Expanding the Use of Continuous Sedation Until Death and Physician-Assisted Suicide.

The controversy over the equivalence of continuous sedation until death (CSD) and physician-assisted suicide/euthanasia (PAS/E) provides an opportunity to focus on a significant extended use of CSD. This extension, suggested by the equivalence of PAS/E and CSD, is designed to promote additional patient autonomy at the end-of-life. Samuel LiPuma, in his article, "Continuous Sedation Until Death as Physician-Assisted Suicide/Euthanasia: A Conceptual Analysis" claims equivalence between CSD and death; his paper is seminal in the equivalency debate. Critics contend that sedation follows proportionality protocols for which LiPuma's thesis does not adequately account. Furthermore, sedation may not eliminate consciousness, and as such LiPuma's contention that CSD is equivalent to neocortical death is suspect. We not only defend the equivalence thesis, but also expand it to include additional moral considerations. First, we explain the equivalence thesis. This is followed by a defense of the thesis against five criticisms. The third section critiques the current use of CSD. Finally, we offer two proposals that, if adopted, would broaden the use of PAS/E and CSD and thereby expand options at the end-of-life.

Carfilzomib combined with rituximab, ifosfamide, carboplatin, and etoposide for relapsed or refractory DLBCL.

The CORAL study highlighted the need to develop novel salvage regimens in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) previously treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Carfilzomib (CFZ) can overcome rituximab chemotherapy resistance in lymphoma preclinical models by targeting the ubiquitin-proteasome system. We conducted an investigator initiated, single-center, open-label, prospective phase 1 study evaluating the safety and efficacy of CFZ in combination with rituximab, ifosfamide, carboplatin, and etoposide (C-R-ICE) in high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) eligible patients with R/R DLBCL (NCT01959698). In the dose-escalation phase, 18 patients were enrolled at 6 dose levels with no dose-limiting toxicities noted. CFZ 45 mg/m2 was selected as the recommended dose for expansion. Eleven additional patients were enrolled in the dose-expansion phase. Overall response rate (ORR) was 66% (48% CR; 17% PR); 52% patients underwent HDC-ASCT. An ORR of 85% was observed in patients with nongerminal center B-cell-like (non-GCB) DLBCL compared with only 13% in those with GCB DLBCL. Median progression-free survival (PFS) was 15.2 months (5.1 months, not reached [NR]), and median overall survival (OS) was 22.6 months (6.8 months, NR). Patients with non-GCB subtype had a significantly longer PFS (NR vs 6.6 months; P = .0001) and OS (NR vs 6.6 months; P = .001) than those with GCB subtype. C-R-ICE is well tolerated in patients with R/R DLBCL with toxicities comparable to rituximab, ifosfamide, carboplatin, and etoposide therapy. Our data show that patients with non-GCB DLBCL benefit significantly from incorporating CFZ into second-line therapy and HDC-ASCT.

Ofatumumab plus HyperCVAD/HD-MA induction leads to high rates of minimal residual disease negativity in patients with newly diagnosed mantle cell lymphoma: Results of a phase 2 study.

BACKGROUND: Ofatumumab is a humanized type 1 anti-CD20 monoclonal antibody. Preclinical studies show improved complement-mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma (MCL). This study evaluates the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL. METHODS: In this single-arm phase 2 study, 37 patients were treated with the combination of O-HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant. Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS). RESULTS: Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months, respectively. Achieving a post-induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post-2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grades 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients. CONCLUSION: The addition of ofatumumab to HyperCVAD/HD-MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with improved overall survival.

Clarifying an Expanded Use of Continuous Sedation Until Death: A Reply to the Commentary by McCammon and Piemonte.

Susan D. McCammon and Nicole M. Piemonte offer a thoughtful and thorough commentary on our manuscript entitled "Expanding the use of Continuous Sedation Until Death." In this reply we attempt to clarify and further defend our position. We show how continuous sedation until death is not a "first resort" but rather a legitimate option among many that should available to terminally ill patients whose life expectancy is less than six months. We also attempt to show that we do not equivocate the meaning of palliative care as the commentators suggested. We argue that the traditional notion of palliative care should move beyond relief of "experienced suffering" to relief of potential suffering for those whose life expectancy is less than six months. Lastly, we challenge the commentator's position that the realm of ordinary medicine" should be the guide to care, by showing how the notion of ordinary medicine has been successfully challenged in both bioethical scholarship and the courts in a way that shows ordinary medicine to be an evolving concept rather than a static, universal guide.

Expanding the Use of Continuous Sedation Until Death: Moving Beyond the Last Resort for the Terminally Ill.

As currently practiced, the use of continuous sedation until death (CSD) is controlled by clinicians in a way that may deny patients a key choice in controlling their dying process. Ethical guidelines from the American Medical Association and the American Academy of Pain Medicine describe CSD as a "last resort," and a position statement from the American Academy of Hospice and Palliative Medicine describe it as "an intervention reserved for extreme situations." Accordingly, patients must progress to unremitting pain and suffering and reach a last-resort stage before the option to pursue CSD is considered. Alternatively, we present and defend a new guideline in which decisionally capable, terminally ill patients who have a life expectancy of less than six months may request CSD before being subjected to the refractory suffering of a treatment of "last resort."

Comparison of five diagnostic modalities for direct detection of Borrelia burgdorferi in patients with early Lyme disease.

Lyme disease, the most commonly reported tick-borne infection in North America, is caused by infection with the spirochete Borrelia burgdorferi. Although an accurate clinical diagnosis can often be made based on the presence of erythema migrans, in research studies microbiologic or molecular microbiologic confirmation of the diagnosis may be required. In this study, we evaluated the sensitivity of 5 direct diagnostic methods (culture and nested polymerase chain reaction [PCR] of a 2-mm skin biopsy specimen, nested PCR and quantitative PCR (qPCR) performed on the same 1-mL aliquot of plasma and a novel qPCR-blood culture method) in 66 untreated adult patients with erythema migrans. Results of one or more of these tests were positive in 93.9% of the patients. Culture was more sensitive than PCR for both skin and blood, but the difference was only statistically significant for blood samples (P<0.005). Blood culture was significantly more likely to be positive in patients with multiple erythema migrans skin lesions compared to those with a single lesion (P=0.001). Positive test results among the 48 patients for whom all 5 assays were performed invariably included either a positive blood or a skin culture. The results of this study demonstrate that direct detection methods such as PCR and culture are highly sensitive in untreated adult patients with erythema migrans. This enabled microbiologic or molecular microbiologic confirmation of the diagnosis of B. burgdorferi infection in all but 4 (6.1%) of the 66 patients evaluated.

Deep brain stimulation and the ethics of protection and caring for the patient with Parkinson's dementia.

Deep brain stimulation (DBS) is an effective neurosurgical treatment for patients with advanced Parkinson's disease (PD) suffering from motor complications that are refractory to further medication management. DBS requires an invasive procedure of implanting brain electrodes while awake, followed by implantation of neurostimulators under general anesthesia. The neurostimulator requires battery monitoring and replacement approximately every 3 to 5 years. These two elements of the technology provide numerous decision points about continuing therapies that can involve ethical choices. Although motor function can be improved with subthalamic nucleus (STN) DBS, the long-term risks of living with implanted hardware should be carefully evaluated for patients with diminishing cognitive capacity. We describe two cases where ethical dilemmas occurred postoperatively as a result of cognitive decline and describe salient ethical dimensions that illustrate the need for a proactive postoperative plan for supervision as a prerequisite for surgery to include neuropsychological testing to predict the likelihood of net benefit to the patient and family beyond just motor improvement.

The research misconception.

Recently, several researchers and philosophers argued that clinical research trials are not therapy. Their position is based on foundational research ethics documents, such as the Belmont Report, on conceptual analysis, and on the general way clinical trials are conducted. After examining and rejecting these arguments, we claim that good research is consistent with good therapy; that often trials are good therapy; and that a blanket attack on clinical trials as non-therapeutic creates a research misconception. This misconception is potentially harmful because it could weaken trial recruitment, could adversely affect funding for trials, and could overturn needed moral safeguards on therapeutic trials. Our more careful and accurate analysis of the nature of clinical trials can avoid such problems.