A Statewide Multi-Institutional Study of Asymptomatic Pretreatment Testing of Radiation Therapy Patients for SARS-CoV-2 in a High-Incidence Region of the United States.

PURPOSE: Our purpose was to establish the prevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in asymptomatic patients scheduled to receive radiation therapy and its effect on management decisions. METHODS AND MATERIALS: Between April 2020 and July 2020, patients without influenza-like illness symptoms at four radiation oncology departments (two academic university hospitals and two community hospitals) underwent polymerase chain reaction testing for SARS-CoV-2 before the initiation of treatment. Patients were tested either before radiation therapy simulation or after simulation but before treatment initiation. Patients tested for indications of influenza-like illness symptoms were excluded from this analysis. Management of SARS-CoV-2-positive patients was individualized based on disease site and acuity. RESULTS: Over a 3-month period, a total of 385 tests were performed in 336 asymptomatic patients either before simulation (n = 75), post-simulation, before treatment (n = 230), or on-treatment (n = 49). A total of five patients tested positive for SARS-CoV-2, for a pretreatment prevalence of 1.3% (2.6% in north/central New Jersey and 0.4% in southern New Jersey/southeast Pennsylvania). The median age of positive patients was 58 years (range, 38-78 years). All positive patients were white and were relatively equally distributed with regard to sex (2 male, 3 female) and ethnicity (2 Hispanic and 3 non-Hispanic). The median Charlson comorbidity score among positive patients was five. All five patients were treated for different primary tumor sites, the large majority had advanced disease (80%), and all were treated for curative intent. The majority of positive patients were being treated with either sequential or concurrent immunosuppressive systemic therapy (80%). Initiation of treatment was delayed for 14 days with the addition of retesting for four patients, and one patient was treated without delay but with additional infectious-disease precautions. CONCLUSIONS: Broad-based pretreatment asymptomatic testing of radiation oncology patients for SARS-CoV-2 is of limited value, even in a high-incidence region. Future strategies may include focused risk-stratified asymptomatic testing.

5-Year Results of a Prospective Phase 2 Trial Evaluating 3-Week Hypofractionated Whole Breast Radiation Therapy Inclusive of a Sequential Boost.

PURPOSE: To report 5-year outcomes of a phase 2 trial of hypofractionated whole breast irradiation (HF-WBI) completed in 3 weeks, inclusive of a sequential boost. METHODS AND MATERIALS: Women with stage 0-IIIA breast cancer (ductal carcinoma in situ through T2N2a) were enrolled on a prospective, phase 2 trial of accelerated HF-WBI. We delivered a whole breast dose of 36.63 Gy in 11 fractions of 3.33 Gy, with an equivalent dose to the regional nodes when indicated, followed by a tumor bed boost of 13.32 Gy in 4 fractions of 3.33 Gy over a total of 15 treatment days. The primary endpoint was locoregional control; secondary endpoints included acute/late toxicity and physician-assessed and patient-reported breast cosmesis. RESULTS: Between 2009 and 2017, we enrolled 150 patients, of whom 146 received the protocol treatment. Median age was 54 years (range, 33-82) and median follow-up was 62 months. Patients with higher-risk disease comprised 59% of the cohort, including features such as young age (33% ≤50 years), positive nodes (13%), triple-negative disease (11%), and treatment with regional nodal irradiation (11%) and/or neoadjuvant/adjuvant chemotherapy (36%). Five-year estimated locoregional and distant control were 97.7% (95% confidence interval [CI], 93.0%-99.3%) and 97.9% (95% CI, 93.6%-99.3%), respectively. Five-year breast cancer-specific and overall survival were 99.2% (95% CI, 94.6%-99.9%) and 97.3% (95% CI, 91.9%-99.1%), respectively. Acute/late grade 2 and 3 toxicities were observed in 30%/10% and 1%/3% of patients, respectively. There were no grade 4 or 5 toxicities. Physicians assessed breast cosmesis as good or excellent in 95% of patients; 85% of patients self-reported slight to no difference between the treated and untreated breast. CONCLUSIONS: Our phase 2 trial offers one of the shortest courses of HF-WBI; at 5 years of follow-up there continues to be excellent locoregional control and low toxicity with favorable cosmetic outcomes in a heterogeneous cohort of patients.

The Role of MRI in the Follow-up of Women Undergoing Breast-conserving Therapy.

OBJECTIVES: Breast-conserving therapy (BCT) represents a standard of care in the management of breast cancer. However, unlike mastectomy, women treated with BCT require follow-up imaging of the treated breast as well as the contralateral breast as part of posttreatment surveillance. Traditionally, surveillance has consisted of clinical exams and mammograms. However, magnetic resonance imaging (MRI) has emerged as a breast imaging technique utilized as part of high-risk screening programs as well as part of the initial diagnosis and workup of women considered for BCT. At this time, the role of MRI as part of follow-up for women treated with BCT remains unclear. METHODS: A systematic review was performed to evaluate the role of MRI following BCT. RESULTS: Although there is no randomized evidence supporting the routine use of MRI in surveillance post-BCT, a review of the literature demonstrates that MRI (1) has increased sensitivity as compared with mammography to detect recurrences, and (2) can help evaluate mammographic abnormalities before biopsy and/or surgery. CONCLUSIONS: In patients with higher risk of local recurrence, surveillance with MRI may represent an effective surveillance strategy though subgroups benefiting have not been identified nor has the impact on quality of life and cost been evaluated.

Novel and Highly Compressed Schedules for the Treatment of Breast Cancer.

Our thinking about radiotherapy (RT) for early-stage breast cancer has evolved considerably over the last several years. Increasingly patients and physicians together are making the decision to use altered fractionation rather than standard 6-7 weeks of conventional whole breast treatment plus lumpectomy bed boost. Adjuvant hypofractionated whole breast irradiation is now viewed as a preferred strategy for many eligible women, and can be completed in 3-4 weeks. Adjuvant accelerated partial breast irradiation is another alternative that is typically delivered in 8-10 fractions over 4-5 days. With improvements in delivery techniques, there has been renewed interest in shortening treatment times even further, with novel intraoperative approaches and ultrashort courses of external beam RT. This article provides a summary of the status and future directions in intraoperative and ultrashort course RT schedules used in the treatment of breast cancer. Outlined are the benefits as well as the drawbacks of these techniques for abbreviated breast RT.

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.

Lumpectomy closure technique does not affect dosimetry in patients undergoing external-beam-based accelerated partial breast irradiation.

BACKGROUND: During the breast lumpectomy procedure, surgeons traditionally elect to use either a superficial or full-thickness closure when sealing the wound depending on surgeon preference as well as desired outcomes. The purpose of this study was to examine dosimetric endpoints in patients with superficial versus full-thickness closures with accelerated partial breast irradiation (APBI). METHODS: Patients who underwent breast conservation surgery followed by 3D conformal external-beam APBI were identified (n = 45) and were separated according to the type of cavity closure performed: superficial and full thickness. Data gathered from the retrospective review of patient charts was analyzed according to criteria in the NSABP B-39 protocol in order to quantify the amount of radiation delivered to organs at risk. The patient seroma cavity was further given a cavity visualization score to assess the impact of wound closure on treatment planning. RESULTS: There was no significant difference in the mean CVS score for the 2 groups. There were no statistical differences in all dosimetric endpoints compared for the 2 types of closure, and both groups met NSABP B-39 guidelines for the ipsilateral breast, heart, and ipsilateral lung dosimetry. CONCLUSIONS: We found no significant difference in dosimetric outcomes in either the superficial or deep closure treatment groups. Breast surgeons should not alter their preferred closure strategy in anticipation of 3D-CRT APBI.

Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glutamate receptor 1 in vitro and in vivo.

PURPOSE: Brain metastases are a common preterminal event in patients with metastatic melanoma and require radiation therapy. Our group has previously shown that human GRM1 (hGRM1) expressing melanoma cells release excess extracellular glutamate and are growth inhibited by riluzole, an inhibitor of glutamate release. Riluzole-treated cells accumulate in G(2)/M phase of the cell cycle at 24 hours, and then undergo apoptotic cell death. We evaluated whether riluzole enhanced radiosensitivity in melanoma cells. EXPERIMENTAL DESIGN: Clonogenic assays were performed to evaluate clonogenic survival after treatment in hGRM1 expressing and nonexpressing melanoma cells. Western immunoblots were performed to confirm apoptotic cell death. A xenograft mouse model was used to validate the in vitro experiments. Tumors harvested from the xenografts were fixed and stained for apoptosis and DNA damage markers. RESULTS: In the hGRM1-positive cell lines C8161 and UACC903, riluzole enhanced the lethal effects of ionizing radiation; no difference was seen in the hGRM1-negative UACC930 cell line. C8161 cells treated with riluzole plus irradiation also showed the highest levels of the cleaved forms of PARP and caspase-3; excised C8161 xenografts showed the greatest number of apoptotic cells by immunohistochemistry (P < 0.001). On cell cycle analysis, a sequence-dependent enrichment in the G(2)/M phase was shown with the combination of riluzole and irradiation. Xenografts treated with riluzole and weekly radiation fractions showed significant growth inhibition and revealed markedly increased DNA damage. CONCLUSIONS: We have shown, in vitro and in vivo, that the combination of riluzole and ionizing radiation leads to greater cytotoxicity. These results have clinical implications for patients with brain metastases receiving whole brain radiation therapy.

Characterization of folate uptake by choroid plexus epithelial cells in a rat primary culture model.

Reduced derivatives of folic acid (folates) play a critical role in the development, function and repair of the CNS. However, the molecular systems regulating folate uptake and homeostasis in the central nervous system remain incompletely defined. Choroid plexus epithelial cells express high levels of folate receptor alpha (FRalpha) suggesting that the choroid plays an important role in CNS folate trafficking and maintenance of CSF folate levels. We have characterized 5-methyltetrahydrofolate (5-MTHF) uptake and metabolism by primary rat choroid plexus epithelial cells in vitro. Two distinct processes are apparent; one that is FRalpha dependent and one that is independent of the receptor. FRalpha binds 5-MTHF with high affinity and facilitates efficient uptake of 5-MTHF at low extracellular folate concentrations; a lower affinity FRalpha independent system accounts for increased folate uptake at higher concentrations. Cellular metabolism of 5-MTHF depends on the route of folate entry into the cell. 5-MTHF taken up via a non-FRalpha -mediated process is rapidly metabolized to folylpolyglutamates, whereas 5-MTHF that accumulates via FRalpha remains non-metabolized, supporting the hypothesis that FRalpha may be part of a pathway for transcellular movement of the vitamin. The proton-coupled folate transporter, proton-coupled folate transporter (PCFT), mRNA was also shown to be expressed in choroid plexus epithelial cells. This is consistent with the role we have proposed for proton-coupled folate transporter in FRalpha-mediated transport as the mechanism of export of folates from the endocytic compartment containing FRalpha.