Noah S. Kalman

The Business Case for Palliative Care: Translating Research Into Program Development in the U.S.

Specialist palliative care (PC) often embraces a “less is more” philosophy that runs counter to the revenue-centric nature of most health care financing in the U.S. A special business case is needed in which the financial benefits for organizations such as hospitals and payers are aligned with the demonstrable clinical benefits for patients. Based on published studies and our work with PC programs over the past 15 years, we identified 10 principles that together form a business model for specialist PC. These principles are relatively well established for inpatient PC but are only now emerging for community-based PC. Three developments that are key for the latter are the increasing penalties from payers for overutilization of hospital stays, the variety of alternative payment models such as accountable care organizations, which foster a population health management perspective, and payer-provider partnerships that allow for greater access to and funding of community-based PC.

Local Radiotherapy Intensification for Locally Advanced Non–small-cell Lung Cancer – A Call to Arms

Chemoradiotherapy, the standard of care for locally advanced non-small-cell lung cancer (NSCLC), often fails to eradicate all known disease. Despite advances in chemotherapeutic regimens, locally advanced NSCLC remains a difficult disease to treat, and locoregional failure remains common. Improved radiographic detection can identify patients at significant risk of locoregional failure after definitive treatment, and newer methods of escalating locoregional treatment may allow for improvements in locoregional control with acceptable toxicity. This review addresses critical issues in escalating local therapy, focusing on using serial positron emission tomography-computed tomography to select high-risk patients and employing stereotactic radiotherapy to intensify treatment. We further propose a clinical trial concept that incorporates the reviews findings.

Current Status of Targeted Radioprotection and Radiation Injury Mitigation and Treatment Agents: A Critical Review of the Literature

As more cancer patients survive their disease, concerns about radiation therapy-induced side effects have increased. The concept of radioprotection and radiation injury mitigation and treatment offers the possibility to enhance the therapeutic ratio of radiation therapy by limiting radiation therapy-induced normal tissue injury without compromising its antitumor effect. Advances in the understanding of the underlying mechanisms of radiation toxicity have stimulated radiation oncologists to target these pathways across different organ systems. These generalized radiation injury mechanisms include production of free radicals such as superoxides, activation of inflammatory pathways, and vascular endothelial dysfunction leading to tissue hypoxia. There is a significant body of literature evaluating the effectiveness of various treatments in preventing, mitigating, or treating radiation-induced normal tissue injury. Whereas some reviews have focused on a specific disease site or agent, this critical review focuses on a mechanistic classification of activity and assesses multiple agents across different disease sites. The classification of agents used herein further offers a useful framework to organize the multitude of treatments that have been studied. Many commonly available treatments have demonstrated benefit in prevention, mitigation, and/or treatment of radiation toxicity and warrant further investigation. These drug-based approaches to radioprotection and radiation injury mitigation and treatment represent an important method of making radiation therapy safer.

Reducing rectal injury in men receiving prostate cancer radiation therapy: current perspectives

Dose escalation is now the standard of care for the treatment of prostate cancer with radiation therapy. However, the rectum tends to be the dose-limiting structure when treating prostate cancer, given its close proximity. Early and late toxicities can occur when the rectum receives large doses of radiation therapy. New technologies allow for prevention of these toxicities. In this review, we examine the evidence that supports various dose constraints employed to prevent these rectal injuries from occurring. We also examine the use of intensity-modulated radiation therapy and how this compares to older radiation therapy techniques that allow for further sparing of the rectum during a radiation therapy course. We then review the literature on endorectal balloons and the effects of their daily use throughout a radiation therapy course. Tissue spacers are now being investigated in greater detail; these devices are injected into the rectoprostatic fascia to physically increase the distance between the prostate and the anterior rectal wall. Last, we review the use of systemic drugs, specifically statin medications and antihypertensives, as well as their impact on rectal toxicity.

Low-dose splenic irradiation prior to hematopoietic cell transplantation in hypersplenic patients with myelofibrosis

For patients with myelofibrosis undergoing hematopoietic cell transplantation (HCT), splenomegaly can lead to a protracted post-transplant course and is associated with lower survival in some series [1–3]. Splenectomy has been used in some patients prior to HCT, and studies have demonstrated that splenectomy prior to HCT reduced engraftment time (13 versus 20 d [2]). However, at many centers, splenectomy has fallen out of favor due to high complication rates (5% peri-operative mortality and 30–45% peri-operative morbidity [4]) and acceptable engraftment rates with HCT even in patients with significant splenomegaly [5]. Splenic irradiation has a long history in treating myelofibrosis, with low-dose treatment effective in alleviating painful splenomegaly [6,7]. In patients undergoing HCT for chronic myeloid leukemia, splenic irradiation has been used prior to transplant to reduce tumor burden and improve post-transplant kinetics [8], with a randomized study showing a survival benefit to splenic irradiation in a subset of patients [9]. Immunomodulatory drugs, JAK inhibitors, and mTOR inhibitors have also demonstrated efficacy in improving splenomegaly but have not been evaluated in the pre-transplant setting [10]. Starting in 2011, it has been standard practice at our institution to refer myelofibrosis patients with splenomegaly for low-dose splenic irradiation (LDSI) prior to HCT to attempt to reduce spleen size and improve posttransplant count recovery without the morbidity of splenectomy. Herein we report the outcomes of these patients. Medical records were examined after approval was obtained from our institution’s institutional review board. Between 2011 and 2015, eight patients received LDSI prior to HCT for myelofibrosis. Radiographic documentation of spleen size preand post-transplantation was available for seven patients. Spleen length is reported as the maximum cranio-caudal dimension on abdominal ultrasound. Regarding HCT, five patients had HLA matched related donors. All patients underwent reduced intensity conditioning regimens with busulfan plus fludarabine or melphalan. Anti-thymocyte globulin was given to one of five related donor patients and to all three unrelated donor patients. No patient received total body irradiation. Graft versus host disease (GVHD) prophylaxis was evenly split between cyclosporine and tacrolimus: one patient, whose donor was an identical twin, did not require GVHD prophylaxis. Median LDSI prescription dose was 4.5 Gray (range 3.0–6.0 Gray), delivered in 3 fractions (range 3–6 fractions) over 6 d (range 3–9 d). Patients finished treatment a median of 14 d prior to HCT (range 7–24 d). The date of graft infusion was defined as day 0 of transplant. Patients achieved neutrophil and platelet engraftment on the first of three consecutive days with an absolute neutrophil count of 0.5 10/L and an absolute platelet count of 50,000 10/L, respectively. At our institution, patients received red blood cell and platelet transfusions if their hemoglobin level fell below 8 g/dL and their platelet level fell below 30,000 10/L, respectively. Change in spleen length was evaluated by the Wilcoxon rank sum test, with continuity correction for continuous variables. Median age and Karnofsky performance score were 60 years and 80, respectively (Table 1). Median pre-transplant spleen length was 27 cm. All patients had a spleen size greater than 20 cm. Median time after HCT to repeat splenic imaging was 5 months (range 2–8 months). The patient cohort experienced a significant reduction in spleen size (median decrease 10cm (36%), p< .01). Acute LDSI treatment toxicity was mild (two patients with grade 1 and two patients with grade 2 nausea); no grade 3 toxicities were observed. Median times to neutrophil and platelet engraftment were 13 and 26 d, respectively. At 2 years post-HCT, 75%

Diabetes mellitus and radiation induced lung injury after thoracic stereotactic body radiotherapy

BACKGROUND Radiographic radiation induced lung injury (RILI) is frequently observed after stereotactic body radiotherapy (SBRT). Models of radiographic change can identify patient risk factors that predict clinical toxicity. We examined the association between radiographic lung changes and lung tissue dose-density response over time with clinical risk factors for RILI, such as diabetes. METHODS 424 baseline and follow up CT scans at 3, 6, and 12 months post-treatment were analyzed in 116 patients (27 with diabetes) undergoing thoracic SBRT. Volumes of dense/hazy regions and lung parenchyma dose-density response curves were evaluated with respect to follow up time, diabetes, and other factors. RESULTS Dense and hazy tissue regions were larger in the diabetic population, with the effect most pronounced at 3 months. Similarly, dose-density response curves showed greater density change versus dose in the diabetic group (all p < 0.05). Diabetes, time, the interaction of diabetes and time, smoking status, African American race, baseline lung density, and tumor location were significantly associated with radiographic changes on mixed effect analyses. PTV size, pulmonary function, and medication exposure did not significantly impact RILI. Clinical grade 1-2 pneumonitis was more prevalent in diabetic patients (p = 0.02). However, radiographic change did not correlate with clinical pneumonitis. CONCLUSIONS The presence of diabetes and other clinical factors is associated with increased volume and density of radiographic RILI after lung SBRT, most prominently early after treatment. This is the first report demonstrating the increased severity of RILI after SBRT in diabetic patients. Increased caution treating diabetic patients may be warranted.

Cardiac radiation dose distribution, cardiac events and mortality in early-stage lung cancer treated with stereotactic body radiation therapy (SBRT)

Background The impact of radiation dose to the heart in early-stage lung cancer patients treated with definitive stereotactic body radiation therapy (SBRT) is not well known. We, therefore, analyzed whether higher radiation dose to the heart would lead to an increase in cardiac toxicity and overall mortality. Methods Seventy-four patients with 75 tumors treated definitively with SBRT for early-stage non-small cell lung cancer (NSCLC) and two cases of limited-stage small cell lung cancer (SCLC) with an average follow-up of 35 months (range, 1-130 months) were retrospectively analyzed. The whole heart and cardiac substructures including atria, ventricles, heart valves, atrioventricular (AV) node and four major coronary artery branches were contoured using commercial treatment planning software. For each structure, multiple dose-volume parameters were recorded. The relation between radiation doses to the heart, tumor location, and preexisting medical conditions with the development of cardiac events and mortality was assessed. Results Overall, there was large variability in dose to cardiac substructures: mean heart dose (MHD) averaged 1.90 Gy (range, 0.04-11.00 Gy) equivalent 2 Gy dose (EQD2) and average max dose to the left anterior descending artery (LAD) was 5.67 Gy (range, 0.04-48.60 Gy) EQD2. Patients with tumor location in the upper lobes received higher cardiac radiation dose compared to other lobes (P<0.0001). There was no difference in MHD between central and peripheral tumor locations. The distance between heart and tumor was negatively associated with MHD (r=-0.61, P<0.0001). Eighteen patients developed cardiac complications including the need for defibrillator placement, arrhythmia development and worsening heart failure. Preexisting cardiac disease was associated with an increased number of cardiac events after radiotherapy (P=0.039). However, neither radiation dose to the whole heart or the cardiac substructures, nor comorbidities such as diabetes, hypercholesterolemia, hypertension or COPD were associated with the number of cardiac events or overall mortality. Conclusions Radiation doses to the heart and its substructures show large variability. Cardiac events occurred more frequently in patients with a history of heart problems. At present, the effect of radiation dose on cardiac toxicity is unclear in patients undergoing SBRT for early-stage lung cancer. Longer follow-up and a larger cohort are needed to assess for late cardiac sequelae.

Image guidance for post-prostatectomy radiotherapy: Are we missing the mark?

56 Background: Image-guided radiation therapy (IGRT) has been widely adopted for both definitive and post-operative prostate radiotherapy. In the postoperative setting, numerous studies of prostate bed motion have recommended tight planning margins (<10mm) if IGRT is used daily. The purpose of this analysis is to determine the effect of IGRT on the efficacy and toxicity of post-operative prostate radiotherapy. METHODS Between 1998 and 2010, 286 patients received radiation therapy after prostatectomy at Duke. Recurrent disease following radiation therapy was defined as PSA >0.2 ng/ml and rising or initiation of salvage ADT. CTCAE v 4.0 and the RTOG/LENT late morbidity scores were used to grade acute and late toxicities. Risk for biochemical failure and late Grade 2+ GI toxicity were compared between IGRT (N = 113) and non-IGRT (N = 173) patients using multivariable adjusted Cox regression controlling for age, treatment technique (3D vs IMRT), radiation dose, androgen suppression, pathologic Gleason Score, margin status, pathologic stage, and pre-radiotherapy PSA level. RESULTS The median margin size for patients with IGRT was 7mm (IQR 6-10mm) and 15mm (IQR 7-15mm) for those without IGRT (p < 0.001). Median follow up was 21 months (IQR 15-33 mo) for patients with IGRT and 49 months (IQR 30-73 mo) for those without IGRT (p < 0.001). On multivariate analysis, patients treated with IGRT had a greater risk of progression versus non-daily imaging (HR = 2.51, p < 0.001), as did patients who received salvage versus adjuvant radiotherapy (HR = 2.41, p = 0.005). Higher pathologic Gleason Score (HR = 1.96, p = 0.026) and pathologic stage (HR = 1.93, p = 0.003) conferred increased risk of progression, while positive margin status was protective (HR = 0.53, p = 0.002). Age, radiation dose, androgen suppression, and treatment technique did not affect biochemical outcome (p > 0.1). There were no differences in acute or late GI toxicity according to treatment technique or use of IGRT (both p > 0.1). CONCLUSIONS The use of IGRT was associated with increased biochemical recurrence for patients receiving post-operative prostate radiotherapy. For these patients, we recommend using treatment margins of at least 10mm to address subclinical disease and organ motion.