Mary K. Buss

Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study

BACKGROUND Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. METHODS In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. FINDINGS Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). INTERPRETATION Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. FUNDING American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

Phase II study: integrated palliative care in newly diagnosed advanced non-small-cell lung cancer patients.

PURPOSE To assess the feasibility of early palliative care in the ambulatory setting in patients with newly diagnosed advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients were eligible if they had a performance status of 0 to 1 and were within 8 weeks of diagnosis of advanced NSCLC. Participants received integrated care from oncology and palliative care throughout the course of their disease. Participants were scheduled to meet with the palliative care team (PCT) and complete quality-of-life (QOL) and mood questionnaires monthly for 6 months. The study was deemed feasible if 64% of patients completed at least 50% of their scheduled visits and QOL assessments. RESULTS Fifty-one patients were enrolled onto the trial. One died within 72 hours and was not assessable. Ninety percent (95% CI, 0.78 to 0.96) of study participants complied with at least 50% of the palliative care visits. Eight-six percent (95% CI, 0.73 to 0.94) of the participants met the full feasibility requirements by both meeting with the PCT and completing QOL assessments at least 50% of the time. QOL and mood analyses confirmed the high symptom burden in patients with newly diagnosed advanced NSCLC. At least 50% of participants experienced some degree of shortness of breath, cough, difficulty breathing, appetite loss, weight loss, or unclear thinking at their baseline assessment. More than one third of patients had a probable mood disorder at baseline. CONCLUSION Integrated palliative and oncology care is feasible in ambulatory patients with advanced NSCLC.

A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer

BACKGROUND Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648). METHODS Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. RESULTS 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia ≥ 4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) > 24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for > 24 weeks. INTERPRETATION The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients.

Hematology/oncology fellows' training in palliative care: results of a national survey.

Palliative care is recognized as integral to the practice of oncology, yet many oncologists report inadequate training in critical palliative care domains, such as symptom management, psychosocial care, and communication skills. The authors of this report sought to assess the quantity and quality of palliative care education within oncology fellowships.

An eHealth system supporting palliative care for patients with non-small cell lung cancer: A randomized trial

In this study, the authors examined the effectiveness of an online support system (Comprehensive Health Enhancement Support System [CHESS]) versus the Internet in relieving physical symptom distress in patients with non–small cell lung cancer (NSCLC).

Integration of Palliative Care in End-Stage Liver Disease and Liver Transplantation

BACKGROUND Patients with end-stage liver disease (ESLD) have a life-limiting illness that causes multiple distressing symptoms and negatively affects quality of life (QOL). This population traditionally has not had much attention within the palliative care community. DISCUSSION This article provides an evidence-based review of palliative care issues that patients with ESLD and those awaiting liver transplant face, including approaches to prognosis, symptom management, advance care planning, and end-of-life care. CONCLUSION Tremendous opportunity exists to integrate palliative medicine into the care of these patients.

Perceived, actual, and desired knowledge regarding Medicare billing and reimbursement. A national needs assessment survey of internal medicine residents.

BACKGROUND: Economics and reimbursement have became a daily part of practicing physicians’ lives. Yet, few internal medicine (IM) programs have offered formal curricula during residency about practice management or economics.OBJECTIVE: To determine perceived, desired, and actual knowledge of Medicare billing and reimbursement among residents compared with community-based General Internists.DESIGN AND PARTICIPANTS: Cross-sectional needs assessment survey of community and university-based second-year IM residents from 4 geographic regions of the United States.RESULTS: One hundred and thirty-three second-year IM residents completed the questionnaire. Residents rated their level of knowledge about Medicare as a 2.0 (SD=0.9) on a Likert scale (1=“quo;very low,”quo; 5=“quo;very high”quo;). Residents agreed that Medicare reimbursement should be taught in residency with a score of 4.0 (SD=1.1; 1=“quo;strongly disagree,”quo; 5=“quo;strongly agree”quo; SD=1.1). On the kowledge assessment portion of the questionnaire, residents scored significantly lower than a group of general IM physicians who completed the same questions (percent correct =41.8% vs 59.0%, P<.001). Residents’ score correlated with their self-assessed level of knowledge (P = .007).CONCLUSIONS: Our study demonstrates that second year IM residents feel they have a low level of knowledge regarding outpatient Medicare billing, and have a lower test score than practicing Internists to back up their feelings. The residents also strongly agree that they do not receive enough education about Medicare reimbursement, and believe it should be a requirement in residency training.

Defining High-Quality Palliative Care in Oncology Practice: An American Society of Clinical Oncology/American Academy of Hospice and Palliative Medicine Guidance Statement

PURPOSE Integrated into routine oncology care, palliative care can improve symptom burden, quality of life, and patient and caregiver satisfaction. However, not all oncology practices have access to specialist palliative medicine. This project endeavored to define what constitutes high-quality primary palliative care as delivered by medical oncology practices. METHODS An expert steering committee outlined 966 palliative care service items, in nine domains, each describing a candidate element of primary palliative care delivery for patients with advanced cancer or high symptom burden. Using modified Delphi methodology, 31 multidisciplinary panelists rated each service item on three constructs: importance, feasibility, and scope within medical oncology practice. RESULTS Panelists endorsed the highest proportion of palliative care service items in the domains of End-of-Life Care (81%); Communication and Shared Decision Making (79%); and Advance Care Planning (78%). The lowest proportions were in Spiritual and Cultural Assessment and Management (35%) and Psychosocial Assessment and Management (39%). In the largest domain, Symptom Assessment and Management, there was consensus that all symptoms should be assessed and managed at a basic level, with more comprehensive management for common symptoms such as nausea, vomiting, diarrhea, dyspnea, and pain. Within the Appropriate Palliative Care and Hospice Referral domain, there was consensus that oncology practices should be able to describe the difference between palliative care and hospice to patients and refer patients appropriately. CONCLUSION This statement describes the elements comprising high-quality primary palliative care for patients with advanced cancer or high symptom burden, as delivered by oncology practices. Oncology providers wishing to enhance palliative care delivery may find this information useful to inform operational changes and quality improvement efforts.

Palliative Oncologists: Specialists in the Science and Art of Patient Care

DOI: 10.1200/JCO.2014.60.3274 Case Vignette “We’ve been waiting for you to come on the oncology service,” the oncology fellow said, as the resident and nurse practitioner on service looked on. “We have a really challenging case.” Our patient was a frail 77-year-old woman with unresectable pancreatic adenocarcinoma, saddle pulmonary embolus, protein calorie malnutrition, hepatitis C, and recurrent infections, all of which had resulted in a lengthy hospital stay. Her cancer had progressed despite two lines of chemotherapy. She wanted more treatment, but had been told she was too weak. In our first meeting, she told me that her goal was “to get strong enough for more chemotherapy.” She had interpreted the previous oncology attending’s statement about her fitness for chemotherapy as a challenge, and thought, “If I can get stronger, I can get more.” Knowing and trusting my colleague, I imagine his statement was meant as a stepping stone toward a transition to hospice. Her family fiercely defended her desire for rehabilitation as well (“Don’t take away her hope,” they had said), so she remained in a hospital-based limbo, too weak for physical therapy and without sufficient understanding of her prognosis to allow a seamless transition to hospice. As a dual board–certified medical oncologist and palliative care physician, I respected her hopefulness and recognized the challenges that I faced as a result of the complex and nuanced conversations that had occurred before I became involved in her care. I also recognized her profound suffering and that of her family, both because of my conversations with them and because of the heaviness I felt in my heart when entering her room. I suspect that every oncologist knows a version of the above scenario, and knows that heaviness of heart, too. As physicians, we are often most comfortable in the medical and fact-based realms. However, in my palliative care training, I was taught to listen to the so-called limbic music in a room to try to identify the causes of suffering. Often the solution in a difficult clinical encounter lies in addressing emotional and spiritual needs as well as physical ones. Our team aggressively managed the patient’s pain and nausea and then explored her suffering. As a member of a three-generation ranching family, she had been physically active until her diagnosis, and felt betrayed by her body. In the hospital, without her daily dose of open sky, she felt trapped. She did not have a will and worried about who would run the ranch after she passed. Her sons had a contentious relationship and often disagreed about how to care for her. She was overwhelmed and, frankly, not ready to die. She suffered in many realms—physical, emotional, interpersonal, financial and existential— and her suffering affected her decision making. By identifying and addressing the causes of her suffering in the context of our goals-of-care discussions, we helped her to understand that she was not going to regain the physical ability to run the ranch, but that she might be able to see it again, that we could begin to address some of her financial and relationship concerns, and that those things were possible without more chemotherapy. Before her death in the hospital, she had completed a medical power of attorney, had met with her sons and a family lawyer to make a will, and had the opportunity to grieve openly with her sons about her anticipated death. From an educational perspective, an oncology fellow, resident, and nurse practitioner learned to recognize and assess “total pain,” Dame Cicely Saunder’s concept of suffering that encompasses physical, psychological, social, and spiritual domains. This vignette illustrates how palliative oncology experts can influence patient care and education in meaningful ways, and also how palliative care training adds a different dimension to the core skills that all oncologists use.

A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

LBA5500 Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Preclinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). METHODS Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). RESULTS Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. CONCLUSIONS Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted. CLINICAL TRIAL INFORMATION NCT01116648.