American Radium Society Appropriate Use Criteria Postmastectomy Radiation Therapy: Executive Summary of Clinical Topics.

PURPOSE: To conduct an appropriate use criteria expert panel update on clinical topics relevant to current clinical practice regarding postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: An analysis of the medical literature from peer-reviewed journals was conducted from May 4, 2010 to May 4, 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to search the PubMed database to retrieve a comprehensive set of relevant articles. A well-established methodology (modified Delphi) was used by the expert panel to rate the appropriate use of procedures. RESULTS: Evidence for key questions in PMRT regarding benefit in special populations and technical considerations for delivery was examined and described. Risk factors for local-regional recurrence in patients with intermediate-risk disease that indicate benefit of PMRT include molecular subtype, age, clinical stage, and pathologic response to neoadjuvant chemotherapy. Use of hypofractionated radiation in PMRT has been examined in several recent randomized trials and is under investigation for patients with breast reconstruction. The use of bolus varies significantly by practice region and has limited evidence for routine use. Adverse effects occurred with both PMRT preimplant and postimplant exchange in 2-staged breast reconstruction. CONCLUSIONS: Most patients with even limited nodal involvement will likely benefit from PMRT with significant reduction in local-regional recurrence and potential survival. Patients with initial clinical stage III disease and/or any residual disease after neoadjuvant chemotherapy should be strongly considered for PMRT. Growing evidence supports the use of hypofractionated radiation for PMRT with equivalent efficacy and decreased acute side effects, but additional evidence is needed for special populations. There is limited evidence to support routine use of bolus in all patients. Timing of PMRT regarding completion of 2-staged breast reconstruction requires a discussion of increased risks with radiation postimplant exchange compared with increased risk of failure of reconstruction or surgical complications with radiation preimplant exchange.

Overexpression of excision repair cross-complementing 1 gene associates with higher risk of therapeutic failure after definitive chemoradiation for unresectable non-small cell lung cancer.

BACKGROUND: Locally advanced non-small cell lung cancer (NSCLC) is typically treated with concurrent chemoradiation (CRT). Excision Repair Cross-Complementing 1 (ERCC1) is a protein involved in DNA damage repair. The objective of this study was to assess whether higher tumoral ERCC1 expression would associate with worse clinical outcomes in NSCLC treated with CRT. METHODS: Twenty-five patients were included. Relative expression levels of messenger RNA (mRNA) for ERCC1 were measured with a quantitative reverse transcription polymerase chain reaction (qRT-PCR) and expressed as scaled ERCC1 mRNA gene expression value. Patients were followed every 3 months with history, physical exam, and imaging to assess clinical outcomes. We evaluated the associations between ERCC1, as well as other prognostic variables including stage, age, gender, race, histology, RT dose, performance status, and progression free survival (PFS) and overall survival (OS) with Kaplan-Meier method and Cox regression. RESULTS: Recursive partitioning analysis identified a GeneExp cutoff of 1.54. Higher ERCC1 expression was associated with worse PFS [hazard ratio (HR) =1.70, P=0.04] and trended towards worse OS (HR =1.53, P=0.11). Increasing tumor volume (HR =1.001, P=0.055), squamous cell (HR =7.86, P=0.008) and poorly differentiated histology (HR =5.25, P=0.06) also associated with worse OS. The cumulative incidence of local recurrence at 1 year trended higher with ERCC1 GeneExp ≥1.54 (78.1%) compared to ERCC1 GeneExp <1.54 (14.9%, P=0.08). Distant relapse at 1 year was 72% with tumor ERCC1 expression ≥1.54 and 52% with ERCC1 expression <1.54 (P=0.28). CONCLUSIONS: Higher ERCC1 expression by qRT-PCR appears to correlate with worse PFS in locally advanced NSCLC treated with CRT. However, the overall sample size of the population was small; thus, larger studies are warranted to integrate molecular biomarkers to identify patients who might benefit from treatment intensification.

Flattening filter free beam energy selection and its impact in multitarget intracranial stereotactic radiosurgery treatments.

Extensive work has been done on the characteristics, dosimetry, and efficacy of flattening filter free (FFF) beams in radiosurgery. However, no study has addressed the dosimetric impact of FFF beam energy selection on treatment plan quality. This study aims to present a systematic dosimetric comparison of plan quality between 10 FFF vs 6 FFF beams in intracranial stereotactic radiosurgery (SRS) treatments using volumetric modulated arc therapy (VMAT). The dosimetric evaluation is based on radiation therapy oncology group (RTOG) dose conformity (CIRTOG) and gradient (GIRTOG) indices, and irradiated normal brain tissue volume. Thirty-five VMAT-based intracranial SRS treatments to multiple brain metastases using a 2.5 mm multileaf collimator (MLC) and 10 MV FFF beam were replanned with a 6 MV FFF and same MLC. The replans incorporated the same arc arrangement, planning target volume (PTV) and organs at risk structures, PTV coverage and prescription isodose normalization. The 6 MV FFF had a sharper dose fall-off compared to the 10 MV FFF (GIRTOG-10 FFF = 4.70, GIRTOG-6 FFF = 4.56; p < 0.05) and comparable conformity index (CIRTOG-10 FFF = 1.11, CIRTOG-6 FFF = 1.10; p = 0.9). On average, the irradiated normal brain tissue volume was 11% lower with 6 MV FFF compared to 10 MV FFF (p < 0.05). However, this difference was diminished for large target volumes and increased number of targets treated. The main dosimetric improvement of a 6 MV FFF over a 10 MV FFF beam is the sharper dose fall-off which directly correlates with less normal brain tissue volume irradiation.

Quantifying the impact of optical surface guidance in the treatment of cancers of the head and neck.

Surface guided radiation therapy (SGRT) is increasingly being adopted for use in radiation treatment delivery for Head and Neck (H&N) cancer patients. This study investigated the improvement of patient setup accuracy and reduction of setup time for SGRT compared to a conventional setup. A total of 60 H&N cancer patients were retrospectively included. Patients were categorized into three groups: oral cavity, oropharynx and nasopharynx/sinonasal sites with 20 patients in each group. They were further separated into two (2) subgroups, depending on whether they were set up with the aid of SGRT. The Align-RT™ system was used for SGRT in this work. Positioning was confirmed by daily kV-kV imaging in conjunction with weekly CBCT scans. Translational and rotational couch shifts along with patient setup times were recorded. Imaging setup time, which was defined as the elapsed time from the acquisition of the first image set to the end of the last image set, was recorded. Average translational shifts were larger in the non-SGRT group. Vertical shifts showed the most significant reduction in the SGRT group for both oropharynx and oral cavity groups. Pitch corrections were significantly higher in the SGRT group for oropharynx patients and higher pitch corrections were also observed in the SGRT groups of oral cavity and nasopharynx/sinonasal patients. The average setup time when SGRT guidance was employed was shorter for all three treatment sites although this did not reach statistical significance. The largest time reduction between the SGRT and non-SGRT groups was seen in the nasopharynx/sinonasal group. This study suggests that the use of SGRT decreases the magnitude of translational couch shifts during patient setup. However, the rotational corrections needed were generally higher with SGRT group. When SGRT was employed, a definite reduction in patient setup time was observed for nasopharynx/sinonasal and hypopharynx cancer patients.

Dosimetric comparison of deep-inspiration breath-hold and free-breathing treatment delivery techniques for left-sided breast cancer using 3D surface tracking.

INTRODUCTION: While radiation therapy has been shown to increase local control and overall survival for breast cancer, late cardiac toxicity remains a concern. Morbidity and mortality have been shown to increase proportionally to the mean heart dose. Deep inspiration breath-hold (DIBH) can reduce heart dose compared to free-breathing (FB) by increasing the heart-to-chest wall distance, especially in left-sided breast cancer. We present our clinical experience with DIBH in left breast and chest-wall irradiation using 3D optical surface tracking. MATERIALS & METHODS: 29 patients were treated with DIBH using a surface tracking system that provides a real time 3D surface image of the patient. Comparisons of maximum and mean heart dose, heart-chest wall separation, and the percentage of lung volume that receives 20 or more Gy (V20) between the DIBH and hypothetical FB treatment plans were conducted with the Student's t-test. Correlation coefficients were also calculated for heart-chest wall separation, heart volume, and lung volume. RESULTS: Comparing DIBH and FB plans showed a decrease in mean and maximum heart doses in all patients. Individual mean heart doses decreased by an average of 1.12 Gy, and the average mean heart dose for DIBH plans was significantly lower than corresponding FB plans (1.02 vs. 2.12 Gy; p < 0.0001). Maximum heart dose decreased by an average of 11.88 Gy and was significantly lower in DIBH versus FB plans (28.33 vs. 43.7 Gy; p = 0.0001). The average difference in heart to chest-wall separation between DIBH and FB images was 2.41 cm. DIBH left lung volume and measured increases in volume on inspiration inversely correlated with maximum heart dose (R = 0.39) and left lung V20 (R = 0.32). CONCLUSIONS: DIBH with 3D surface tracking can significantly benefit patients with left sided disease by limiting the mean and maximum heart dose. DIBH appears to viably reduce heart dose for left-breast cancer patients and thus potentially reduce long-term complications without prolonging treatment delivery.

Radiation dermatitis caused by a bolus effect from an abdominal compression device.

American Association of Physicists in Medicine (AAPM) Task Group 176 evaluated the dosimetric effects caused by couch tops and immobilization devices. The report analyzed the extensive physics-based literature on couch tops, stereotactic body radiation therapy (SBRT) frames, and body immobilization bags, while noting the scarcity of clinical reports of skin toxicity because of external devices. Here, we present a clinical case report of grade 1 abdominal skin toxicity owing to an abdominal compression device. We discuss the dosimetric implications of the utilized treatment plan as well as post hoc alternative plans and quantify differences in attenuation and skin dose/build-up between the device, a lower-density alternative device, and an open field. The description of the case includes a 66-year-old male with HER2 amplified poorly differentiated distal esophageal adenocarcinoma treated with neoadjuvant chemo-radiation and the use of an abdominal compression device. Radiation was delivered using volumetric modulated arc therapy (VMAT) with 2 arcs using abdominal compression and image guidance. The total dose was 50.4Gy delivered over 40 elapsed days. With 2 fractions remaining, the patient developed dermatitis in the area of the compression device. The original treatment plan did not include a contour of the device. Alternative post hoc treatment plans were generated, one to contour the device and a second with anterior avoidance. In conclusion, replanning with the device contoured revealed the bolus effect. The skin dose increased from 27 to 36Gy. planned target volume (PTV) coverage at 45Gy was reduced to 76.5% from 95.8%. The second VMAT treatment plan with an anterior avoidance sector and more oblique beam angles maintained PTV coverage and spared the anterior wall, however at the expense of substantially increased dose to lung. This case report provides an important reminder of the bolus effect from external devices such as abdominal compression. Special consideration must be given to contour and/or avoiding beam entrance to the device, and to the use of such devices in patients who may have heightened radiosensitivity, such as those who are human immunodeficiency virus (HIV)-positive.

The dosimetric impact of image guided radiation therapy by intratumoral fiducial markers.

PURPOSE: Pancreatic fiducials have proven superior over other isocenter localization surrogates, including anatomical landmarks and intratumoral or adjacent stents. The more clinically relevant dosimetric impact of image guided radiation therapy (IGRT) using intratumoral fiducial markers versus bony anatomy has not yet been described and is therefore the focus of the current study. METHODS AND MATERIALS: Using daily orthogonal kV or cone beam computed tomography (CBCT) images and positional and dosimetric data were analyzed for 12 consecutive patients treated with fiducial based IGRT and volumetric modulated arc therapy to the intact pancreas. The shifts from fiducial to bone (ΔFid-Bone) required to realign the daily fiducial-matched pretreatment images (kV, CBCTs) to the planning computed tomography (CT) using bony anatomic landmarks were recorded. The isocenter was then shifted by (ΔFid-Bone) for 5 evenly spaced treatments, and the dosimetric impact of ΔFid-Bone was calculated for planning target volume coverage (PTV50.4 and PTV47.9) and organs at risk (liver, kidney, and stomach/duodenum). RESULTS: The ΔFid-Bone were greatest in the superoinferior direction (ΔFid-Bone anteroposterior, 2.7 ± 3.0; left-right, 2.8 ± 2.8; superoinferior, 6.3 ± 7.9 mm; mean ± standard deviation; P = .03). PTV50.4 coverage was reduced by 13% (fiducial plan 95 ± 2.0 vs bone plan 82 ± 12%; P = .005; range, 5%-52%; >5% loss in all; and >10% loss in 42% of patients), and to a lesser degree for PTV47.9 (difference, -8%; range, 1%-30%; fiducial plan 100 ± 0.3% vs bone plan 92 ± 7.6%; P = .003; with reductions of >5% in 66% and >10% in 33% of patients). The dosimetric impact of ΔFid-Bone on the organs at risk was not significant. Positional shifts for kV- and CBCT-based realignments were nearly identical. CONCLUSION: Compared with matching by fiducial markers, IGRT matched by bony anatomy substantially reduces the PTV50.4 and PTV47.9 coverage, supporting the use of intratumoral pancreatic markers for improved targeting in IGRT for pancreatic cancer.

ACR Appropriateness Criteria® Resectable Stomach Cancer.

For resectable gastric cancer, perioperative chemotherapy or adjuvant chemoradiation with chemotherapy are standards of care. The decision making for adjuvant therapeutic management can depend on the stage of the cancer, lymph node positivity, and extent of surgical resection. After gastric cancer resection, postoperative chemotherapy combined with chemoradiation should be incorporated in cases of D0 lymph node dissection, positive regional lymph nodes, poor clinical response to induction chemotherapy, or positive margins. In the setting of a D2 lymph node dissection, especially those with negative regional lymph nodes, adjuvant chemotherapy alone could be considered. The American College of Radiology (ACR) Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review includes an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Practice patterns in the delivery of radiation therapy after mastectomy among the University of California Athena Breast Health Network.

BACKGROUND: Practice patterns vary with the planning and delivery of PMRT. In our investigation we examined practice patterns in the use of chest wall bolus and a boost among the Athena Breast Health Network (Athena). MATERIALS AND METHODS: Athena is a collaboration among the 5 University of California Medical Centers that aims to integrate clinical care and research. From February 2011 to June 2011, all physicians specializing in the multidisciplinary treatment of breast cancer were invited to take a Web-based practice patterns survey. Sixty-two of the 239 questions focused on radiation therapy practice environment, decision-making processes, and treatment management, including the use of a bolus or boost in PMRT. RESULTS: Ninety-two percent of the radiation oncologists specializing in breast cancer completed the survey. All of the responders use a material to increase the surface dose to the chest wall during PMRT. Materials used included brass mesh, commercial bolus, and custom-designed wax bolus. Fifty percent used tissue equivalent superflab bolus. Fifty-five percent of the respondents routinely use a boost to the chest wall in PMRT. Eighteen percent give a boost depending on the margin status, and 3 of 11 (27%) do not use a boost. CONCLUSION: Our investigation documents practice pattern variation for the use of a PMRT boost and the use of chest wall bolus among the University of California breast cancer radiation oncologists. Further understanding of the practice pattern variation will help guide clinicians in our cancer centers to a more uniform approach in the delivery of PMRT.

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.

Utilization of breast conserving therapy in stages 0, I, and II breast cancer patients in New Jersey: an American College of Surgeons National Cancer Data Base (NCDB) analysis.

BACKGROUND: The purpose of the study was to determine the use of breast conservation surgery (BCS) followed by whole breast irradiation [BCS+radiation therapy (RT)] in stages 0, I, and II breast cancer patients treated in New Jersey using the National Cancer Database. MATERIALS AND METHODS: A retrospective analysis was conducted using the data from 13 hospitals in New Jersey certified by the American College of Surgeons Commission on Cancer and members of the Cancer Institute of New Jersey's Network affiliates. Subjects with a first primary malignancy of the breast (stages 0, I, and II) treated from 2000 to 2006 were included in the analysis. RESULTS: A total of 11,146 patients with stage 0 (n=2843), stage I (n=4757), and stage II (n=3546) were treated for their breast cancer. Of stage 0, I, and II patients, 72% (n=2053), 73% (n=3482), and 53% (n=1865) received BCS, respectively. Of these patients, 40% (n=826), 67.6% (n=2353), and 63% (n=1177) received adjuvant RT after BCS for their stages 0, I, and II, respectively. Use of BCS+RT was equivalent across racial groups and all ages, except patients above 70 years of age (61% <40 y, 57% 40 to 49 y, 60% 50 to 59 y, 65% 60 to 69 y, and 51% >70 y). CONCLUSIONS: These data report an underutilization of RT after BCS in patients with stage 0 breast cancer treated across 13 hospitals in New Jersey. The Commission on Cancer's Rapid Quality Reporting System may be one method of identifying groups of patients not receiving care according to evidence-based guidelines.

A novel paradigm in the treatment of oligometastatic non-small cell lung cancer.

BACKGROUND: Stage IV non-small cell lung cancer (NSCLC) is thought to uniformly carry a poor prognosis with a median survival of less than 1 year and 5-year survival of less than 5%. In patients with a low volume (i.e. single site) of distant disease, the prognosis is slightly more favorable than that of more advanced (i.e. multiple sites of metastases) disease. For those with limited metastases, we developed a paradigm of adding concurrent chemotherapy and radiotherapy to the primary tumor once the tumor demonstrated chemotherapy sensitivity. METHODS: Charts of patients from 1999-2006 with non-small cell lung cancer were reviewed to find those with a single extra-thoracic site of disease treated with combined modality therapy. We found nine patients of 640 who met these criteria. Initial treatment consisted of induction chemotherapy, except for brain metastases which were managed first (n=1). If patients experienced a response to chemotherapy without new metastases, the extra-thoracic site was treated for total control with curative dose chemoradiotherapy to the primary site. Survival, time to progression, and sites of progression were assessed. RESULTS: Median survival was 28 months (95% CI 18-50 mo) with median time to progression of 15 months (95% CI 8-24 mo). All except one patient progressed in the CNS, either with brain metastases (n=7) or leptomeningeal disease (n=1). CONCLUSIONS: Such an approach offers the potential for enhanced quality and quantity of survival by incorporating aggressive RT for select patients without disease progression after induction chemotherapy. Patients tended to fail in the CNS, suggesting the importance of continued surveillance of the neuraxis or possibly prophylactic cranial irradiation. Future plans will correlate outcomes with molecular markers.

Hydrogen peroxide induces topoisomerase I-mediated DNA damage and cell death.

Reactive oxygen species modify DNA, generating various DNA lesions including modified bases such as 8-oxoguanine (8-oxoG). These base-modified DNA lesions have been shown to trap DNA topoisomerase I (TOP1) into covalent cleavage complexes. In this study, we have investigated the role of TOP1 in hydrogen peroxide toxicity. We showed that ectopic expression of TOP1 in Saccharomyces cerevisiae conferred sensitivity to hydrogen peroxide, and this sensitivity was dependent on RAD9 checkpoint function. Moreover, in the mammalian cell culture system, hydrogen peroxide-induced growth inhibition and apoptosis were shown to be partly TOP1-dependent as evidenced by a specific increase in resistance to hydrogen peroxide in TOP1-deficient P388/CPT45 murine leukemia cells as compared with their TOP1-proficient parental cell line P388. In addition, hydrogen peroxide was shown to induce TOP1-DNA cross-links. These results support a model in which hydrogen peroxide promotes the trapping of TOP1 on oxidative DNA lesions to form TOP1-DNA cleavage complexes that contribute to hydrogen peroxide toxicity.

Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug.

8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6] naphthyridin-6-one (ARC-111, topovale) is a new synthetic antitumor agent. In the current study, we show that ARC-111 is highly potent in scid mice carrying human tumor xenografts. ARC-111 was shown to be as active as camptothecin (CPT)-11 in the HCT-8 colon tumor model, and compared favorably with CPT-11 and topotecan in the SKNEP anaplastic Wilms' tumor model. In tissue culture models, ARC-111 exhibited low nM cytotoxicity against a panel of cancer cells. ARC-111 cytotoxicity as well as ARC-111-induced apoptosis was reduced >100-fold in CPT-resistant topoisomerase I (TOP1)-deficient P388/CPT45 cells as compared with P388 cells. Similarly, ARC-111 cytotoxicity was greatly reduced in CPT-resistant CPT-K5 and U937/CR cells, which express CPT-resistant mutant TOP1, suggesting that the cytotoxic target of ARC-111 is TOP1. Indeed, ARC-111, like CPT, was shown to induce reversible TOP1 cleavage complexes in tumor cells as evidenced by specific reduction of the TOP1 immunoreactive band in a band depletion assay, as well as elevation of small ubiquitin modifier-TOP1 conjugate levels and activation of 26S proteasome-mediated degradation of TOP1. Unlike CPT, ARC-111 is not a substrate for the ATP-binding cassette transporter breast cancer resistance protein. In addition, ARC-111 cytotoxicity was not significantly reduced in the presence of human serum albumin. These results suggest that ARC-111 is a promising new TOP1-targeting antitumor drug with a different drug resistance profile than CPT.