Carolyn Revta

Novel investigational biologics for the treatment of cancer cachexia

Introduction: Cancer cachexia is a complex multifactorial syndrome characterized by ongoing, irreversible skeletal muscle loss, leading to progressive functional impairment. Several investigational biologics targeting key inflammatory pathways and/or the myostatin/activin type II receptor pathway are in development. Areas covered: Novel therapies include ALD518, MABp1, IP-1510, OHR/AVR118, bimagrumab and REGN1033 and are discussed. For each investigational therapy, the mechanism of action, preclinical data, cachexia definition, indication and clinical data are discussed. Expert opinion: A critical look of the study protocols and two key challenges limiting the successful evaluation of these agents include: i) lack of a clinically meaningful cachexia definition; and ii) identification and treatment of cachexia in late stage. We describe our observations and clinical experience in an effort to redirect and promote successful strategies to evaluate these novel investigational biologics.

Weight loss versus muscle loss: re-evaluating inclusion criteria for future cancer cachexia interventional trials.

PurposeParticipation in cancer cachexia clinical trials requires a defined weight loss (WL) over time. A loss in skeletal muscle mass, measured by cross-sectional computed tomography (CT) image analysis, represents a possible alternative. Our aim was to compare WL versus muscle loss in patients who were screened to participate in a cancer cachexia clinical trial.MethodsThis was a single-center, retrospective analysis in metastatic colorectal cancer patients screened for an interventional cancer cachexia trial requiring a ≥5xa0% WL over the preceding 6xa0months. Concurrent CT images obtained as part of standard oncology care were analyzed for changes in total muscle and fat (visceral, subcutaneous, and total).ResultsOf patients screened (nxa0=xa036), 3 (8xa0%) enrolled in the trial, 17 (47xa0%) were excluded due to insufficient WL (<5xa0%), 3 (8xa0%) were excluded due to excessive WL (>20xa0%), and 16 (44xa0%) met inclusion criteria for WL. Patients who met screening criteria for WL (5–20xa0%) had a meanxa0±xa0SD of 7.7xa0±xa08.7xa0% muscle loss, 24.4xa0±xa037.5xa0% visceral adipose loss, 21.6xa0±xa022.3xa0% subcutaneous adipose loss, and 22.1xa0±xa024.7xa0% total adipose loss. Patients excluded due to insufficient WL had 2xa0±xa06.4xa0% muscle loss, but a gain of 8.5xa0±xa039.8xa0% visceral adipose, and 4.2xa0±xa028.2xa0% subcutaneous adipose loss and 0.8xa0±xa028.4xa0% total adipose loss. Of the patients excluded due to WL <5xa0% (nxa0=xa017), 7 (41xa0%) had a skeletal muscle loss >5xa0%.ConclusionsDefining cancer cachexia by WL over time may be limited as it does not capture skeletal muscle loss. Cross-sectional CT body composition analysis may improve early detection of muscle loss and patient participation in future cancer cachexia clinical trials.

Advance Care Planning and Palliative Care Integration for Patients Undergoing Hematopoietic Stem-Cell Transplantation

PURPOSEnAdvance care planning (ACP) in hematopoietic stem-cell transplantation (HSCT) is challenging, given the potential for cure despite increased morbidity and mortality risk.The aim of this study was to evaluate ACP and palliative care (PC) integration for patients who underwent HSCT.nnnMETHODSnA retrospective analysis was conducted and data were extracted from electronic medical records of patients who underwent HSCT between January 2011 and December 2015. Patients who received more than one transplant and who were younger than 18 years of age were excluded. The primary objective was to determine the setting and specialty of the clinician who documented the initial and final code status. Secondary objectives included evaluation of advance directive and/or completion of the Physician Orders for Life-Sustaining Treatment form, PC consultation, hospice enrollment, and location of death.nnnRESULTSnThe study sample comprised 39% (n = 235) allogeneic and 61% (n = 367) autologous HSCTs. All patients except one (n = 601) had code status documentation, and 99.2% (n = 596) were initially documented as full code. Initial and final code status documentation in the outpatient setting was 3% (n = 17) and 24% (n = 143), respectively. PC consultation occurred for 19% (n = 114) of HSCT patients, with 83% (n = 95) occurring in the hospital. Allogeneic transplant type and age were significantly associated with greater rates of advance directive and/or Physician Orders for Life-Sustaining Treatment completion. Most patients (85%, n = 99) died in the hospital, and few were enrolled in hospice (15%, n = 17).nnnCONCLUSIONnTo our knowledge, this is the largest single-center study of ACP and PC integration for patients who underwent HSCT. Code status documentation in the outpatient setting was low, as well as utilization of PC and hospice services.

Transmucosal Immediate-Release Fentanyl for Breakthrough Cancer Pain: Opportunities and Challenges for Use in Palliative Care

ABSTRACT Opioids are used to treat breakthrough cancer pain (BTCP) and can be classified by relative duration and onset of action. Regulatory approvals of numerous transmucosal immediate-release fentanyl (TIRF) formulations provide alternative options to palliative care–trained providers in the management of BTCP. TIRFs have been formulated as a sublingual tablet, sublingual spray, intranasal spray, pectin-based nasal spray, buccal tablet, and buccal soluble film. Differences exist between TIRFs regarding formulation design and dosing to treat BTCP. Opportunities for use include palliation of BTCP in head and neck cancer and/or radiation-induced mucositis. The purpose of this review is to discuss TIRF formulation and dosing, pharmacokinetics, clinical efficacy, patient acceptability, and safety/tolerability. In addition, barriers to TIRF utilization will be discussed.

Transfusion practices at end of life for hematopoietic stem cell transplant patients

PurposeLimited data exist regarding transfusion practices at end of life (EOL) for hematopoietic stem cell transplant (HSCT) patients. The purpose of this study was to examine red blood cell (RBC) and platelet transfusion practices in HSCT patients who enrolled or did not enroll in hospice.MethodsThis was a single-center, retrospective chart review in deceased HSCT patients. The primary objective was to determine the mean difference between the last transfusion and death in HSCT patients (nu2009=u2009116) who enrolled or did not enroll in hospice.ResultsSixteen (14%) and 100 (86%) patients were enrolled in hospice and not enrolled in hospice, respectively. Hospice patients observed a larger mean difference between death and last transfusion (45.9u2009±u200966.7 vs. 14.6u2009±u200948.1xa0days, pu2009<u20090.0001). A higher amount of platelet, but not RBC, transfusions occurred in patients not enrolled in hospice (pu2009=u20090.04). The last transfusion that occurred more than 96xa0h before death was observed in 12 (75%) and 22 (22%) in hospice and non-hospice patients, respectively. For HSCT patients not enrolled in hospice, 17 patients received a transfusion on the same day of death and 31 patients received the last transfusion 24xa0h before death.ConclusionsBlood transfusion practices differed in HSCT patients enrolled and not enrolled in hospice. For most patients not enrolled in hospice, the last transfusion occurred 24xa0h before death. Future efforts should explore if limited access to blood products is a barrier to hospice enrollment for HSCT patients.

Molecular tumor profiling ordering trends in cancer patients.

165 Background: Molecular tumor profiling may provide information as to whether to initiate or not initiate a targeted therapy. As to the timing of when the tumor profiling is ordered relative to date of diagnosis, date of death, and palliative care (PC) consultations are unknown. The primary objective of this study was to examine molecular tumor profiling ordering trends in the course of cancer illness.nnnMETHODSnA preliminary, retrospective chart review was conducted in a cohort of patients with a confirmed diagnosis of cancer at an academic, NCI-designated comprehensive cancer center. Patients were identified from a tumor registry and then matched to a next generation sequencing molecular tumor profiling database. The date of palliative care consultation was collected from the electronic medical record. Differences in the date of when tumor profiling was ordered and date of diagnosis, date of PC consultation, and/or date of death were determined. Data were compiled into a single database and descriptive statistical analyses were performed.nnnRESULTSnA cohort of 397 (205 women) cancer patients was included. Metastatic disease was present in 108 (27.2%) patients, with mean±SD age of 58.7 ± 13.5 yrs. One-hundred and nine (27.6%) patients received a PC consultation (n=60 inpatient, n = 49 outpatient). As of February 2016, 119 (30%) patients died, with 58 (48.7%) out of 119 receiving a PC consultation. The difference between date of cancer diagnosis and date of tumor profiling ordered was 2467.4 ± 6865.7 days (n = 376), while the difference between date of tumor profiling ordered and date of death was 229.1 ± 185.7 days (n = 111). The difference between date of cancer diagnosis and date of death was 1507.5 ± 2002.1 days (n = 119). In patients were the tumor profiling was ordered before the PC consultation (n = 29), the difference between date of PC consultation and date tumor profiling ordered was 157.3 ± 258.1 days. In contrast, in patients were the tumor profiling was ordered after the PC consultation (n = 76), the difference was 194.6 ± 168 days.nnnCONCLUSIONSnThis analysis suggests that molecular tumor profiling is ordered at the end and not at the beginning of a cancer illness. PC consultations are not routinely performed in patients who participate in tumor profiling.

Advance care planning and palliative care consultation for stem cell transplant patients.

113 Background: Advance care planning (ACP) in stem cell transplantation (SCT) is particularly challenging given the potential for cure for patients with blood cancers despite an increased risk of suffering and even death. Data regarding ACP and palliative care (PC) integration in SCT is limited.nnnMETHODSnA retrospective chart review was conducted of patients with hematologic malignancies who underwent SCT at UCSD from January 2011 to December 2015. The primary objective was to determine the medical discipline of the initial and last code status documentation. Secondary objectives included evaluation of AD and/or POLST completion, PC consultation, hospice enrollment, and location of death. Data were compiled from a single electronic medical record and descriptive statistical analyses performed.nnnRESULTSnA total of 633 SCT were performed from 2011 to 2015 including 39% (n = 245) allogeneic and 61% (n = 388) autologous transplants (n = 29 patients had 2 transplants). Mean age of SCT patients was 55 years (±13). All but one (n = 632) had code status documentation, and 0.8% (n = 5) were initially DNR. The initial code status was documented outpatient for 3% (n = 17), and by the primary SCT physician for 1 patient. The final code status was documented outpatient for 22% (n = 14), and by the primary SCT physician for 0.9% (n = 6). Nearly half (44%, n = 279) had an AD and/or POLST completed. PC consultation occurred for 19% (n = 121) with the majority (83%, n = 101) completed inpatient. PC consultation requests were made by the primary SCT physician (18%, n = 22), inpatient SCT team (68%, n = 82), critical care (8%, n = 10), or other (5%, n = 6).The most common reason for consultation was symptom management (80%, n = 94). As of January 2016, 20% (n = 127) of SCT patients died with a mean time from transplant of 312 days (± 317). Of those that died, the majority (83%, n = 106) died in the hospital, 15% (n = 19) were full code, 48% (n = 62) had an AD and/or POLST, and 14% (n = 18) were enrolled in hospice.nnnCONCLUSIONSnThese single center data suggest ACP and PC integration in SCT is limited. Opportunities exist to expand integration to the outpatient setting and earlier in the course of illness.

Code status documentation in the electronic medical record for patients with stage IV pancreatic cancer.

125 Background: Improving incidence of code status documentation in the electronic medical record (EMR) has been suggested a better guidance for clinical care compared with a traditional advance directive. We have previously reported that in the absence of a template in the EMR, code status documentation was 36% and inconsistent in patients with advanced cancer. Utilizing a different cohort of patients with metastatic pancreatic cancer, we examined the prevalence of EMR code status documentation.nnnMETHODSnA retrospective analysis in patients with analytic metastatic pancreatic cancer (2008-2014) was conducted at a single, academic medical center. The primary objective was to determine prevalence of code status documentation in the EMR. Secondary objectives were to determine documentation author, location in the EMR, and time from documentation until death. Patients were identified from a tumor registry and code status documentation was identified in the scanned media, demographics tab, problem list, or using key search terms in the EMR.nnnRESULTSn169 patients with stage IV pancreatic cancer were identified. Seventy-five percent (n = 127) had a code status documented. Of those with documented code status, 44.9% (n = 57) were full code/full care, 22.0% (n = 28) were DNR/comfort care, 18.9% (n = 24) were DNR/full care, 13.4% (n = 17) were DNR/not specified, and 0.8% (n = 1) was limited DNR/full code. EMR locations for code status documentation included: 71.7% (n = 91) discharge summary, 10.2% (n = 13) inpatient encounter, 10.2% (n = 13) history & physical, 6.3% (n = 8) media tab, 0.8% (n = 1) telephone encounter, and 0.8% (n = 1) admission note. Code status documentation was completed by hospitalists (42.5%, n = 54), medicine residents (21.3%, n = 27), and primary oncologists (4.7%, n = 6). Mean difference for date of code status documentation and death was 67±145 d.nnnCONCLUSIONSnCode status documentation was higher for patients with metastatic pancreatic cancer compared to patients with advanced cancer from a previous study at our institution. Research is needed to determine if full code/full care is a default selection or a true representation of a patients wishes. Future efforts need to consider a standardized location for code status documentation in the EMR.

Blood transfusions at end of life for stem cell transplant patients.

115 Background: Transfusions are an essential palliative tool in the stem cell transplant (SCT) population. Limited data exist regarding transfusion practices at end-of-life for SCT patients and whether these practices may limit enrollment in hospice.nnnMETHODSnA retrospective chart review was conducted of deceased patients with hematologic malignancies who underwent SCT at an academic medical center from 2011 to 2015. The primary objective was to determine the difference between the dates of last transfusion and death in patients enrolled and not enrolled in hospice. A secondary objective was evaluation of the number of transfusions between groups. Data were compiled from a single electronic medical record. Descriptive analyses were performed. Days to last transfusion were analyzed using the Wilcoxon-Mann-Whitney test. Number of packed red blood cell (PRBC) transfusions and platelets transfusions on the last day were analyzed using Fisher and chi-squared tests, respectively.nnnRESULTSnA total of 633 SCT were performed from 2011 to 2015 including 39% (n = 245) allogeneic and 61% (n = 388) autologous transplants (n = 29 patients had 2 transplants). Mean ± SD age of SCT patients was 55 ± 13 years. As of January 2016, 20% (n = 119) of these SCT patients have died. Of those that died, 15% (n = 18) were enrolled in hospice. For SCT patients enrolled in hospice, the mean ± SD time of last blood transfusion from death was 42.3 ± 63.4 days, with mean ± SD 0.67 ± 0.77 units of PRBCs and 0.72 ± 0.75 units of platelets administered. For SCT patients not enrolled in hospice, the mean ± SD time of last blood transfusion from death was 14.2 ± 47.9 days, with mean±SD total 0.69 ± 1.03 units of PRBCs and 1.14 ± 1 units of platelets administered. Hospice patients had a statistically significant longer number of days until last blood transfusion compared to non-hospice patients (p < 0.001). There was no difference between SCT patients enrolled in hospice and not enrolled in PRBC transfusions (p = 0.069), but there was a significantly higher amount of platelet transfusions in patients not enrolled in hospice (p < 0.005).nnnCONCLUSIONSnThis data suggests that time to last transfusion may be a significant obstacle for SCT patients when enrolling in hospice, but requires further validation.

Inclusion criteria for cancer cachexia clinical trials: CT-defined skeletal muscle loss versus body weight loss.

67 Background: Cancer cachexia is defined by skeletal muscle loss, with or without fat loss (Fearon et al 2011); however, inclusion criteria for cachexia clinical trials requires a defined weight loss over time rather than muscle loss. We hypothesized that cross sectional imaging may reveal the presence of cachexia otherwise obscured by fat mass changes.nnnMETHODSnA retrospective analysis of longitudinal CT scans was performed in metastatic colorectal cancer (mCRC) patients screened for a cancer cachexia trial, which required ≥5% weight loss in the prior 6 mos. De-identified CT images were analyzed for total muscle, subcutaneous, and visceral fat cross-sectional areas (cm2) at the 3rd lumbar vertebra at baseline and up to 12 mos prior (Lieffers et al 2009). Logistic regression was used to test differences between patients with <5% vs ≥5% weight loss. Random intercept regression was used to evaluate significant trends in CT measures over time.nnnRESULTSn42 mCRC patients were screened and 3(7%) enrolled. Patients were excluded for comorbidity/contraindication 14 (33%), excessive [>20%] weight loss 4 (9.5%), and insufficient [<5%] weight loss 19 (45%). For the <5% weight loss subset, there was a mean of 6.7 CT scans (SD=2.67) and of 9% (SD=5.4, min=0%, 25th percentile=4.9%) mean max muscle loss. Notably this group was simultaneously losing muscle (p=0.002) and gaining visceral adipose (p=0.007). For the ≥5% weight loss subset, there was a mean of 7.5 CT scans (SD=4.5) and 20% (SD=10.0, min=5.2%, 25th percentile =10.6) mean max muscle loss. Greater max muscle loss increased the odds of being in the ≥5% weight loss subset (OR=1.19, 95% CI: 1.06,1.33). This group also had a significant decrease in visceral adipose over time (p<0.001). Redefined inclusion criteria of ≥5% muscle loss would have included 14 of the 19 patients excluded because of <5% weight loss.nnnCONCLUSIONSnDefining cancer cachexia as weight loss over time may be limited as it does not capture body composition changes and hinders trial accrual. Cross-sectional CT body composition analysis may improve early detection of muscle loss and improve trial accrual.