Erratum: Multidisciplinary Management of Breast Cancer During Pregnancy.

[This corrects the article DOI: 10.1634/theoncologist.2016-0208.].

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.

PURPOSE: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. PATIENTS AND METHODS: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. RESULTS: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. CONCLUSION: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. CLINICAL TRIAL: (NCT01305941).

Multidisciplinary Management of Breast Cancer During Pregnancy.

BACKGROUND: Although breast cancer during pregnancy (BCDP) is rare (occurring with only 0.4% of all BC diagnoses in female patients aged 16-49 years), management decisions are challenging to both the patient and the multidisciplinary team. MATERIALS AND METHODS: Experts in breast cancer at the University of North Carolina conducted a targeted literature search regarding the multidisciplinary treatment approaches to BCDP: medical, surgical, and radiation oncology. Supportive care, including antiemetic agents, and imaging approaches were also reviewed. RESULTS: Review of the literature revealed key points in the management of BCDP. Surgical management is similar to that in nonpregnant patients; pregnant patients may safely undergo breast-conserving surgery. Recommendations should be tailored to the individual according to the clinical stage, tumor biology, genetic status, gestational age, and personal preferences. Anthracycline-based chemotherapy can be safely initiated only in the second and third trimesters. The rate of congenital abnormalities in children exposed to chemotherapy is similar to the national average (approximately 3%). Dosing of chemotherapy should be similar to that in the nonpregnant patient (i.e., actual body surface area). Antihuman epidermal growth factor receptor 2 therapy, radiation, and endocrine treatment are contraindicated in pregnancy and lactation. Care should include partnership with obstetricians. The literature regarding prognosis of BCDP is mixed. CONCLUSION: To maximize benefit and minimize risk to the mother and fetus, an informed discussion with the patient and her medical team should result in an individualized treatment plan, taking into account the timing of the pregnancy and the stage and subtype of the breast cancer. Because BCDP is rare, it is essential to collect patient data in international registries. The Oncologist 2017;22:324-334 IMPLICATIONS FOR PRACTICE: Breast cancer during pregnancy is a major ethical and professional challenge for both the patient and the multidisciplinary treatment team. Although the oncologic care is based on that of the non-pregnant breast cancer patient, there are many challenges from regarding the medical, surgical and radiation oncology and obstetrical aspects of care that need to be considered to deliver the safest and best treatment plan to both the mother and developing fetus.

Early cardiac perfusion defects after left-sided radiation therapy for breast cancer: is there a volume response?

PURPOSE: Cardiac single-photon emission computed tomography (SPECT) is often used to identify defects in myocardial perfusion due to atherosclerotic coronary artery disease. It was also used in studies to evaluate radiation therapy (RT)-associated cardiac abnormalities. In the current review, we aim to evaluate the rates of post-RT cardiac SPECT early perfusion abnormalities and relate this to the irradiated left ventricular volume. METHODS: The studies cited in this systematic review were identified using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS: Six studies between 1996 and 2016 fulfilled the inclusion criteria. The reported perfusion defects in these studies were seen in the apical and anterolateral aspects of the left ventricle. Three studies show correlation between the percent of the left ventricle within the RT-field and percent of patients with early perfusion defects on cardiac SPECT. In two studies that used cardiac sparing techniques (such as deep inspiration), that resulted in a low mean heart dose, no perfusion defects were noted. CONCLUSIONS: Data suggest that incidental irradiation of the heart in cases of left breast/chest wall RT can result in early post-RT perfusion defects on cardiac SPECT. There appears to be strong dose/volume dependence to the risk, and hence techniques to reduce cardiac exposure are recommended.

The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy.

Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.

The prognostic value of pre-diagnosis health-related quality of life on survival: a prospective cohort study of older Americans with lung cancer.

PURPOSE: Health-related quality of life (HRQOL) after cancer diagnosis is prognostic for overall survival (OS). However, no studies have assessed if HRQOL before diagnosis is predictive for OS. The objective of this study was to determine the association between pre-lung cancer diagnosis HRQOL and OS. METHODS: Our prospective cohort study used surveillance, epidemiology, and end results linked to the Medicare Health Outcomes Survey. We included 6290 individuals 65 years or older diagnosed with incident lung cancer from 1998 to 2013. We assessed the prognostic value of (1) short-form 36 summary component and domain-specific scores, (2) activities of daily living (ADL), and (3) two global HRQOL questions. Cox-proportional hazards models were used to examine associations between HRQOL and OS, adjusting for demographics, comorbid conditions, and clinical characteristics. RESULTS: Worse pre-diagnosis HRQOL was significantly associated with greater risk of death across HRQOL measures. An above average physical or mental component summary score was associated with 16 and 24% decreases in the hazard of death, respectively (p < 0.0001). Being unable to perform ADLs, such as bathing oneself, was associated with an 89% increased hazard of death (p < 0.0001). Reporting "poor" versus "excellent" health was associated with a 74% increase in the hazard of death (p < 0.0001). CONCLUSION: This population-based study reinforces the importance of self-reported health status as a predictor for OS. Routine HRQOL screening may identify patients who could benefit from early interventions to improve HRQOL. Future studies should explore associations between changes in HRQOL before and after cancer diagnosis and OS.

A Multidisciplinary Breast Cancer Brain Metastases Clinic: The University of North Carolina Experience.

BACKGROUND: Breast cancer brain metastasis (BCBM) confers a poor prognosis and is unusual in requiring multidisciplinary care in the metastatic setting. The University of North Carolina at Chapel Hill (UNC-CH) has created a BCBM clinic to provide medical and radiation oncology, neurosurgical, and supportive services to this complex patient population. We describe organization and design of the clinic as well as characteristics, treatments, and outcomes of the patients seen in its first 3 years. METHODS: Clinical and demographic data were collected from patients in a prospectively maintained database. Descriptive statistics are reported as percentages and means. The Kaplan-Meier method was used to estimate time-to-event outcomes. RESULTS: Sixty-five patients were seen between January 2012 and January 2015. At the time of presentation to the BCBM clinic, most patients (74%) had multiple (≥2) brain metastases and had received prior systemic (77%) and whole-brain radiation therapy and/or central nervous system stereotactic radiosurgery (65%) in the metastatic setting. Seventy-eight percent returned for a follow-up visit; 32% were enrolled in a clinical trial. Median time from diagnosis of brain metastasis to death was 2.11 years (95% confidence interval [CI] 1.31-2.47) for all patients, 1.15 years (95% CI 0.4-2.43) for triple-negative breast cancer, 1.31 years (95% CI 0.51-2.52) for hormone receptor-positive/HER2- breast cancer, and 3.03 years (95% CI lower limit 1.94, upper limit not estimable) for HER2+ breast cancer (p = .0037). CONCLUSION: Patients with BCBM have unique and complex needs that require input from several oncologic disciplines. The development of the UNC-CH multidisciplinary BCBM clinic is a model that can be adapted at other centers to provide coordinated care for patients with a challenging and complex disease. IMPLICATIONS FOR PRACTICE: Patients with breast cancer brain metastases often require unique multidisciplinary care to meet the numerous and uncommon challenges associated with their conditions. Here, the development and characteristics of a clinic designed specifically to provide for the multidisciplinary needs of patients with breast cancer brain metastases are described. This clinic may serve as a model for other institutions interested in creating specialty clinics with similar objectives.

Multidisciplinary Management of Breast Cancer Brain Metastases.

This review summarizes the most up-to-date approach to the multidisciplinary management of patients with breast cancer brain metastases. A brief overview of the epidemiology and biology of breast cancer brain metastasis is provided. The perspectives of radiation oncology, neurosurgery, and medical oncology-and landmark studies from each discipline-are all discussed. We also offer practical tips to help guide the treating physician, including data on antiseizure medications. Finally, we introduce the concept of a multidisciplinary clinic that combines input from medical and radiation oncology, neurosurgery, and support services, which we developed at the University of North Carolina as a coordinated and optimal approach to the management of patients with this complex disease.

Dosimetric effect due to the motion during deep inspiration breath hold for left-sided breast cancer radiotherapy.

Deep inspiration breath-hold (DIBH) radiotherapy for left-sided breast cancer can reduce cardiac exposure and internal motion. We modified our in-house treatment planning system (TPS) to retrospectively analyze breath-hold motion log files to calculate the dosimetric effect of the motion during breath hold. Thirty left-sided supine DIBH breast patients treated using AlignRT were studied. Breath-hold motion was recorded ­ three translational and three rotational displacements of the treatment surface ­ the Real Time Deltas (RTD). The corresponding delivered dose was estimated using the beam-on portions of the RTDs. Each motion was used to calculate dose, and the final estimated dose was the equally weighted average of the multiple resultant doses. Ten of thirty patients had internal mammary nodes (IMN) purposefully included in the tangential fields, and we evaluated the percentage of IMN covered by 40 Gy. The planned and delivered heart mean dose, lungs V20 (volume of the lungs receiving > 20 Gy), percentage of IMN covered by 40 Gy, and IMN mean dose were compared. The averaged mean and standard deviation of the beam-on portions of the absolute RTDs were 0.81 ± 1.29 mm, 0.68 ± 0.85mm, 0.76 ± 0.85 mm, 0.96° ± 0.49°, 0.93° ± 0.43°, and 1.03° ± 0.50°, for vertical, longitudinal, lateral, yaw, roll, and pitch, respectively. The averaged planned and delivered mean heart dose were 99 and 101 cGy. Lungs V20 were 6.59% and 6.74%. IMN 40 Gy coverage was 83% and 77%, and mean IMN dose was 4642 and 4518 cGy. The averaged mean motion during DIBH was smaller than 1 mm and 1°, which reflects the relative reproducibility of the patient breath hold. On average, the mean heart dose and lungs V20 were reasonably close to what have been planned. IMN 40 Gy coverage might be modestly reduced for certain cases.

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer.

PURPOSE: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population. PATIENTS AND METHODS: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40-42 °C. In the first trial 18 subjects received LTLD at 20, 30, or 40 mg/m2; in the second trial, 11 subjects received LTLD at 40 or 50 mg/m2. RESULTS: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256 mg/m2 of prior anthracyclines and a median dose of 61 Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50 mg/m2, with seven subjects (24%) developing reversible grade 3-4 neutropenia and four (14%) reversible grade 3-4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30-66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses. CONCLUSION: LTLD at 50 mg/m2 and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.

A case report of stereotactic radiosurgery in a patient with Ehlers-Danlos syndrome.

In this report, we outline the case of a patient who has Ehlers-Danlos Syndrome (EDS) who received two courses of CyberKnife stereotactic radiosurgery (SRS) for metastatic non-small cell lung cancer. Patients with EDS have increased blood vessel fragility, and therefore are subject to increased risk of bleeding. There are no published data regarding the risks of hemorrhage associated with SRS for intracranial metastases in this patient population. The patient described in this case report had two courses of SRS for two sites of brain metastases. She tolerated treatment well, with no acute toxicity and good local control to date. We have also included a discussion of published literature regarding toxicity of intracranial radiation in patients with EDS.

Adoption and effectiveness of de-escalated radiation and endocrine therapy strategies for older women with low-risk breast cancer.

PURPOSE: Recent clinical trials support de-escalation of adjuvant radiation therapy following lumpectomy in some older women with low-risk HR+ breast cancers planning to take endocrine therapy. The adoption of these findings into clinical practice, and the effectiveness of de-escalated therapy in real-world populations, remain under investigation. MATERIALS AND METHODS: We evaluated use of adjuvant radiation therapy and/or endocrine therapy among older women with T1-2 node-negative, HR+ breast cancer in the United States between 2007 and 2011. The study included patients from the Surveillance, Epidemiology and End Results-Medicare linked database and the North Carolina Cancer Information and Population Health Resource database. RESULTS: Radiation therapy was received by 65.5% of patients, with no decrease over time. Older women and those with T2 (compared to T1) tumors were less likely to receive radiation therapy. In propensity-adjusted analyses, both radiation therapy alone (HR 0.75, 95% CI 0.67-0.84) and radiation + endocrine therapy (HR 0.62, 95% CI 0.54-0.69) were associated with significantly lower recurrence risk compared to endocrine therapy alone. Non-adherence to endocrine therapy was common (37%) and similar across groups. With a median follow-up of 48 months (range 13-84), we were not able to detect an association of non-adherence with recurrence risk in endocrine therapy-containing treatment arms. CONCLUSION: Most older women with stage I HR+ breast cancers continue to receive radiation, at higher rates than patients with node-negative stage II tumors. These findings suggest that while multiple evidence-based treatment options exist in these patients, improvements are needed to ensure that radiation therapy is applied equitably and rationally.

Cost-effectiveness of endocrine therapy versus radiotherapy versus combined endocrine and radiotherapy for older women with early-stage breast cancer.

PURPOSE: To evaluate the cost-effectiveness of endocrine therapy (ET), radiation therapy (XRT), and combination ET + XRT as post-surgical treatment for older women with early-stage breast cancer from the societal perspective. METHODS: We constructed a Markov state-transition model consisting of three mutually exclusive health-states: Disease-Free, Recurrence, or Death. Osteoporotic fracture, radiation-induced breast fibrosis, and radiation pneumonitis were modeled as treatment-related adverse events (AEs). Cancer registry-linked-Medicare data were used to assess probability of recurrence and total costs, after propensity adjustment to account for treatment selection, among women aged >65 years diagnosed with estrogen receptor positive or progesterone receptor positive (ER+/PR+) breast cancer receiving ET, XRT, or ET + XRT in 2007-2011. Following randomized controlled trials, overall survival was assumed equivalent, but locoregional recurrence varied. Indirect costs and health-state utilities were literature-driven and varied in sensitivity analyses. Costs and outcomes were discounted at 3% annually. RESULTS: In a cohort of 10,000 women over ten years, we estimated 1620 total recurrences in the ET-only group, 1296 in the XRT-only group, and 1076 with ET + XRT. Compared to ET-only, the base-case incremental cost-effectiveness ratio (ICER) was $10,826 per quality-adjusted life-year (QALY)-gained for XRT-only and $26,834/QALY-gained for ET + XRT. Similarities in cost and effectiveness between treatments led to highly sensitive results. We also present clinically-relevant patient preference scenarios for recurrence risk-averse patients and near-term AE risk-averse patients. CONCLUSIONS: The cost-effectiveness of regimens including ET and/or XRT in older women with early-stage breast cancer is sensitive to small differences in costs, as well as risk of, and utilities associated with, locoregional recurrence, suggesting that patient preferences concerning treatment benefits and risks should be considered by physicians.

Intensity-modulated radiation therapy for anal cancer: toxicity versus outcomes.

The treatment of cancer of the anal canal has changed significantly over the past several decades. Although the abdominoperineal resection (APR) was the historical standard of care, a therapeutic paradigm shift occurred with the seminal work of Nigro, who reported that anal canal cancer could be treated with definitive chemoradiation, with APR reserved for salvage therapy only. This remains an attractive approach for patients and physicians alike and the standard of care in this disease. Now, nearly four decades later, a similar approach continues to be utilized, albeit with higher radiation doses; however, this strategy remains fraught with considerable treatment-related morbidities. With the advent of intensity-modulated radiation therapy (IMRT), many oncologists are beginning to utilize this technology in the treatment of anal cancer in order to decrease these toxicities while maintaining similar treatment efficacy. This article reviews the relevant literature leading up to the modern treatment of anal canal cancer, and discusses IMRT-related toxicity and disease-related outcomes in the context of outcomes of conventionally treated anal cancer.

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data.

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.

Hyperthermia for locally advanced breast cancer.

Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use.

Phase II study of stereotactic radiosurgery for the treatment of patients with oligoprogression on erlotinib.

INTRODUCTION: Retrospective studies have evaluated the approach of stereotactic radiotherapy (SRT) to address oligoprogression in patients with EGFR mutant NSCLC on TKI therapy, it has never been prospectively studied. MATERIALS AND METHODS: We treated 25 patients with EGFR mutant NSCLC on erlotinib who had 3 or fewer sites of extra-cranial progression with SRT to progressing sites, followed by re-initiation of erlotinib. RESULTS: Median PFS from the initiation of SRT was 6 months (95% CI 2.5 to 11.6) and median OS was 29 months (95% CI 21.7 to 36.3). Neither baseline nor changes in the Veristrat proteomic predicted PFS. CONCLUSIONS: SRT and TKI continuation may be considered for select patients with EGFR mutant NSCLC and oligo-progression on EGFR TKI therapy.

Prospective Assessment of Patient-Reported Dry Eye Syndrome After Whole Brain Radiation.

PURPOSE: Dry eye is not typically considered a toxicity of whole brain radiation therapy (WBRT). We analyzed dry eye syndrome as part of a prospective study of patient-reported outcomes after WBRT. METHODS AND MATERIALS: Patients receiving WBRT to 25 to 40 Gy were enrolled on a study with dry mouth as the primary endpoint and dry eye syndrome as a secondary endpoint. Patients received 3-dimensional WBRT using opposed lateral fields. Per standard practice, lacrimal glands were not prospectively delineated. Patients completed the Subjective Evaluation of Symptom of Dryness (SESoD, scored 0-4, with higher scores representing worse dry eye symptoms) at baseline, immediately after WBRT (EndRT), and at 1 month (1M), 3 months, and 6 months. Patients with baseline SESoD ≥3 (moderate dry eye) were excluded. The endpoints analyzed were ≥1-point and ≥2-point increase in SESoD score at 1M. Lacrimal glands were retrospectively delineated with fused magnetic resonance imaging scans. RESULTS: One hundred patients were enrolled, 70 were eligible for analysis, and 54 were evaluable at 1M. Median bilateral lacrimal V20Gy was 79%. At 1M, 17 patients (32%) had a ≥1-point increase in SESoD score, and 13 (24%) a ≥2-point increase. Lacrimal doses appeared to be associated with an increase in SESoD score of both ≥1 point (V10Gy: P = .042, odds ratio [OR] 1.09/%; V20Gy: P = .071, OR 1.03/%) and ≥2 points (V10Gy: P = .038, OR 1.15/%; V20Gy: P = .063, OR 1.04/%). The proportion with increase in dry eye symptoms at 1M for lacrimal V20Gy ≥79% versus <79% was 46% versus 15%, respectively, for ≥1 point SESoD increase (P = .02) and 36% versus 12%, respectively, for ≥2 point SESoD increase (P = .056). CONCLUSIONS: Dry eye appears to be a relatively common, dose/volume-dependent acute toxicity of WBRT. Minimization of lacrimal gland dose may reduce this toxicity, and patients should be counseled regarding the existence of this potential side effect and treatments for dry eye.