy Treated with Breast-Conserving Therapy

Purpose  

The goal of the current study is to help refine guidelines for the need for re-excision and the appropriate amount of breast tissue to re-excise in patients with early breast cancer following excisional breast biopsy when treated with breast-conserving therapy (BCT).     

ASO Author Reflections: Undertreatment of Early-Stage Breast Cancer in Elderly Women Undergoing Lumpectomy Without Radiotherapy Increases the Risk of Locoregional Recurrence

Annals of Surgical Oncology -