Leveraging intelligent optimization for automated, cardiac-sparing accelerated partial breast treatment planning.

Background: Accelerated partial breast irradiation (APBI) yields similar rates of recurrence and cosmetic outcomes as compared to whole breast radiation therapy (RT) when patients and treatment techniques are appropriately selected. APBI combined with stereotactic body radiation therapy (SBRT) is a promising technique for precisely delivering high levels of radiation while avoiding uninvolved breast tissue. Here we investigate the feasibility of automatically generating high quality APBI plans in the Ethos adaptive workspace with a specific emphasis on sparing the heart. Methods: Nine patients (10 target volumes) were utilized to iteratively tune an Ethos APBI planning template for automatic plan generation. Twenty patients previously treated on a TrueBeam Edge accelerator were then automatically replanned using this template without manual intervention or reoptimization. The unbiased validation cohort Ethos plans were benchmarked via adherence to planning objectives, a comparison of DVH and quality indices against the clinical Edge plans, and qualitative reviews by two board-certified radiation oncologists. Results: 85% (17/20) of automated validation cohort plans met all planning objectives; three plans did not achieve the contralateral lung V1.5Gy objective, but all other objectives were achieved. Compared to the Eclipse generated plans, the proposed Ethos template generated plans with greater evaluation planning target volume (PTV_Eval) V100% coverage (p = 0.01), significantly decreased heart V1.5Gy (p< 0.001), and increased contralateral breast V5Gy, skin D0.01cc, and RTOG conformity index (p = 0.03, p = 0.03, and p = 0.01, respectively). However, only the reduction in heart dose was significant after correcting for multiple testing. Physicist-selected plans were deemed clinically acceptable without modification for 75% and 90% of plans by physicians A and B, respectively. Physicians A and B scored at least one automatically generated plan as clinically acceptable for 100% and 95% of planning intents, respectively. Conclusions: Standard left- and right-sided planning templates automatically generated APBI plans of comparable quality to manually generated plans treated on a stereotactic linear accelerator, with a significant reduction in heart dose compared to Eclipse generated plans. The methods presented in this work elucidate an approach for generating automated, cardiac-sparing APBI treatment plans for daily adaptive RT with high efficiency.

Factors associated with loss to follow-up after radiation therapy for head and neck cancer.

OBJECTIVES: Head and neck cancer (HNC) patients are at high risk for late occurring radiation-related morbidity and recurrence, necessitating close long-term medical surveillance. This study identified factors associated with becoming lost to follow-up (LTFU) at a comprehensive cancer center. MATERIALS AND METHODS: Patients were drawn from survivors who received radiation for HNC at a single institution between 2001 and 2018. LTFU was defined as living patients without a clinical encounter within 2 years of the data query. RESULTS: In total, 537 patients met the inclusion criteria and 57 (10.6%) were identified as LTFU. Individual comparisons identified time since completing radiation, non-White race and being unmarried as associated with LTFU. Multiple regression identified time since treatment and being unmarried as factors associated with LTFU. A decision tree correctly sorted 89.4% using time, distance, and marital status. CONCLUSION: Time since radiation, distance to clinic, and being unmarried were factors associated with becoming LTFU.

Combining PARP and DNA-PK Inhibitors With Irradiation Inhibits HPV-Negative Head and Neck Cancer Squamous Carcinoma Growth.

Novel targeted agents to inhibit DNA repair pathways to sensitize tumors to irradiation (IR) are being investigated as an alternative to chemoradiation for locally advanced human papilloma virus negative (HPV-negative) head and neck squamous cell carcinoma (HNSCC). Two well-characterized targets that, when inhibited, exhibit potent IR sensitization are PARP1 and DNA-PKcs. However, their cooperation in sensitizing HPV-negative HNSCC to IR remains to be explored given that PARP1 and DNA-Pk CS bind to unresected stalled DNA replication forks and cooperate to recruit XRCC1 to facilitate double-strand break repair. Here, we show that the combination of the DNA-PK inhibitor NU7441 and the PARP inhibitor olaparib significantly decrease proliferation (61-78%) compared to no reduction with either agent alone (p < 0.001) in both SCC1 and SCC6 cell lines. Adding IR to the combination further decreased cell proliferation (91-92%, p < 0.001) in SCC1 and SCC6. Similar results were observed using long-term colony formation assays [dose enhancement ratio (DER) 2.3-3.2 at 4Gy, p < 0.05]. Reduced cell survival was attributed to increased apoptosis and G2/M cell cycle arrest. Kinomic analysis using tyrosine (PTK) and serine/threonine (STK) arrays reveals that combination treatment results in the most potent inhibition of kinases involved in the CDK and ERK pathways compared to either agent alone. In vivo, a significant delay of tumor growth was observed in UM-SCC1 xenografts receiving IR with olaparib and/or NU7441, which was similar to the cisplatin-IR group. Both regimens were less toxic than cisplatin-IR as assessed by loss of mouse body weight. Taken together, these results demonstrate that the combination of NU7441 and olaparib with IR enhances HPV-negative HNSCC inhibition in both cell culture and in mice, suggesting a potential innovative combination for effectively treating patients with HPV-negative HNSCC.

Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today.

PURPOSE: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts. METHODS AND MATERIALS: A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively. RESULTS: Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01). CONCLUSIONS: MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

Estrogen/progesterone receptor and HER2 discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival.

BACKGROUND: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). METHODS: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. RESULTS: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08). CONCLUSIONS: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. KEY POINTS: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

The Evolving Role of Postmastectomy Radiation Therapy.

Throughout various eras of breast cancer therapy, postmastectomy radiation therapy (PMRT) has played an important role in the treatment of locally advanced breast cancer. PMRT decreases locoregional recurrence and may improve overall survival in patients with tumors over 5 cm or positive lymph nodes. As novel cancer therapies improve survival in breast cancer, the role of radiation therapy is evolving. Individualized recommendations for PMRT dependent on pathologic response after neoadjuvant systemic therapy are under investigation. This review summarizes the role of PMRT during breast cancer therapy and discusses open questions that may change the landscape of future breast cancer treatment.

Postmastectomy Radiation Therapy: Are We Ready to Individualize Radiation?

Contemporary recommendations for postmastectomy radiation have undergone a shift in thinking away from simple stage based recommendations (one size fits all) to a system that considers both tumor biology and host factors. While surgical staging has traditionally dictated indications for postmastectomy radiation therapy (PMRT), our current understanding of tumor biology, host, immunoprofiles, and tumor microenvironment may direct a more personalized approach to radiation. Understanding the interaction of these variables may permit individualization of adjuvant therapy aimed at appropriate escalation and deescalation, including recommendations for PMRT. This article summarizes the current data regarding tumor and host molecular biomarkers in vitro and in vivo that support the individualization of PMRT and discusses open questions that may alter the future of breast cancer treatment.

Changes in neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios during chemoradiation predict for survival and pathologic complete response in trimodality esophageal cancer patients.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) predict for survival in cancer patients. In patients receiving multimodality therapy, the effect of therapy on the NLR and PLR is not well understood. We evaluated changes in NLR and PLR among locally advanced esophageal cancer patients who received trimodality therapy. METHODS: We performed a retrospective analysis of nonmetastatic patients with esophageal cancer who received neoadjuvant chemoradiation therapy (CRT) followed by esophagectomy at our institution between March 2000 and April 2012. NLR and PLR values were obtained for the following time points (TPs): (I) at diagnosis before CRT; (II) after CRT but prior to surgery; and (III) after surgery. We evaluated changes in NLR and PLR using the difference and ratio between TPs. Overall survival (OS) was evaluated by Kaplan-Meier analysis. Univariate and multivariate Cox regression models were applied to evaluate the independent prognostic significance of NLR and PLR. RESULTS: This IRB-approved study included the records of 83 consecutive patients with stage II-IV esophageal cancer. The median age was 60 years, and median follow-up was 29.3 months. Patients were treated to a median prescription dose of 50.4 Gy (range, 50.4-56.4 Gy) in 28-33 fractions. Median NLR and PLR were 3.3 and 157.2, 12 and 645, and 11.5 and 391.7 at TPs 1, 2, and 3, respectively. On multivariate analysis, superior OS was associated with PLR ≥250 at TP3 (P=0.03), PLR decrease ≥609.2 between TP2 and TP3 (P=0.02), and PLR ratio (TP3/TP1) ≥1.08 (P=0.03). Inferior progression-free survival (PFS) was associated with NLR ≥36 at TP2 (P=0.0008), NLR increase ≥28.3 between TP1 and TP2 (P=0.0005), and PLR ratio (TP2/TP3) ≥0.38 (P=0.1). Pathologic complete response (PCR) was less likely for adenocarcinoma (AC) histology (P=0.03), NLR ≥10.6 at TP2 (P=0.04), and NLR increase ≥4.6 from TP1 to TP2 (P=0.03). CONCLUSIONS: To our knowledge, this is the first study to examine NLR and PLR values at various time intervals throughout treatment and demonstrate a correlation between OS, PFS, and PCR in patients undergoing trimodality therapy for esophageal cancer.

Primary Gross Tumor Volume is an Important Prognostic Factor in Locally Advanced Esophageal Cancer Patients Treated with Trimodality Therapy.

PURPOSE: This study investigated the relationship between tumor volume and outcomes in patients receiving trimodality therapy for locally advanced esophageal cancer. METHODS: Between 2001 and 2012, 67 patients treated for esophageal cancer with chemoradiotherapy followed by esophagectomy who had available gross tumor volume (GTV) information were analyzed (35 node-negative, 32 node-positive patients with primary and nodal GTV contoured as separate regions of interest). All gross tumor volumes (GTVs) were contoured at the time of radiotherapy treatment planning. GTV optimal cutoff values were determined with receiver operating characteristic analysis and deemed significant when χ (2) analysis demonstrated differences in examined prognostic variables. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Cox proportional hazards model. RESULTS: GTVprimary (P = 0.034) and N stage were significant multivariate predictors for improved local control; GTVprimary was the only multivariate predictor of PFS (P = 0.0299) and OS (P = 0.001228) at 5 years. Univariate predictors of 5-year PFS and OS included GTVprimary, node number, and metastatic lymph node ratio. GTVprimary >85 cc was the best predictor for local failure (33.3 %; 8.7 % if ≤85 cc). GTVprimary >46 cc correlated with an increased risk of 5-year distant failure (37.1 %; 6.7 % if ≤46 cc). CONCLUSIONS: GTVprimary was a significant multivariate predictor for improved local control, PFS, and OS. GTVprimary is a more powerful predictor of patient outcomes than traditional TNM staging and should be part of the decision-making process when determining optimal local and systemic options for patients with locally advanced esophageal cancer.

Stereotactic radiotherapy using tomotherapy for early-stage non-small cell lung carcinoma: analysis of intrafraction tumour motion.

INTRODUCTION: Intrafraction tumour motion in helical tomotherapy was investigated by comparing pre- and mid-fraction CT scans in patients with early non-small cell lung carcinoma (NSCLC) to assess the efficacy of a 7-mm margin around gross tumour volumes (GTVs) in stereotactic body radiation therapy (SBRT). METHODS: Thirty patients with early-stage NSCLC received SBRT in four or five fractions for a total of 141 treatments. A slow positron emission tomography/CT scan was fused with the simulation CT to determine the GTV. A planning target volume was created by placing an isotropic margin of 7 mm around the GTV. Data were retrospectively analyzed to assess translational tumour positional changes along the x, y and z axes and vector changes in millimeters from the pretreatment megavoltage (MV)-CT to the mid-fraction MV-CT. RESULTS: Average movements for all 141 treatment days along the x, y and z axes were 0.5 ± 2.3, -0.3 ± 3.0 and 0.9 ± 3.0 mm, respectively. Average movements for each patient along the x, y and z axes were 0.5 ± 1.5, -0.2 ± 2.0 and 0.9 ± 1.9 mm, respectively. Average vector displacement was 4.3 ± 2.4 mm for all treatment days and 4.2 ± 1.7 mm for each patient. Of 141 treatments, 137 (97.2%) fell within 7.0 mm in all axes. CONCLUSION: The addition of a 7-mm margin to the GTV for patients receiving SBRT for NSCLC using tomotherapy is adequate to account for tumour movement. Mid-fraction CT scans proved to be valuable in assessing intrafraction tumour motion.

Potential of glyburide to reduce intracerebral edema in brain metastases.

Metastatic disease to the brain results in significant morbidity because of edema in the central nervous system. Current anti-edema therapies are either expensive or result in unwanted long-term side effects. Sulfonylurea receptor 1 (Sur1) is a transmembrane protein that, when activated in the central nervous system, allows for unregulated sodium influx into cells, a process that has been linked to cytotoxic edema formation in ischemic stroke, subarachnoid hemorrhage, spinal cord injury, traumatic brain injury, and, most recently, brain metastases. In this focused review, we explore preclinical data linking Sur1 channel formation to development of edema and reference evidence suggesting that the antidiabetic sulfonylurea drug glyburide (a Sur1 inhibitor) is an inexpensive and well-tolerated agent that can be clinically tested to reduce or prevent malignancy and/or treatment-associated edema.