Citations

Nanoliposomal irinotecan (nal‐IRI) is a liposomal formulation of irinotecan with a longer half‐life (t1/2), higher plasma total irinotecan (tIRI), and lower SN‐38 maximum concentration (Cmax) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal‐IRI was performed for tIRI and total SN‐38 (tSN38) using patient samples from six studies. PK‐safety association was evaluated for neutropenia and diarrhea in 353 patients. PK‐efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN‐38 (uSN38) above a threshold and higher Cavgof tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38Cmaxand diarrhea with tIRICmax. Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal‐IRI dose of 70 mg/m2(free‐base; equivalent to 80 mg/m2salt base) Q2W over 100 mg/m2Q3W.

48 Background: The purpose of this study is to identify differences in toxicity, quality of life (QOL), and dosimetric endpoints among patients with low-risk prostate adenocarcinoma treated with either standard fractionation or hypofractionation proton-beam therapy. Methods: We analyzed the results of the first 75 patients treated in our phase III trial comparing 38Gy relative biological effectiveness (RBE) in 5 fractions (fx) (n = 46) vs. 79.2Gy (RBE) in 44 fx. (n = 29). All patients had low-risk prostate cancer and were treated with proton radiation using fiducial markers and daily image guidance. We evaluated American Urological Association (AUA) Symptom Index, adverse events (AEs), and Expanded Prostate Index Composite (EPIC) domains at pretreatment and 3, 6, 12, 18, 24, 36 and 48 months. Doses to the prostate were selected based on similar long term effects to normal tissue based on an α/β = 3.5 for an EQD2 of 76Gy. Results: The median follow-up was 36 months for both groups; 23 (30%) patients reached a follow-up of 48 months. We observed a small difference in AUA score (3.2 vs. 8.6, p = 0.002) at 1-year favoring the 79.2Gy arm. AUA scores were not statistically different at 18 months and after. Similarly, EPIC Urinary symptoms favored the 79.2Gy arm at 1 year (92.3 vs. 84.5, p = 0.009) and 18 months (92.3 vs. 85.3, p = 0.03); bother scores were not significantly different at any other time points. G2 or higher GU toxicity was similar between arms (p = 0.8). No differences in EPIC Bowel symptoms, EPIC Sexual symptoms, or bowel G2 or higher toxicities were seen. One death was observed in the 38Gy arm due to an unrelated case of multiple myeloma. The bladder V80 (79.2Gy arm, p = 0.04) and V39 (38Gy arm, p = 0.05) were predictive for G2 or higher GU AE. There was no association observed between rectal dose and G2 or higher rectal toxicity. Conclusions: Patients treated in the hypofractionated and standard arms tolerated treatment well. A small and temporary difference in the GU domain was seen favoring the standard arm. As predicted long term effects on the GU domain and bowel were similar for both arms, suggesting that the α/β is similar to 3.5 for long term effects. Clinical trial information: 01230866.

3 Background: There is a clear need to develop a clinically relevant molecular subtyping approach for prostate cancer. We hypothesized that prostate cancer can be subtyped based on luminal versus basal lineage. Methods: We applied the PAM50 classifier, which is used clinically to identify luminal and basal cancers in breast cancer, to subtype a total of 3,782 prostate cancer samples using a high-density microarray platform run in a CLIA-certified laboratory. We examined the associations of these subtypes and clinical outcomes. Results: We demonstrate that PAM50 segregates prostate cancer into three reproducible subtypes in both retrospective cohorts and on prospective validation: luminal A (33.3%-34.3%), luminal B (28.5%-32.6%), and basal (34.1%-37.1%). Luminal B prostate cancers exhibited the worst clinical prognoses, followed by basal and luminal A subtypes (10-year biochemical recurrence-free survival: 29/39/41%; distant metastasis-free survival: 53/73/73%; prostate cancer-specific survival: 78/86/89%; overall survival: 69/80/82% respectively) on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors. Known luminal lineage markers, such as NKX3.1 and KRT18, and the basal lineage CD49f signature, were enriched in luminal- and basal-like cancers respectively, demonstrating the connection between these subtypes and established prostate cancer biology. While both luminal-like subtypes were associated with increased AR expression and signaling, only luminal B prostate cancers were significantly associated with post-operative response to androgen deprivation therapy (ADT) in a subset analysis matching patients based on clinicopathologic variables (interaction p = 0.006, luminal B 10-year metastasis: 33% (treated) vs. 55% (untreated), non-luminal B: 37% (treated) vs. 21% (untreated)). Conclusions: These findings contribute novel insight into the biology of prostate cancer, and provide translatable clinical tools for personalizing post-operative ADT for patients with prostate cancer. Similar to breast cancer, these findings suggest that luminal/basal subtyping may be useful in treatment selection in prostate cancer.

AbstractBackgroundVascularized lymph node (VLN) transfer for lymphedema treatment has shown promising results. Optimal donor and recipient sites remain a matter of debate. We describe the technique and outcomes of a laparoscopically harvested extended gastroepiploic VLN flap with two levels of inset.Patients and MethodsBetween 2014 and 2015, four‐patients with upper limb breast cancer‐related lymphedema and three‐patients with lower limb pelvic cancer‐related lymphedema who underwent VLN transfers were included. After harvest, the gastroepiploic VLN flap was divided into two halves that were separately inset at the level of elbow and wrist (upper limb) or knee and ankle (lower limb). The mean patient age was 53.1 years (range, 42–65 years).ResultsThe average flap size after division was 6.3 cm in length (range, 5–7 cm) and 3.4 cm in width (range, 3–4 cm). The mean pedicle length was 3.2 cm (range, 2.5–4 cm). All flaps survived completely. No donor or recepient site complication was noted. At a mean follow‐up of 9.7 months (range, 8–11 months), the mean circumference reduction rate was 43.7 ± 2.5% along the entire limb (P < 0.05). No episode of infection was noted postoperatively.ConclusionsDouble gastroepiploic VLN transfers to middle and distal limb are a safe approach with very promising results. This technique may be used to improve clinical outcomes by enhancing the lymphatic drainage of the entire affected limb in a uniform fashion. In addition, the laparoscopic harvest can provide decreased donor site morbidity with a faster recovery.

Acute respiratory compromise describes a deterioration in respiratory function with a high likelihood of rapid progression to respiratory failure and death. Identifying patients at risk for respiratory compromise coupled with monitoring of patients who have developed respiratory compromise might allow earlier interventions to prevent or mitigate further decompensation. The National Association for the Medical Direction of Respiratory Care (NAMDRC) organized a workshop meeting with representation from many national societies to address the unmet needs of respiratory compromise from a clinical practice perspective. Respiratory compromise may arise de novo or may complicate preexisting lung disease. The group identified distinct subsets of respiratory compromise that present similar opportunities for early detection and useful intervention to prevent respiratory failure. The subtypes were characterized by the pathophysiological mechanisms they had in common: impaired control of breathing, impaired airway protection, parenchymal lung disease, increased airway resistance, hydrostatic pulmonary edema, and right-ventricular failure. Classification of acutely ill respiratory patients into one or more of these categories may help in selecting the screening and monitoring strategies that are most appropriate for the patient's particular pathophysiology. Standardized screening and monitoring practices for patients with similar mechanisms of deterioration may enhance the ability to predict respiratory failure early and prevent its occurrence.

131 Background: Research demonstrating a volume-outcome relationship has resulted in regionalization of complex cancer surgery to high volume hospitals. A simultaneous national trend towards improved surgical outcomes brings into question whether the potential benefits of regionalization are still relevant. We hypothesize that the difference in adjusted post-operative mortality between low and high volume hospitals has decreased over time. Methods: The National Cancer Database (NCDB) was used to identify patients with colon, esophageal, and pancreatic cancer undergoing curative intent surgery from 2003-2011. Hospitals were divided into low ( < 25th percentile), medium (25th-75th) and high ( > 75thpercentile) volume groups depending on annual volume of cancer-specific surgery. Year-specific hospital averaged observed/expected (O/E) ratios were calculated for 90-day mortality. Poisson regression was used to model hospital averaged O/E ratios over time. Results: Our study population included 343,929 patients with colon (88%), esophageal (5%) and pancreatic (7%) cancer. There were significant (p < 0.05) improvements in adjusted 90-day mortality from 2003 and 2011 for all volume categories and cancer types, except in high volume hospitals for esophageal cancer. In 2003, high volume hospitals had significantly better outcomes compared to low volume hospitals for all cancer types, as suggested by lower O/E ratios for 90 day mortality (p < 0.05). However, by 2011 the difference in O/E ratios for 90 day mortality was no longer significantly lower for high compared to low volume hospitals (p > 0.05); this was true for all three cancer types (Figure1). Conclusions: During the period of our study, 90-day mortality following gastrointestinal cancer surgery improved in low, medium and high volume hospitals. However, by 2011 the difference in adjusted post-operative mortality between low and high volume hospitals was not significantly different, likely due to global improvements in operative and peri-operative care. This attenuation of the volume-outcome curve has important implications for policy pertaining to regionalization of cancer care in the US.